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(11) EP 1 364 069 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12Q 1/68 (2006.01) 22.04.2009 Bulletin 2009/17 (86) International application number: (21) Application number: 02724190.0 PCT/EP2002/002255

(22) Date of filing: 01.03.2002 (87) International publication number: WO 2002/070742 (12.09.2002 Gazette 2002/37)

(54) METHOD FOR THE DEVELOPMENT OF PANELS FOR DIAGNOSTIC AND THERAPEUTIC PURPOSES BASED ON THE EXPRESSION AND METHYLATOIN STATUS OF THE VERFAHREN ZUR ENTWICKLUNG VON GENSÄTZEN ZU DIAGNOSTISCHEN UND THERAPEUTISCHEN ZWECKEN AUF GRUNDLAGE DES EXPRESSIONS- UND METHYLIERUNGSSTATUS DER GENE PROCEDE DE MISE AU POINT DE GROUPES D’ECHANTILLONS DE GENES A DES FINS DE DIAGNOSTIC ET DE THERAPIE QUI SONT BASES SUR L’EXPRESSION ET L’ETAT DE METHYLATION DES GENES

(84) Designated Contracting States: (56) References cited: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU WO-A-00/39347 WO-A-00/44934 MC NL PT SE TR WO-A-00/70090 WO-A-01/18241

(30) Priority: 01.03.2001 US 272549 P • HERMAN J G ET AL: "INCIDENCE AND FUNCTIONAL CONSEQUENCES OF HMLH1 (43) Date of publication of application: PROMOTOR HYPERMETHYLATION IN 26.11.2003 Bulletin 2003/48 COLORECTAL CARCINOMA" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF (73) Proprietor: Epigenomics AG USA, NATIONAL ACADEMY OF SCIENCE. 10178 Berlin (DE) WASHINGTON, US, vol. 95, June 1998 (1998-06), pages 6870-6875, XP002944676 ISSN: 0027-8424 (72) Inventors: • GUO YONGJING ET AL: "DNA methylation status • OLEK, Alexander of uPA promoter directly affects the expression 10115 Berlin (DE) of uPA in breast cancer cells to alter their • BERLIN, Kurt invasive potential" PROCEEDINGS OF THE 14532 Stahndorf (DE) ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH, NEW (74) Representative: Krauss, Jan et al YORK, NY, US, vol. 42, March 2001 (2001-03), Forrester & Boehmert pages 625-626, XP002195787 ISSN: 0197-016X Pettenkoferstrasse 20-22 • WU HUA-KANG ET AL: "Transcriptional 80336 München (DE) activation of human LIM-HOX gene hLH-2 in chronic myelogenous is due to a cis- acting effect of Bcr-Abl." BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 234, no. 3, 1997, pages 742-747, XP002203941 ISSN: 0006-291X

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 364 069 B1

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Description micro-characterization for large-scale identifica- tion of and their post-translational modifications; FIELD OF THE INVENTION (2) ’differential display’ proteomics for comparison of pro- tein levels with potential application in a wide range of [0001] The present invention concerns a method for 5 diseases; and (3) studies of protein-protein interactions the development of gene panels for diagnostic and ther- using techniques such as mass spectrometry or the yeast apeutic purposes. The invention further concerns gene two-hybrid system. Because it is often difficult to predict panels developed using the method of the present inven- the function of a protein based on to other pro- tion and their uses. teins or even their three-dimensional structure, determi- 10 nation of the components of a protein complex or of a BACKGROUND OF THE INVENTION cellular structure is central in functional analysis (Pandey A et al. "Proteomics to study genes and ." Na- [0002] The levels of observation that have been well ture 2000 Jun 15;405(6788):837-46). studied by the methodological developments of recent [0006] Due to the complexity of higher eukaryotic cells, years in molecular biology include the gene itself, the 15 single-step characterization of a proteome is likely to be translation of genes in RNA, and the resulting proteins. difficult to achieve. Jung et al. ("Proteomics meets cell When, during the course of the development of an indi- biology: the establishment of subcellular proteomes" vidual, a gene is switched on, and how the activation and Electrophoresis 2000 Oct;21(16):3369-77) describe, that inhibition of certain genes in certain cells and tissues is advantage can be taken of the macromolecular architec- controlled, can be correlated with a high degree of prob- 20 ture of a cell, e.g., subcellular compartments, organelles, ability with the extent and the character of the methylation macromolecular structures and multiprotein complexes, of the gene or the . In this regard, it is reasonable to establish subcellular proteomes. to assume that pathogenic conditions are expressed in [0007] Despite the recent developments in the art, the a modified methylation pattern of individual genes or of detection of proteins that are of regulatory importance, the genome. 25 from small quantities of cells still fails because of the fact that the sensitivity of the methods used is much too low. STATE OF THE ART Indeed, in contrast to nucleic acids, proteins cannot be amplified. In addition, the method is very complex, not 1. State of the art of molecular analysis of cell phe- amenable to automation, and very expensive. In contrast, notypes 30 RNA analysis presents considerable advantages, and due to of the use of PCR it is more sensitive. Above all, [0003] The study of can be at the RNA each RNA species recognized to be important can be level or at the protein level. Both levels in principle reflect identified immediately by its sequence. important phenotypic parameters. Protein assays using [0008] Overexpression or underexpression of individ- two-dimensional gels (McFarrel method) have been 35 ual RNAs with a known sequence can usually be easily known for approximately 15 years. Using these assays, detected; however, in connection with the applications it is possible to elaborate the analysis of the chromato- discussed here, they are only valid in exceptional cases. graphic positions of several thousand proteins. Very early [0009] The method of "differential displays" at best al- on, such electropherograms were already processed or lows a semiquantitative study of expression. Expression evaluated with data processing means. In principle, the 40 products amplified by PCR are separated by gel electro- validity of the method is high, however, it is inferior to the phoresis. The validity is limited as a result of the resolu- modem methods of gene expression based on RNA anal- tion of the gel electrophoresis. In addition, the method is ysis in two regards. insufficiently sensitive and robust for use in routine diag- [0004] The global analysis of cellular proteins has re- nosis (Liang, P. and Pardee, A. B., Science 257, cently been termed proteomics and is a key area of re- 45 967-971). search that is developing in the post-genome era. Pro- [0010] Genes with high overexpression or underex- teomics uses a combination of sophisticated techniques pression are frequently identified by subtractive tech- including two-dimensional (2D) gel electrophoresis, im- niques. Here, cDNA clones of a cell or tissue species to age analysis, mass spectrometry, sequenc- be examined are plated. Against the clones, cDNA is ing, and bio-informatics to resolve comprehensively, to 50 hybridized as comparison material. Expression patterns quantify, and to characterize proteins (for reviews, see cannot be reliably prepared using this technique. Chambers G et al. "Proteomics: a new approach to the [0011] Sturtevant et al. ("Applications of differential- study of disease" J Pathol 2000 Nov;192(3):280-8; Banks display reverse -PCR to molecular patho- RE et al. "Proteomics: new perspectives, new biomedical genesis and medical mycology. Clin Microbiol Rev 2000 opportunities" Lancet 2000 Nov 18;356(9243):1749-56). 55 Jul;13(3):408-27) describe the characterisation of host- [0005] Proteomics is further said to contribute greatly fungus interactions by changes in gene expression in to the understanding of gene function in the post-genomic both host and pathogen. Differential-display reverse tran- era. Proteomics can be divided into three main areas: (1) scription PCR (DDRT-PCR) is a PCR-based method that

2 3 EP 1 364 069 B1 4 allows extensive analysis of gene expression among sev- impossible to examine the gene expression or the me- eral cell populations. DDRT-PCR has been used to ad- tabolism of a cell in its totality. Chip technology for the dress biological questions in mammalian systems, in- first time provided such a possibility (Schena, M. et al., cluding cell differentiation, cell activation, cell stress, and Science 270, 467-470). identification of drug targets. In microbial pathogenesis 5 [0014] If one wishes to solve the diagnostic problem and plant pathogenesis, DDRT-PCR has allowed the of early diagnosis of tumors on the molecular level, then identification of virulence factors, genes involved in cell one is confronted, today, with an insurmountable difficul- death, and signaling genes. Further, To ("Identification ty. With very few exceptions, for most tumors, the knowl- of differential gene expression by high throughput edge of the molecular events, that is, the different muta- analysis" Comb Chem High Throughput Screen 2000 10 tions, is only fragmentary. Researchers do not know what Jun;3(3):235-41) describes the high throughput analysis to look for in medical examination material. This means of differential gene expression as a powerful tool that can it is absolutely impossible to apply the remarkable sen- be applied to many areas in molecular cell biology, in- sitivity and specificity of the polymerase chain reaction. cluding differentiation, development, physiology, and Examples are certain intestinal tumors, Ewing’s sarco- pharmacology. In recent years, a variety of techniques 15 ma, and certain forms of leukemia, which are in fact each have been developed to analyze differential gene expres- defined by a single, precisely described mutation. In sion, including comparative expressed sequence tag se- those cases, it is possible to identify the degenerated cell quencing, differential display, representational differ- among millions of normal cells. However, even within ence analysis, cDNA or arrays, and serial these apparently unambiguously defined tumor groups, analysis of gene expression. Similar strategies are de- 20 there are such differences in the behavior that the con- scribed by Oetting ("Gene expression analysis. Pigment clusion must be drawn that additional unknown genetic Cell Res 2000 Feb;13(1):21-7) and Watson ("Differential parameters (such as, for example, the genetic back- cDNA screening strategies to identify novel stage-spe- ground of the individual) play an important role. Immu- cific proteins in the developing mammalian brain. Dev nological tumor markers are helpful auxiliary parameters, Neurosci 1993;15(2):77-86). 25 but they continue to make only a modest contribution, in [0012] One activity of the American " addition to the other conventional diagnostic parameters. Project" is the systematic sequencing of expressed However, they can be used for the purpose of preselect- genes. The data obtained from this can be used to build ing suspect cells. expression chips, which allow the study of practically all [0015] Histology plays an important and indispensable expressed sequences of a cell or tissue type in a single 30 role in the identification of degenerated tissues, but not experiment. precisely in early diagnosis. [0016] Thus, because most tumors are not sufficiently 2. State of the art in the analysis of cancer diseases characterized for diagnostic purposes on the molecular level, as a rule, no possibilities exist to proceed to a sub- [0013] Mutations in genes can trigger cancer diseases, 35 division into stages or even a subdivision by degrees of that is, cell transformation. The causes of these muta- risk. Such a subdivision, however, is an absolute prereq- tions can be exogenous influences, or events in the cell. uisite for an improved selection of treatments and, above In a few exceptional cases, an individual mutation, which all, for the development of effective new drugs and of frequently affects larger regions of the genome (translo- gene therapy. cations, deletions), results in the degeneration of the cell; 40 but in most cases a chain of mutations on different genes 3. State of the art in research on the number, type is involved, and it is only their combined effect that results and properties of the possible stable states of cells in the malignant disease. These changes at the DNA of higher organisms level are also reflected on the RNA and protein levels. In this context, it is highly probable that a multiplication oc- 45 [0017] In recent times, there has been an increase in curs, because it is certain that in many cases the quantity the number of indications that complex regulatory sys- and type of one RNA influences the extent of the synthe- tems (an excellent example of which is cell regulation), sis of several other RNA species. This leads to a change when left alone, can exist in only a limited number of in the synthesis rates of the corresponding proteins, stable states, above a critical minimum complexity and which, in turn, can result in the deregulation of metabo- 50 below a critical maximum connectivity (of the average lism, and thus initiate the mechanism of regulation and number of the components, with which any given com- counter regulation. The result is a gene expression pat- ponent is connected) (Kauffman, S. A., Origins of Order, tern of the cells in question, that has been modified in a Oxford University Press, 1993). In this context, the word very specific (but largely nondeterminable) manner,the state should be understood as the concept of selection specificity is for a certain carcinoma, for the stage of the 55 for the general phenomenon. In connection with cells as carcinoma, and the degree of malignancy of the carcino- biological regulatory systems, one can also talk of differ- ma. So far, such phenomena have been outside the entiation state or cell type. Although no such connection realm of study of natural sciences. Indeed, it has been has been demonstratedand even a mere limitation of the

3 5 EP 1 364 069 B1 6 possible states for biological systems has not been dem- the molecular biology laboratory techniques proper, the onstrated--the practical implications would be of very availability of a relatively large number of patients and great importance: if, regarding the constant information relatives affected by each disease is a crucial prerequi- content of the cells of an organism (de facto, such con- site for genetic elucidation. In the past two years it has stancy essentially exists within one species), there were 5 become apparent that the number of several hundred only a limited number of stable states, then it would be patients that were originally used for the linkage analysis likely that degenerated cells could also be in only one of of polygenic diseases very likely is too low by one order these states or in a transition between the possible states. of magnitude. This applies, in any case, to cases where At this time, it is not possible to define these states on a the entire spectrum of the causal gene is to be elucidated. molecular basis. It is hardly possible to achieve a corre- 10 Because the level of manual work required for such a lation between the individual states and the behavior of linkage analysis is extraordinarily high, only very slow the cells according to the state of the art. However, such progress can be expected in the analysis of polygenic an analysis could make decisive contributions to the di- diseases. Alternative strategies are sought because it is agnosis and prognosis of diseases. It is even possible precisely these diseases that are of enormous social and that a correlation could be established between the pos- 15 economic importance. sible states of diseased cells and the best suited therapy. Furthermore, it is probable that such a method could also 5. State of the art in methylation analysis have a decisive influence in the selection of the time of treatment. For example, if one were to discover that the [0020] The modification of the genomic base cytosine cells of a tumor are in a transition between possible 20 to 5’-methylcytosine represents the epigenetic parame- states, one could assume that such a population of cells ter which to date is the most important one and has been would be more likely to yield to the selection pressure best examined. Nevertheless, methods exist today to de- resulting from the treatment, and thus could escape more termine comprehensive genotypes of cells and individu- easily. A cell population in such a scenario, within such als, but no comparable methods exist to date to generate transitional states, would have a considerably increased 25 and evaluate epigenotypic information on a large scale. flexibility, and it would be easily forced into a possible [0021] In principle, there are three methods that differ stable state, in which the selection pressure would be in principle for determining the 5-methyl state of a cyto- eliminated, and the treatment would thus be without ef- sine in the sequence context. fect. [0022] The first method is based in principle on the use [0018] A method which could classify cells and cell 30 of restriction endonucleases (RE), which are methyla- groups according to states would then also contribute to tion-sensitive". REs are characterized in that they pro- recognizing, understanding and possibly solving such duce a cut in the DNA at a certain DNA sequence which problems. However, according to the state of the art, it is usually 4-8 bases long. The position of such cuts can is not possible to determine whether only a limited be detected by gel electrophoresis, transfer to a mem- number of states of cells exists. It follows that it is not 35 brane and hybridization. Methylation-sensitive means possible to differentiate groups of cells according to an that certain bases within the recognition sequence must abstract criterion concerning their states, and to predict be unmethylated for the step to occur. The band pattern these states with a certain behavior of the cells. after a restriction cut and gel electrophoresis thus chang- es depending on the methylation pattern of the DNA. 4. Hereditary diseases 40 However, most CpG that can be methylated are outside of the recognition sequences of REs, and thus cannot be [0019] Today, the genetic map of the human genome examined. comprises 2500 so-called microsatellites. These instru- [0023] The sensitivity of this method is extremely low ments are used to locate a multitude of genes, usually (Bird, A. P., Southern, E. M., J. Mol. Biol. 118, 27-47). A genes whose defect causes a genetic disease, per link- 45 variant combines PCR with this method; an amplification age analysis, and then to identify them. Common genetic by two primers located on both sides of the recognition diseases caused by a single defective gene are thus elu- sequence occurs after a cut only if the recognition se- cidated, from the point of view of the geneticist’s principle, quence is in the methylated form. In this case, the sen- polygenic diseases should also be understood in this sitivity theoretically increases to a single molecule of the manner. Many polygenic diseases are very common, so 50 target sequence; however, only individual positions can common that they are included among the so-called be examined, at great cost (Shemer, R. et al., PNAS 93, widespread diseases. Asthma and diabetes are exam- 6371-6376). ples. Many carcinoma types are also included. The use [0024] The second variant is based on the partial of the above described strategy of linkage analysis also chemical cleavage of whole DNA, using the model of a produced enormous initial successes. In many instanc- 55 Maxam-Gilbert sequencing reaction, ligation of adaptors es, numerous causal genes of important polygenic dis- to the ends thus generated, amplification with generic eases such as diabetes, , atherosclerosis primers, and separation by gel electrophoresis. Using and obesity have been found. Besides the availability of this method, defined regions having a size of less than

4 7 EP 1 364 069 B1 8 thousands of base pairs can be examined. However, the dromes" Leukemia 2000 Apr;14(4):586-93; Nosaka method is so complicated and unreliable that it is practi- K et al. "Increasing methylation of the CDKN2A gene cally no longer used (Ward, C, et al., J. Biol. Chem. 265, is associated with the progression of adult T-cell 3030-3033). leukemia" Cancer Res 2000 Feb 15;60(4):1043-8; [0025] A new method for the examination of DNA to 5 Asimakopoulos FA et al. "ABL1 methylation is a dis- determine the presence of 5-methylcytosine is based on tinct molecular event associated with clonal evolu- the specific reaction of bisulfite with cytosine. The latter tion of chronic myeloid leukemia" 1999 Oct 1; is converted under appropriate conditions into uracil, 94(7):2452-60; Fajkusova L. et al. "Detailed Mapping which, as far as base pairing is concerned, is equivalent of Methylcytosine Positions at the CpG Island Sur- to thymidine, and which also corresponds to another 10 rounding the Pa Promoter at the - in base. 5-Methylcytosine is not modified. As a result, the CML Patients and in Two Cell Lines, K562 and BV original DNA is converted in such a manner that methyl- 173" Blood Cells Mol Dis 2000 Jun;26(3):193-204; cytosine, which originally could not be distinguished from Litz CE et al. "Methylation status of the major break- cytosine by its hybridization behavior, now can be de- point cluster region in Philadelphia tected by "normal" molecular biological techniques. All 15 negative " Leukemia 1992 Jan;6(1): of these techniques are based on base pairing, which 35-41) can now be completely exploited. The state of the art, as far as sensitivity is concerned, is defined by a method - Head and neck cancer (Sanchez-Cespedes M et al. which includes the DNA to be examined in an agarose "Gene promoter hypermethylation in tumors and se- matrix, intended to prevent the diffusion and renaturing 20 rum of head and neck cancer patients" Cancer Res of the DNA (bisulfite reacts only with single-stranded 2000 Feb 15;60(4):892-5) DNA) and to replace all precipitation and purification steps by rapid dialysis (Olek, A., et al., Nucl. Acids. Res. - Hodgkin’s disease (Garcia JF et al. "Loss of p16 pro- 24, 5064-5066). Using this method, individual cells can tein expression associated with methylation of the be examined, which illustrates the potential of the meth- 25 p16INK4A gene is a frequent finding in Hodgkin’s od. However, so far only individual regions up to approx- disease" Lab Invest 1999 Dec;79(12): 1453-9) imately 3000 base pairs in length have been examined, and an overall examination of cells to identify thousands - Gastric cancer (Yanagisawa Y et al. "Methylation of of possible methylation events is not possible. However, the hMLH1 promoter in familial gastric cancer with this method is not capable of reliably analyzing minute 30 microsatellite instability" Int J Cancer 2000 Jan 1;85 fragments from small sample quantities. In spite of pro- (1):50-3) tection against diffusion, such samples are lost through the matrix. - Prostate cancer (Rennie PS et al. "Epigenetic mech- anisms for progression of prostate cancer" Cancer 6. State of the art with respect to Methylation and 35 Metastasis Rev 1998-99;17(4):401-9) the diagnosis of human diseases - Renal cancer (Clifford SC et al. "Inactivation of the [0026] In the past, modification of the methylation pat- von Hippel-Lindau (VHL) tern was analyzed in order to study and understand the and allelic losses at chromosome arm 3p in primary genetic mechanisms which are involved in the outbreak 40 renal cell carcinoma: evidence for a VHL-independ- or the progression of a disease. All this research was ent pathway in clear cell renal tumourigenesis" done in a piece-by-piece fashion by studying only one Genes Cancer 1998 Jul;22(3):200-9) gene/chromosomal region at a time and no diagnosis/ therapeutic treatment regimen was based on the meth- - (Sardi I et al. "Molecular genetic al- ylation pattern modifications. In fact, the type of disease 45 terations of c- oncogene in superficial and locally associated with the modification of the methylation pat- advanced bladder cancer" Eur Urol 1998;33(4): tern was known before methylation analysis was per- 424-30) formed. Therefore, the following publications only indi- cate the widespread connection between modifications - Breast cancer (Mancini DN et al. "CpG methylation of the methylation patterns and human diseases. Modi- 50 within the 5’ regulatory region of the BRCA1 gene is fications can include both hyper- or hypomethylation of tumor specific and includes a putative CREB binding selected sites of the DNA. site" Oncogene 1998 Mar 5;16(9):1161-9; Zrihan- [0027] Disease associated with a modification of the Licht S et al. "DNA methylation status of the MUC1 methylation patterns are, for example: gene coding for a breast-cancer-associated protein" 55 Int J Cancer 1995 Jul 28;62(3):245-51; Kass DH et - Leukemia (Aoki E et al. "Methylation status of the al. "Examination of DNA methylation of chromosom- p15INK4B gene in hematopoietic progenitors and al hot spots associated with breast cancer" Antican- peripheral blood cells in myelodysplastic syn- cer Res 1993 Sep-Oct;13(5A):1245-51)

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- Burkitt’s lymphoma (Tao Q et al. "Epstein-Barr virus art of the analysis of gene expression, a screening and/or (EBV) in endemic Burkitt’s lymphoma: molecular the diagnosis for a potential disease or medical condition analysis of primary tumor tissue" Blood 1998 Feb is still a laborious and time consuming task, since in order 15;91(4):1373-81) to achieve a reliable result one has to analyse a vast 5 number of differently expressed genes in parallel. - Wilms tumor (Kleymenova EV et al. "Identification of [0029] This makes the analyses unreliable, time con- a tumor-specific methylation site in the Wilms tumor suming, expensive, non-automateable and limits it to the suppressor gene" Oncogene 1998 Feb 12;16(6): analysis of single genes. No methods exist so far which 713-20) address these problems to reasonably scale down the 10 effort which has to be applied in order to achieve a result - Prader-Willi/Angelman syndrome (Zeschnigh et al. while maintaining its statistical quality. "Imprinted segments in the human genome: different [0030] Therefore, it is an object of the present invention DNA methylation patterns in the Prader-Willi/Angel- to provide a method which allows for a streamlining of man syndrome region as determined by the genomic the effort for a reliable cell expression analysis. This anal- sequencing method" Human Mol. Genetics (1997) 15 ysis shall then be used for less time consuming and more (6)3 pp 387-395; Fang P et al. "The spectrum of mu- effective diagnostic and therapeutic purposes, in partic- tations in UBE3A causing Angelman syndrome" ular in personalised medical treatments. Hum Mol Genet 1999 Jan;8(1):129-35) [0031] A further object of the invention is to provide the gene panel which is obtained using a method according - ICF syndrome (Tuck-Muller et al. "CMDNA hy- 20 to the invention for the use in a treatment of a disease pomethylation and unusual chromosome instability and/or medical condition. in cell lines from ICF syndrome patients" Cytogenet [0032] A further object of the invention is to provide Cell Genet 2000;89(1-2):121-8) systems, methods and computer program products for performing any of the inventive methods. - Dermatofibroma (Chen TC et al. "Dermatofibroma is 25 [0033] A further object of the invention is to provide a a clonal proliferative disease" J Cutan Pathol 2000 treatment of a disease and/or medical condition, based Jan;27(1):36-9) on a gene panel according to the invention. [0034] This object is solved according to the present - (Lee SD et al. "Monoclonal endothelial invention by providing a method for the development of cell proliferation is present in primary but not sec- 30 gene panels for diagnostic and therapeutic purposes, ondary pulmonary hypertension" J Clin Invest 1998 which comprises the steps of: a)isolating at least one Mar 1;101(5):927-34) biological sample from each of at least two groups of biological material containing mRNA and/or proteins; b) - Pediatric Neurobiology (Campos-Castello J et al. analysing the expression level of at least one gene in the "The phenomenon of genomic "imprinting" and its 35 at least one biological samples; c) selecting the gene(s) implications in clinical neuropediatrics" Rev Neurol exhibiting a different expression level between said at 1999 Jan 1-15;28(1):69-73) least two groups of biological material, whereby a first knowledge base is generated; d) analysing the level of - Autism (Klauck SM et al. "Molecular genetic analysis cytosine methylation in the methylation relevant regions of the FMR-1 gene in a large collection of autistic 40 of at least one gene of at least one of the biological sam- patients" Hum Genet 1997 Aug;100(2):224-9) ples of step a), wherein the gene is selected on the basis of the first knowledge base; e) selecting the gene(s) ex- - Ulcerative colitis (Gloria L et al. "DNA hypomethyla- hibiting a different level of cytosine methylation between tion and proliferative activity are increased in the rec- said at least two groups of biological material, whereby tal mucosa of patients with long-standing ulcerative 45 a second knowledge base is generated; and f) adding colitis" Cancer 1996 Dec 1;78(11):2300-6) selected genes from the second knowledge base to a gene panel. - Fragile X syndrome (Hornstra IK et al. "High resolu- [0035] Thus, the present invention provides a method tion methylation analysis of the FMR1 gene trinucle- for generating a gene panel combining only the advan- otide repeat region in fragile X syndrome" Hum Mol 50 tages of the presently known expression analysis tech- Genet 1993 Oct;2(10):1659-65) niques, which results in a powerful tool for the fast and reliable diagnosis and/or therapy of a enormous number - Huntington’s disease (Ferluga J et al. "Possible or- of diseases and/or medical conditions. gan and age-related epigenetic factors in Hunting- [0036] Celis et al. ("Gene expression profiling: moni- ton’s disease and colorectal carcinoma" Med Hy- 55 toring transcription and translation products using DNA potheses 1989 May;29(1):51-4) microarrays and proteomics" FEBS Lett 2000 Aug 25; 480(1):2-16) describe a theoretical approach to combin- [0028] In view of the above, despite the advance in the ing different technologies such as DNA microarrays and

6 11 EP 1 364 069 B1 12 proteomics, which have made possible the analysis of biological diseases, autism, ulcerative colitis, fragile X the expression levels of multiple genes simultaneously syndrome, and Huntington’s disease. both in health and disease. In combination, these tech- [0041] A preferred method according to the invention nologies are said to revolutionise biology, in particular in is characterised in that the isolation of said biological the area of molecular medicine as they are expected to 5 sample comprises isolating subcellular compartments, reveal gene regulation events involved in disease pro- organelles, macromolecular structures and multiprotein gression as well as to pinpoint potential targets for drug complexes, partial or complete preparation of the mRNA, discovery and diagnostics. Celis et al. review the current reverse transcription or partial digestion of the material status of these technologies and highlight some studies with an selected from proteases, RNAses and/or in which they have been applied in concert to the analysis 10 DNAses or combinations thereof. Such isolations and/ of biopsy specimens. Nevertheless, Celis et al. fail to preselections can initially even further limit the amount describe or propose the combination of, in particular, data and complexity of the genes which take part in the inven- obtained in proteomics expression studies and methyla- tive method. tion analyses in order to provide gene panels for further [0042] Further preferred is a method according to the therapeutic or diagnostic purposes. 15 invention in which the analysis of the expression level of [0037] Other preferred embodiments of the invention the at least one gene in the biological sample comprises will become apparent to the person skilled in the art after determining the relative amount of mRNA or protein de- reading the features of the dependent claims. rived from said at least one gene. In general, all currently [0038] In one embodiment of the method according to known methods for the expression analysis of genes ex- the invention, the biological sample is isolated by means 20 cept methylation analysis can be used for this first step of a biopsy, by means of an operation on an individual, of the inventive method. Preferred are analyses that com- by means of a dissection, derived from a preserved bio- prise one or more of one- or two-dimensional gel elec- logical sample, collected from body fluid(s) and/or col- trophoresis, differential display, analysis of selected sets lected directly from the environment. of tumour markers, subtractive hybridisation, mass spec- [0039] In another embodiment of the method accord- 25 trometry, comparative expressed sequence tag se- ing to the invention, the biological sample comprises a quencing, representational difference analysis, cDNA or eucaryotic and/or procaryotic cell line, a biopsy sample, oligonucleotide arrays, serial analysis of gene expres- blood, sputum, faeces, urine, cerebral liquid, tissue em- sion, enzymatic, fluorescent, radioactive, dye and/or an- bedded in paraffin, tissue derived from eyes, intestine, tibody labelling. Even more preferred are methods ac- brain, heart, prostata, , lung, breast or liver, histo- 30 cording to the invention which comprise measuring in- logical samples or a combination thereof. tensities of expression during one- or two-dimensional [0040] A preferred method according to the invention gel electrophoresis, differential display, subtractive hy- is characterised in that the at least one biological sample bridisation, DNA, RNA or protein sequencing, mass is derived from biological material of healthy and/or dis- spectrometry, and enzymatic, radioactive, dye and/or an- eased individuals. Such diseases include all diseases 35 tibody labelling. and/or medical conditions which involve a modification [0043] In another embodiment of the method accord- of the expression of genes of the cell and include, for ing to the invention, the analysis is at least partially per- example, unwanted side effects of medicaments, can- formed by means of a suited automate, for example a cers, metastasis, dysfunctions, damages or diseases of robot and/or a computer device. Such device would be the (CNS), aggressive symptoms 40 equipped with the necessary software for the analysis of or behavioural disorders, clinical, psychological and so- the expression and could be connected to an inter- or cial consequences of brain injuries, psychotic disorders intranet, be part of a neural network or the like. The nec- and disorders of the personality, dementia and/or asso- essary data/information for the analyses can be present ciates syndromes, cardiovascular diseases, malfunc- on the system directly or at a remote source, to which tions or damages, diseases, malfunctions or damages 45 the device is directly or indirectly connected, for example of the gastrointestine, diseases, malfunctions or damag- via the internet. es of the respiratory system, injury, , infec- [0044] In a preferred method according to the inven- tion, immunity and/or reconvalescence, diseases, mal- tion, the expression levels of at least two genes are an- functions or damages as consequences of modifications alysed in parallel. More preferably, at least 100 genes in the developmental process, diseases, malfunctions or 50 are analysed in parallel. damages of the skin, muscles, connective tissue or [0045] In another preferred embodiment of the method bones, endocrine or metabolic diseases, malfunctions or according to the invention the selection is based on a damages, headache, and sexual malfunctions or combi- combination of the analysis of both mRNA level and pro- nations thereof, leukemia, head and neck cancer, Hodg- tein expression. In another embodiment of the inventive kin’s disease, gastric cancer, prostate cancer, renal can- 55 method, the selection is based on the result of at least cer, bladder cancer, breast cancer, Burkitt’s lymphoma, two individual rows of analyses. This provides for an in- Wilms tumor, Prader-Willi/Angelman syndrome, ICF syn- ternal control run of the data which is used for the selec- drome, dermatofibroma, hypertension, pediatric neuro- tion and increases the preciseness of the results. This

7 13 EP 1 364 069 B1 14 will further reduce the statistical error for the value of the JA et al. "Genetic analysis of genomic methylation pat- expression of a selected gene with an only limited in- terns in plants and mammals." C Biol Chem 1996 Oct; crease of the costs for the analysis. 377(10):605-10 and others. [0046] In another preferred method according to the [0051] Preferred is a method according to the invention invention, the selection is performed in such a way as to 5 in which the analysis is at least partially performed by give a first knowledge base comprising only one set of means of a suited automate, for example a robot. Such selected genes. Thus, the knowledge base will comprise device would be equipped with the necessary software only "on" and "off" type of data which allows for a very for the analysis of the expression and could be connected simple decision between expressed or non-expressed to an inter- or intranet, be part of a neural network or the genes. In yet another embodiment of the inventive meth- 10 like. The necessary data/information for the analyses can od, the selection is performed in such a way as to give a be present on the system directly or at a remote source, first knowledge base comprising different subsets of se- to which the device is directly or indirectly connected, for lected genes. Such classes can be referred to as "quality example via the internet. classes" which allows for a much more differentiated se- [0052] Another preferred method according to the in- lection of the gene panel. The term "quality classes" as 15 vention is characterised in that all potentially methylated used herein comprises all different possibilities of group- sites of the DNA are analysed. Such sites usually include ings the different expression levels. Such grouping could, all so-called "CpG"-islands on a given DNA sequence for example, include different importance for the selected and are readily detectable by the person skilled in the sites for the analysis of the expression as well as statis- art. Preferably, the level of cytosine methylation of at least tical preciseness and/or quality of the analysis data of 20 two genes are analysed in parallel. Preferably, the level the selected gene. of at least 100 cytosine methylation sites is analysed in [0047] In a preferred method according to the inven- parallel. The analysis of a multitude of sites in parallel tion, the selection is at least partially performed automat- allows for both a effective screening and a statistically ically by means of a suited automate, like a computer highly relevant result of the method. device. Such device would be equipped with the neces- 25 [0053] A further preferred method according to the in- sary software for the analysis of the expression and could vention is characterised in that the selection is based on be connected to an inter- or intranet, be part of a neural the result of at least two individual rows of analyses. This network or the like. The necessary data/information for will reduce the statistical error for the value of the meth- the analyses can be present on the system directly or at ylation sensitivity of a selected site with an only limited a remote source, to which the device is directly or indi- 30 increase of the costs for the analysis. In another preferred rectly connected, for example via the internet. method according to the invention, the selection is per- [0048] In a preferred method according to the inven- formed in such a way to give a second knowledge base tion, at least two genes are selected in parallel. More comprising only one set of selected genes. Thus, the preferably, at least 100 sites are selected in parallel. knowledge base will comprise only "on" and "off" type of [0049] According to the invention it is further preferred 35 data which allows for a very simple decision between to analyse methylation relevant regions comprising the different methylation states. complete genes and/or promoters, introns, first exons [0054] In yet another embodiment of the inventive and/or enhancers of the genes to be analysed. From the method, the selection is performed in such a way to give analysis of the methylation sites which are relevant for a second knowledge base comprising different subsets the expression of a certain gene, but not localised inside 40 of selected genes. Such classes can be referred to as the sequence of the gene itself, the effect of the site for "quality classes" which allows for a much more differen- the expression of the gene can be readily extrapolated tiated analysis. by the person skilled in the art. [0055] In a preferred method according to the inven- [0050] In another embodiment of the method accord- tion, the selection is at least partially performed automat- ing to the invention, the analysis of the level of cytosine 45 ically by means of a suited automate, like a computer methylation comprises chemical treatment with bisul- device. Such device would be equipped with the neces- phite, hydrogen sulphite or disulphite, polymerase chain sary software for the analysis of the methylation sites and reaction (PCR), hybridisation analyses, sequencing, could be connected to an inter- or intranet, be part of a mass spectrometry and fluorescent, enzymatic, radioac- neural network or the like. The necessary data/informa- tive, dye and/or antibody labelling. In general, all methods 50 tion for the analyses can be present on the system directly for the analysis of the methylation statuses at selected or at a remote source, to which the device is directly or sites of the DNA can be employed. Such methods are indirectly connected, for example via the internet. known to the skilled artisan and are described in, for ex- [0056] In a preferred method according to the inven- ample, Dahl et al., "Analysis of in vivo methylation." Meth- tion, at least two genes are selected in parallel. More ods Mol Biol 2000;130:47-57; Zhou Y. et al., "Use of a 55 preferably, at least 100 genes are selected in parallel. single sequencing termination reaction to distinguish be- [0057] Another embodiment of the method according tween cytosine and 5-methylcytosine in bisulfite-modi- to the invention is characterised in that all or a part of the fied DNA." Biotechniques 1997 May;22(5):850-4; Yoder genes of the second knowledge base are added to the

8 15 EP 1 364 069 B1 16 gene panel. malfunctions or combinations thereof, leukemia, head [0058] In another embodiment of the method accord- and neck cancer, Hodgkin’s disease, gastric cancer, ing to the invention, additional information about methyl- prostate cancer, renal cancer, bladder cancer, breast ation relevant regions of the selected genes is added to cancer, Burkitt’s lymphoma, Wilms tumor, Prader-Willi/ the gene panel. This additional information can comprise 5 Angelman syndrome, ICF syndrome, dermatofibroma, personal patient data, disease specific data, prior treat- hypertension, pediatric neurobiological diseases, au- ment data and/or additional methylation specific data. tism, ulcerative colitis, fragile X syndrome, and Hunting- [0059] Another embodiment of the method according ton’s disease. to the invention is characterised in that steps a) to f) are [0062] Further preferred is a gene panel according to repeated. Repeating the method of the invention suits 10 the invention which comprises additional information da- several different purposes. First, as mentioned above, ta about methylation relevant regions of the selected the statistical quality of the of the resulting data increases. genes, like the regions of the complete genes and/or pro- Second, an internal control can be provided, whether the moters, introns, first exons and/or enhancers. According biological sample was taken correctly and resembles e.g. to the invention, the gene panel can be present in the the tissue of interest. The number of repeating "cycles" 15 form of a knowledge base on a computer disc, RAM, of the invention can vary depending on the individual ROM, or a printed table or listing. case, e.g. depending on the quality of the sample to be [0063] According to the present invention, a "gene analyse. One possibility would be to repeat the method panel" designates a knowledge base, listing, table or oth- of the invention for at least 5 to 50 times. Preferably, such er information source, that contains information about method according to the invention is characterised in that 20 selected genes, herein also designated as "candidate the method is at least partially performed by means of a genes". According to the present invention, the term suited automate, for example a robot and/or a computer "gene panel" should not be understood as merely con- system. The inventive method can be conveniently au- taining information about the names or designations of tomated and/or computerized and respective devices the candidate genes. The panel further can contain ad- and programs are readily known to the person skilled in 25 ditional information about the candidate genes, like se- the art. quence data, information about the origin (heredity) of [0060] In another aspect according to the method ac- the gene, species information, and information about the cording to the invention, the identical biological material, genetic elements and/or factors that influence expres- different biological material or a combination thereof is sion of the candidate gene(s). Such elements can be the used in step a). Further, in another aspect according to 30 complete genes and/or promoters, introns, first exons the method according to the invention, the steps are per- and/or enhancers of the candidate genes. Factors can formed in the following order: step a), step d), step e), be growth conditions, developmental stage of the biolog- step b), step c), and step f). This simply interchanges the ical material from which the candidate gene is derived or order of the different steps of the inventive method which other medical data. should nevertheless lead to a similar or identical result. 35 [0064] In another aspect of the invention, the gene According to the invention, this method can also at least panel can be used for the diagnosis of a disease. Such partially be performed by means of a suited automate, diseases can include unwanted side effects of medica- for example a robot. ments, cancers, metastasis, dysfunctions, damages or [0061] Another aspect of the present invention is re- diseases of the central nerval system (CNS), aggressive lated to a gene panel which is obtained according to a 40 symptoms or behavioural disorders, clinical, psycholog- method according to the invention. This gene panel can ical and social consequences of brain injuries, psychotic be further used for the diagnosis and/therapy of different disorders and disorders of the personality, dementia diseases, like, for example, unwanted side effects of and/or associates syndromes, cardiovascular diseases, medicaments, cancers, metastasis, dysfunctions, dam- malfunctions or damages, diseases, malfunctions or ages or diseases of the central nervous system (CNS), 45 damages of the gastrointestine, diseases, malfunctions aggressive symptoms or behavioural disorders, clinical, or damages of the respiratory system, injury, inflamma- psychological and social consequences of brain injuries, tion, infection, immunity and/or reconvalescence, diseas- psychotic disorders and disorders of the personality, de- es, malfunctions or damages as consequences of mod- mentia and/or associates syndromes, cardiovascular ifications in the developmental process, diseases, mal- diseases, malfunctions or damages, diseases, malfunc- 50 functions or damages of the skin, muscles, connective tions or damages of the gastrointestine, diseases, mal- tissue or bones, endocrine or metabolic diseases, mal- functions or damages of the respiratory system, injury, functions or damages, headache, and sexual malfunc- inflammation, infection, immunity and/or reconvales- tions or combinations thereof. Particularly preferred is a cence, diseases, malfunctions or damages as conse- use according to the invention which is characterised in quences of modifications in the developmental process, 55 that the genes are related with leukemia, head and neck diseases, malfunctions or damages of the skin, muscles, cancer, Hodgkin’s disease, gastric cancer, prostate can- connective tissue or bones, endocrine or metabolic dis- cer, renal cancer, bladder cancer, breast cancer, eases, malfunctions or damages, headache, and sexual Burkitt’s, lymphoma, Wilms tumor, Prader-Willi/Angel-

9 17 EP 1 364 069 B1 18 man syndrome, ICF syndrome, dermatofibroma, hyper- personality, dementia and/or associates syndromes, car- tension, pediatric neurobiological diseases, autism, ul- diovascular diseases, malfunctions or damages, diseas- cerative colitis, fragile X syndrome, and Huntington’s dis- es, malfunctions or damages of the gastrointestine, dis- ease. eases, malfunctions or damages of the respiratory sys- [0065] Another aspect of the present invention is re- 5 tem, injury, inflammation, infection, immunity and/or re- lated to a device for the generation of a gene panel ac- convalescence, diseases, malfunctions or damages as cording to the invention, which comprises means for gen- consequences of modifications in the developmental erating a first and second knowledge base according to process, diseases, malfunctions or damages of the skin, invention and means for adding selected genes from the muscles, connective tissue or bones, endocrine or met- second knowledge base to a gene panel. 10 abolic diseases, malfunctions or damages, headache, [0066] Another aspect of the present invention is re- and sexual malfunctions or combinations thereof. Partic- lated to a method for the diagnosis of a disease, com- ularly preferred is a use for the diagnosis of leukemia, prising the following steps: a) providing a gene panel ac- head and neck cancer, Hodgkin’s disease, gastric can- cording to the invention; b) analysing the level of cytosine cer, prostate cancer, renal cancer, bladder cancer, breast methylation at selected sites of the DNA based on said 15 cancer, Burkitt’s lymphoma, Wilms tumor, Prader-Willi/ gene panel in biological material of at least one diseased Angelman syndrome, ICF syndrome, dermatofibroma, individual with a known disease or medical condition hypertension, pediatric neurobiological diseases, au- and/or at least one healthy individual, thereby generating tism, ulcerative colitis, fragile X syndrome, and Hunting- a first knowledge base; c) analysing the level of cytosine ton’s disease. methylation at selected sites of the DNA based on said 20 [0071] In an even further aspect, the invention provides gene panel in biological material of at least one diseased a method for the treatment of a disease or medical con- individual with an unknown disease or medical condition, dition which comprises a) providing at least one diagnosis thereby generating a second knowledge base; and d) according to a method as mentioned above; and b) in- providing a third knowledge base comprising a plurality stalling a specific treatment for said at least one diag- of expert rules for comparing the first and second knowl- 25 nosed disease or medical condition. Preferably, said spe- edge base; e) selecting a type of disease or medical con- cific treatment is disease specific and/or personalised. dition for the at least one diseased individual with an un- In one embodiment this method is used for the treatment known disease or medical condition based on said first of unwanted side effects of medicaments, cancers, dys- to third knowledge bases. functions, damages or diseases of the central nerval sys- [0067] A preferred method for the diagnosis of a dis- 30 tem (CNS), aggressive symptoms or behavioural disor- ease is characterised in that the selected sites of the ders, clinical, psychological and social consequences of genes to be analysed are located in the promoters, in- brain injuries, psychotic disorders and disorders of the trons, first exons and/or enhancers or combinations personality, dementia and/or associates syndromes, car- thereof. The inventive method can further comprise the diovascular diseases, malfunctions or damages, diseas- analysis of the level of cytosine methylation comprises 35 es, malfunctions or damages of the gastrointestine, dis- chemical treatment with bisulphite, hydrogen sulphite or eases, malfunctions or damages of the respiratory sys- disulphite, polymerase chain reaction (PCR), hybridisa- tem, injury, inflammation, infection, immunity and/or re- tion analyses, sequencing, mass spectrometry and fluo- convalescence, diseases, malfunctions or damages as rescent, enzymatic, radioactive, dye and/or antibody la- consequences of modifications in the developmental belling. Preferably, the method according to the invention 40 process, diseases, malfunctions or damages of the skin, is characterised in that the analysis is at least partially muscles, connective tissue or bones, endocrine or met- performed by means of a suited automate, for example abolic diseases, malfunctions or damages, headache, a robot. and sexual malfunctions or combinations thereof. Most [0068] Further, in another embodiment of the inventive preferred is a use for the treatment of leukemia, head method, steps b) to d) are repeated before performing 45 and neck cancer, Hodgkin’s disease, gastric cancer, step e). Preferably, the identical biological material, dif- prostate cancer, renal cancer, bladder cancer, breast ferent biological material or a combination thereof is used cancer, Burkitt’s lymphoma, Wilms tumor, Prader-Willi/ in step c). Angelman syndrome, ICF syndrome, dermatofibroma, [0069] In a preferred embodiment, the method accord- hypertension, pediatric neurobiological diseases, au- ing to the invention is at least partially performed by 50 tism, ulcerative colitis, fragile X syndrome, and Hunting- means of a suited automate, for example a robot. ton’s disease. [0070] In another aspect of the invention, one embod- [0072] The invention shall now be explained in more iment of the inventive method is used for the diagnosis detail by the following examples with reference to the of unwanted side effects of medicaments, cancers, dys- attached listing of genes and the accompanying drawings functions, damages or diseases of the central nerval sys- 55 without limiting the scope of the concept of the invention. tem (CNS), aggressive symptoms or behavioural disor- [0073] The attached sequence listing shows a panel ders, clinical, psychological and social consequences of of genes, whose methylation statuses are altered de- brain injuries, psychotic disorders and disorders of the pending on cellular states as indicated above each sub-

10 19 EP 1 364 069 B1 20 group of the listing. (CD48 antigen (B-cell ); CD53 (CD53 antigen); CD59 (CD59 antigen p18-20 (antigen identified EXAMPLES by monoclonal antibodies 16.3A5, EJ16, EJ30, EL32 and G344); CD63 (CD63 antigen (melanoma 1 antigen); Example 1 5 CD68 (CD68 antigen); CD7 (CD7 antigen (p41)); CD72 (CD72 antigen); CD8A (CD8 antigen, alpha polypeptide Proteomics plus subsequent methylation screening (p32)); CD9 (CD9 antigen (p24)); CD97 (CD97 antigen); CDW52 (CDW52 antigen (CAMPATH-1 antigen)); [0074] In this example, a proteomics-derived step was COL4A2 (Collagen, type IV, alpha 2); COL4A4 (Colla- used in order to analyse the expression level of a set of 10 gen, type IV, alpha 4); DAF (Decay accelerating factor proteins. First, a 2-D Gelelectrophoresis according to for complement (CD55, Cromer blood group system)); standard protocols (see above) was perfomed for both a DPP4 (Dipeptidylpeptidase IV (CD26, adenosine deam- prostate cancer cell line and cells derived from a healthy inase complexing protein 2)); EGF (Epidermal growth prostate in which a staining with Sypro Ruby dye was factor); EGFR (Epidermal (avian used. Then, the resulting gels were scanned using a 15 erythroblastic leukemia viral (v-erb-b) oncogene ho- CCD-camera and the scanned picture were analysed us- molog)); EMAPII (Endothelial -activating ing a computer-based analysis software, e.g. "Image- polypeptide); EMAPL (Echinoderm microtubule-associ- master" (Amersham-Pharmacia) or "Z3" (Compugen). ated protein-like); ENG ( (Osler-Rendu-Weber [0075] Proteins that were differently expressed in both syndrome 1)); F3 ( ( factor III (thromboplas- analysis pattern were excised by a robot (Flexys robot, 20 tin, )); F8C (Coagulation factor VIIIc, proco- genomic solutions) and tryptically digested. The agulant component (hemophilia A)); FAP (Fibroblast ac- were analysed using a MALDI-TOF mass spectrometry. tivation protein, alpha); FGF 1 ( The resulting fragments were analysed via map- 1 (acidic)); FGF2 (Fibroblast growth factor 2 (basic)); ping and compared to the protein database (which one). FGFR1 (Fibroblast 1 (fms-related Finally, the differently expressed proteins were listed and 25 2, Pfeiffer syndrome)); FGFR2 (Fibrob- displayed. This listing included several differently ex- last growth factor receptor 2 (-expressed kinase, pressed proteins. keratinocyte growth factor receptor, craniofacial dysos- [0076] On the basis of the listing obtained in the first tosis 1, Crouzon syndrome, Pfeiffer syndrome, Jackson- step, a methylation analysis was performed according to Weiss syndrome)); FIGF (C-fos induced growth factor the methods described above. The analysis revealed, 30 (vascular endothelial growth )); FLT1 (Fms-relat- that the methylation statuses of the several proteins were ed 1 (vascular endothelial growth factor/ significantly different compared to the non-prostate can- vascular permeability factor receptor)); FLT4 (Fms-relat- cer cell line. ed tyrosine kinase 4); FN1 (Fibronectin 1); GRB2 (Growth [0077] Taken together, these selected genes can be factor receptor-bound protein 2); HGF (Hepatocyte further used in diagnosis and/or therapy as a minimal set 35 growth factor (hepapoietin A; scatter factor)); HIF1A (Hy- of markers for prostate cancer while providing a result of poxia-inducible factor 1, alpha subunit (basic helix-loop- maximal reliably. helix )); IGF1 (-like growth fac- tor 1 ( C)); IGF2 (Insulin-like growth factor Listing of genes for panels 2 (somatomedin A)); ITGBL1 (, beta-like 1 (with 40 EGF-like repeat domains)); JAG1 (Jagged1 (Alagille syn- drome)); JAG2 (Jagged 2); KAI1 (Kangai 1 (suppression of tumorigenicity 6, prostate); CD82 antigen (R2 leuko- [0078] ADM (); ANG (Angiogenin, ri- cyte antigen, antigen detected by monoclonal and anti- bonuclease, RNase A family, 5); ANGPT1 ( body IA4)); KDR (Kinase insert domain receptor (a type 1); ANGPT2 (Angiopoietin 2); ANGPT3 (Angiopoietin 3); 45 III )); LAG3 (-activa- ANGPT4 (Angiopoietin 4); ANPEP (Alanyl (membrane) tion gene 3); LAMA1 (Laminin, alpha 1); LAMA2 (Lam- aminopeptidase (aminopeptidase N, aminopeptidase M, inin, alpha 2 (merosin, congenital muscular dystrophy)); microsomal aminopeptidase, CD 13, p150)); ARNT (Aryl LAMA4 (Laminin, alpha 4); LAMA5 (Laminin, alpha 5); hydrocarbon receptor nuclear translocator); BDK (Brady- LY64 (Lymphocyte antigen 64 (mouse) homolog, radio- ); BDKRB2 ( receptor B2); BTN (Buty- 50 protective, 105kD); LYZ (Lysozyme (renal amyloidosis)); rophilin); CD14 (CD14 antigen); CD19 (CD19 antigen); MDU1 (Antigen identified by monoclonal antibodies 4F2, CD1D (CDID antigen, d polypeptide); CD2 (CD2 antigen TRA1.10, TROP4, and T43); MET (Met proto-oncogene (p50), sheep receptor); CD20 (CD20 anti- ( receptor)); MIC2 (Antigen gen); CD22 (CD22 antigen); CD33 (CD33 antigen identified by monoclonal antibodies 12E7, F21 and 013); (gp67); CD34 (CD34 antigen); CD37 (CD37 antigen); 55 MICA (MHC class I polypeptide-related sequence A); CD38 (CD38 antigen (p45)); CD39 (CD39 antigen); CD4 MME (Membrane metallo-endopeptidase (neutral en- (CD4 antigen (p55)); CD47 (CD47 antigen (Rh-related dopeptidase, enkephalinase, CALLA, CD10)); MMP1 antigen, integrin-associated signal transducer); CD48 (Matrix metalloproteinase 1 (interstitial collagenase));

11 21 EP 1 364 069 B1 22

MMP10 (Matrix metalloproteinase 10 (stromelysin 2)); member 3); TNF ( (TNF superfami- MMP2 (Matrix metalloproteinase 2 (gelatinase A, 72kD ly, member 2)); TNFRSF1A (Tumor necrosis factor re- gelatinase, 72kD type IV collagenase)); MMP9 (Matrix ceptor superfamily, member 1A (); TNFSF12 (Tumor metalloproteinase 9 (gelatinase B, 92kD gelatinase, necrosis factor () superfamily, member 12); 92kD type IV collagenase)); NEO1 (Neogenin (chicken) 5 TNFSF4 (Tumor necrosis factor (ligand) superfamily, homolog 1); NOS2A (Nitric oxide synthase 2A (inducible, member 4 (tax-transcriptionally activated glycoprotein 1, hepatocytes)); NOS3 (Nitric oxide synthase 3 (endothe- 34kD)); TNFSF5 (Tumor necrosis factor (ligand) super- lial cell)); NRP1 ( 1); NRP2 (Neuropilin 2); PAI1 family, member 5); TNFSF7 (Tumor necrosis factor (lig- (Plasminogen activator inhibitor, type I); PAI2 (Plasmino- and) superfamily, member 7); VCAM1 (Vascular cell ad- gen activator inhibitor, type II (-serpin)); PDNP1 10 hesion molecule 1); VEGF (Vascular endothelial growth (Phosphodiesterase I/nucleotide pyrophosphatase 1 factor); VEGFB (Vascular endothelial growth factor B); (homologous to mouse Ly-41 antigen)); PF4 ( VEGFC (Vascular endothelial growth factor C); VTN (Vit- factor 4); PF4V1 (Platelet factor 4 variant 1); PLAU (Plas- ronectin (serum spreading factor, somatomedin B, com- minogen activator, ); PLAUR (Plasminogen ac- plement S-protein)); and VWF (). tivator, ); PLG (Plasminogen); PRK- 15 CA ( C, alpha); PRKCB1 (Protein kinase Apoptosis C, beta 1); PRKM1 (Protein kinase, -activated 1 (MAP kinase 1; p40, p41)); PRKM10 (Protein kinase mi- [0079] APAF1 (Apoptotic protease activating factor); togen-activated 10 (MAP kinase)); PRKM3 (Protein ki- API1 (Apoptosis inhibitor 1); API2 (Apoptosis inhibitor 2); nase, mitogen-activated 3 (MAP kinase 3; p44)); PTAFR 20 API3 (Apoptosis inhibitor 3); API4 (Apoptosis inhibitor 4 (Platelet-activating factor receptor); PTCH (Patched (survivin)); BAD (BCL2-antagonist of cell death); BAD (Drosophila) homolog); PTK2 (PTK2 protein tyrosine ki- (BCL2-antagonist of cell death); BAG4 (BCL2-associat- nase 2); PTK2B (Protein beta); RHO ed athanogene 4); BAK1 (BCL2-antagonist/killer 1); BAX ( (retinitis pigmentosa 4, autosomal domi- (BCL2-associated X protein); BCL10 (B-cell CLL/lym- nant)); RTN1 (Reticulon 1); SDC1 (Syndecan 1); SDC2 25 phoma 10); BCL2 (B-cell CLL/lymphoma 2); BCL2A1 (Syndecan 2 (heparan sulfate proteoglycan 1, cell sur- (BCL2-related protein A1); BCL2L1 (BCL2-like 1); face-associated, fibroglycan)); SDC4 (Syndecan 4 (am- BCL2L2 (BCL2-like 2); BNIP1 (BCL2/adenovirus E1B phiglycan, ryudocan)); SELPLG ( P ligand); 19kD-interacting protein 1); BNIP2 (BCL2/adenovirus SIAT1 ( 1 (beta-galactoside alpha-2,6- E1B 19kD-interacting protein 2); BNIP3 (BCL2/adenovi- sialytransferase)); SLAM (Signaling lymphocytic activa- 30 rus E1B 19kD-interacting protein 3); CASP1 (Caspase tion molecule); SOS1 ( (Drosophila) ho- 1, apoptosis-related protease ( 1, be- molog 1); SST (Somatostatin); SSTR1 (Somatostatin re- ta, convertase) ); CASP10 (Caspase 10, apoptosis-re- ceptor 1); SSTR2 ( 2); SSTR3 (So- lated cysteine protease); CASP2 (Caspase 2, apoptosis- matostatin receptor 3); SSTR4 (Somatostatin receptor related cysteine protease (neural precursor cell ex- 4); SSTR5 (); ST2 (Suppression 35 pressed, developmentally down-regulated 2)); CASP3 of tumorigenicity 2); STAT1 (Signal transducer and acti- (Caspase 3, apoptosis-related cysteine protease); vator of transcription 1, 91kD); TEK (TEK tyrosine kinase, CASP4 (Caspase 4, apoptosis-related cysteine pro- endothelial); TFPI (Tissue factor pathway inhibitor (lipo- tease); CASP5 (Caspase 5, apoptosis-related cysteine protein-associated coagulation inhibitor)); TGFB 1 protease); CASP6 (Caspase 6, apoptosis-related (Transforming growth factor, beta 1); TGFB1 (Transform- 40 cysteine protease); CASP7 (Caspase 7, apoptosis-relat- ing growth factor, beta 1); TGFB1 (Transforming growth ed cysteine protease); CASP8 (Caspase 8, apoptosis- factor, beta 1); TGFBR1 (Transforming growth factor, be- related cysteine protease); CASP9 (Caspase 9, apopto- ta receptor I (activin A receptor type II-like kinase, 53kD)); sis-related cysteine protease); DAP (Death-associated TGFBR1 (Transforming growth factor, beta receptor I protein); DAP3 (Death associated protein 3); DAPK3 (activin A receptor type II-like kinase, 53kD)); TGFBR1 45 (Death-associated protein kinase 3); DAXX (Death-as- (Transforming growth factor, beta receptor I (activin A sociated protein 6); DFFA (DNA fragmentation factor, 45 receptor type II-like kinase, 53kD)); TGFBR2 (Transform- kD, alpha subunit); MCL1 (Myeloid cell leukemia se- ing growth factor, beta receptor II (70-80kD)); THBS1 quence 1 (BCL2-related)); MDM4 (Mouse double minute (Thrombospondin 1); THBS1 (Thrombospondin 1); 4, human homolog of; -binding protein); MYD88 (My- THBS2 (Thrombospondin 2); THBS4 (Thrombospondin 50 eloid differentiation primary response gene (88)); NAIP 4); TIE (Tyrosine kinase with immunoglobulin and epi- (Neuronal apoptosis inhibitory protein); PAWR (PRKC, dermal growth factor homology domains); TIEG (TGFB apoptosis, WT1, regulator); PDCD1 (Programmed cell inducible early growth response); TIEG2 (TGFB induci- death 1); PDCD2 (Programmed cell death 2); PSEN2 ble early growth response 2); TIMP1 (Tissue inhibitor of (Presenilin 2 (Alzheimer disease 4)); REQ (Requiem, ap- metalloproteinase 1 (erythroid potentiating activity, col- 55 optosis response gene); SFRP5 (Secreted lagenase inhibitor) ); TIMP2 (Tissue inhibitor of metallo- -related protein 5); STK17A (/threonine ki- proteinase 2); TM4SF2 (Transmembrane 4 superfamily nase 17a (apoptosis-inducing)); STK17B (Serine/threo- member 2); TM4SF3 (Transmembrane 4 superfamily nine kinase 17b (apoptosis-inducing)); TNFAIP1 (Tumor

12 23 EP 1 364 069 B1 24 necrosis factor, alpha-induced protein 1 (endothelial)); E2); CCNF (Cyclin F); CCNH (Cyclin H); CCNK (Cyclin TNFRSF6 (Tumor necrosis factor receptor superfamily, K); CD48 (CD48 antigen (B-cell membrane protein)); member); and TP53BP2 (Tumor protein p53-binding pro- CD69 (CD69 antigen (p60, early T-cell activation anti- tein). gen)); CDC10 (Cell division cycle 10 (homologous to 5 CDC 10 of S. cerevisiae)); CDC18L (CDC18 (cell division Behavior cycle 18, S.pombe, homolog)-like); CDC2 (Cell division cycle 2, G1 to S and G2 to M); CDC25A (Cell division [0080] ADRA1A (Adrenergic, alpha-1A-, receptor); cycle 25A); CDC25A (Cell division cycle 25A); CDC25C ADRA1C (Adrenergic, alpha-1C-, receptor); ADRA2A (Cell division cycle 25C); CDC25C (Cell division cycle (Adrenergic, alpha-2A-, receptor); ADRA2B (Adrenergic, 10 25C); CDC27 (Cell division cycle 27); CDC2L1 (Cell di- alpha-2B-, receptor); ADRA2C (Adrenergic, alpha-2C-, vision cycle 2-like 1 (PITSLRE proteins)); CDC42 (Cell receptor); ADRB1 (Adrenergic, beta-1-, receptor); division cycle 42 (GTP-binding protein, 25kD)); CDC7L1 ADRB2 (Adrenergic, beta-2-, receptor, surface); ADRB3 (CDC7 (cell division cycle 7, S. cerevisiae, homolog)-like (Adrenergic, beta-3-, receptor); ADRBK1 (Adrenergic, 1); CDK2 (Cyclin-dependent kinase 2); CDK2 (Cyclin- beta, receptor kinase 1); ADRBK2 (Adrenergic, beta, re- 15 dependent kinase 2); CDK5 (Cyclin-dependent kinase ceptor kinase 2); COMT (Catechol-O-methyltrans- 5); CDK6 (Cyclin-dependent kinase 6); CDK6 (Cyclin- ferase); DBH ( beta-hydroxylase (dopamine dependent kinase 6); CDK7 (Cyclin-dependent kinase 7 beta-monooxygenase)); DDC (Dopa decarboxylase (ar- (homolog of Xenopus MO15 cdk-activating kinase)); omatic L-amino acid decarboxylase)); DRD 1 (Dopamine CDK7 (Cyclin-dependent kinase 7 (homolog of Xenopus receptor D1); DRD2 ( D2); DRD3 20 MO15 cdk-activating kinase)); CDK8 (Cyclin-dependent (); DRD4 (Dopamine receptor kinase 8); CDK8 (Cyclin-dependent kinase 8); CDKN1B D4); DRD5 (Dopamine receptor D5); MAOA (Monoamine (Cyclin-dependent kinase inhibitor 1B (p27, Kip1)); oxidase A); MAOB (Monoamine oxidase B); OPRM1 CDKN1C (Cyclin-dependent kinase inhibitor 1C (p57, (, mu 1); PNMT (Phenylethanolamine N- Kip2)); CDKN2B (Cyclin-dependent kinase inhibitor 2B methyltransferase); and TH (Tyrosine hydroxylase) 25 (p15, inhibits CDK4)); CHC1 (Chromosome condensa- tion 1); CHEK1 (CHK1 (checkpoint, S.pombe) homolog); Cell cycle CHES 1 (Checkpoint suppressor 1); CHUK (Conserved helix-loop-helix ubiquitous kinase); CKS1 (CDC28 pro- [0081] ABL2 (V-abl Abelson murine leukemia viral on- tein kinase 1); CKS2 (CDC28 protein kinase 2); CLK2 cogene homolog 2 (arg, Abelson-related gene)); ACP1 30 (CDC-like kinase 2); CLK3 (CDC-like kinase 3); CNK (Cy- (Acid phosphatase 1, soluble); ACP2 (Acid phosphatase tokine-inducible kinase); COT (Cot (cancer Osaka thy- 2, lysosomal); ACP5 (Acid phosphatase 5, tartrate resist- roid) oncogene); CSNK1A1 (, alpha 1); ant); ACPP (Acid phosphatase, prostate); ACVR1B (Ac- CSNK1D (Casein kinase 1, delta); CSNK1E (Casein ki- tivin A receptor, type IB); ADK (Adenosine kinase); nase 1, epsilon); CSNK2A2 (, alpha ADRBK1 (Adrenergic, beta, receptor kinase 1); AK1 35 prime polypeptide); CSNK2B (Casein kinase 2, beta (Adenylate kinase 1); AK2 (Adenylate kinase 2); AK3 polypeptide); DENR (Density-regulated protein); DGKA (Adenylate kinase 3); AKT1 (V-akt murine thymoma viral (Diacylglycerol kinase, alpha (80kD)); DGKG (Diacylg- oncogene homolog 1); AKT2 (V-akt murine thymoma vi- lycerol kinase, gamma (90kD)); DGKQ (Diacylglycerol ral oncogene homolog 2); ALPI (Alkaline phosphatase, kinase, theta (110kD)); DMPK (Dystrophia myotonica- intestinal); ALPL (Alkaline phosphatase, liver/bone/kid- 40 protein kinase); DUSP3 (Dual specificity phosphatase 3 ney); ALPP (Alkaline phosphatase, placental (Regan iso- (vaccinia virus phosphatase VH1-related)); DUSP4 (Du- zyme)); ARAF1 (V-raf murine sarcoma 3611 viral onco- al specificity phosphatase 4); DYRK1 (Dual-specificity gene homolog 1); BLK (B lymphoid tyrosine kinase); tyrosine-(Y)- regulated kinase 1); BMPR2 (Bone morphogenetic protein receptor, type II ( transcription factor 2); (E2F transcription fac- (serine/threonine kinase)); BMX (BMX non-receptor ty- 45 tor 5, p130-binding); EFNA1 (-A1); EFNA5 rosine kinase); BRAF (V-raf murine sarcoma viral onco- (Ephrin-A5); EFNB1 (Ephrin-B1); EFNB2 (Ephrin-B2); gene homolog B1); BTK (Bruton agammaglobulinemia EGR1 (Early growth response 1); EPHA2 (EphA2); tyrosine kinase); CAK ( kinase); CALM1 EPHA4 (EphA4); EPHA5 (EphA5); EPHA7 (EphA7); ( 1 ( kinase, delta)); CAMK4 EPHB3 (EphB3); EPHB4 (EphB4); EPHB6 (EphB6); (/calmodulin-dependent protein kinase IV); 50 ERBB3 (V-erb-b2 avian erythroblastic leukemia viral on- CBFA2T1 (Core-binding factor, runt domain, alpha sub- cogene homolog 3); FAP (Fibroblast activation protein, unit 2; translocated to, 1; cyclin D-related); CBFA2T2 alpha); FBL (Fibrillarin); FES (Feline sarcoma (Snyder- (Core-binding factor, runt domain, alpha subunit 2; trans- Theilen) viral (v-fes)/Fujinami avian sarcoma (PRCII) vi- located to, 2); CBFA2T3 (Core-binding factor, runt do- ral (v-fps) oncogene homolog); FGFR1 (Fibroblast main, alpha subunit 2; translocated to, 3); CCNA2 (Cyclin 55 growth factor receptor 1 (fms-related tyrosine kinase 2, A2); CCNB1 (Cyclin B1); CCND1 (Cyclin D1 (PRAD1: Pfeiffer syndrome)); FGFR2 (Fibroblast growth factor re- parathyroid adenomatosis 1)); CCND2 (Cyclin D2); ceptor 2 (bacteria-expressed kinase, keratinocyte growth CCND3 (Cyclin D3); CCNE1 (Cyclin E1); CCNE2 (Cyclin factor receptor, craniofacial dysostosis 1, Crouzon syn-

13 25 EP 1 364 069 B1 26 drome, Pfeiffer syndrome, Jackson-Weiss syndrome)); 1, catalytic subunit, beta isoform); PPP1CC (Protein FGR (Gardner-Rasheed feline sarcoma viral (v-) on- phosphatase 1, catalytic subunit, gamma isoform); cogene homolog); FLT1 (Fms-related tyrosine kinase 1 PPP1R3 (Protein phosphatase 1, regulatory (inhibitor) (vascular endothelial growth factor/vascular permeability subunit 3 (glycogen and sarcoplasmic reticulum binding factor receptor)); FLT3LG (Fms-related tyrosine kinase 5 subunit, skeletal muscle)); PPP2CA (Protein phos- 3 ligand); FLT4 (Fms-related tyrosine kinase 4); FRK phatase 2 (formerly 2A), catalytic subunit, alpha isoform); (Fyn-related kinase); GAS2 (Growth arrest-specific 2); PPP2R1B ( (formerly 2A), regu- GLA (Galactosidase, alpha); GPRK6 (-coupled latory subunit A (PR 65), beta isoform); PPP2R2A (Pro- receptor kinase 6); GSPT1 (G1 to S phase transition 1); tein phosphatase 2 (formerly 2A), regulatory subunit B HMR ( receptor (growth factor-inducible nucle- 10 (PR 52), alpha isoform); PPP2R3 (Protein phosphatase ar protein N10)); HUS 1 (HUS1 (S. pombe) checkpoint 2 (formerly 2A), regulatory subunit B" (PR 72), alpha iso- homolog); IFI56 (-induced protein 56); IGFBP1 form and (PR 130), beta isoform); PPP2R4 (Protein (Insulin-like growth factor binding protein 1); ILK (In- phosphatase 2A, regulatory subunit B’ (PR 53)); tegrin-linked kinase); INP10 (Interferon (gamma)-in- PPP2R5A (Protein phosphatase 2, regulatory subunit B duced cell line; protein 10 from); INPP5D (Inositol 15 (B56), alpha isoform); PPP2R5B (Protein phosphatase polyphosphate-5-phosphatase, 145kD); ISG20 (Interfer- 2, regulatory subunit B (B56), beta isoform); PPP2R5D on stimulated gene (20kD)); JAK1 ( 1 (a (Protein phosphatase 2, regulatory subunit B (B56), delta protein tyrosine kinase)); JAK3 ( (a protein isoform); PPP2R5E (Protein phosphatase 2, regulatory tyrosine kinase, leukocyte)); KDR (Kinase insert domain subunit B (B56), epsilon isoform); PPP3CA (Protein receptor (a type III receptor tyrosine kinase)); LCAT (Lec- 20 phosphatase 3 (formerly 2B), catalytic subunit, alpha iso- ithin-cholesterol acyltransferase); LIMK1 (LIM domain ki- form (calcineurin A alpha)); PPP3CB (Protein phos- nase 1); LIMK2 (LIM domain kinase 2); LRP1 (Low den- phatase 3 (formerly 2B), catalytic subunit, beta isoform sity lipoprotein-related protein 1 (alpha-2-macroglobulin (calcineurin A beta)); PPP4C (Protein phosphatase 4 receptor)); LTK (Leukocyte tyrosine kinase); LY6E (Lym- (formerly X), catalytic subunit); PRKAA2 (Protein kinase, phocyte antigen 6 complex, locus E); MAD 1L 1 (MAD1 25 AMP-activated, alpha 2 catalytic subunit); PRKACA (Pro- (mitotic arrest deficient, yeast, homolog)-like 1); MAD2L1 tein kinase, cAMP-dependent, catalytic, alpha); (MAD2 (mitotic arrest deficient, yeast, homolog)-like 1); PRKACB (Protein kinase, cAMP-dependent, catalytic, MATK (Megakaryocyte-associated tyrosine kinase); beta); PRKACG (Protein kinase, cAMP-dependent, cat- MCL1 (Myeloid cell leukemia sequence 1 (BCL2-relat- alytic, gamma); PRKAG1 (Protein kinase, AMP-activat- ed)); MCM4 (Minichromosome maintenance deficient (S. 30 ed, gamma 1 non-catalytic subunit); PRKAR1A (Protein cerevisiae) 4); MEKK3 (MAP/ERK kinase kinase 3); kinase, cAMP-dependent, regulatory, type I, alpha (tis- MEKK5 (MAP/ERK kinase kinase 5); MKI67 (Antigen sue specific extinguisher 1)); PRKAR1B (Protein kinase, identified by monoclonal antibody Ki-67); MST1R (Mac- cAMP-dependent, regulatory, type I, beta); PRKAR2B rophage stimulating 1 receptor (c-met-related tyrosine (Protein kinase, cAMP-dependent, regulatory, type II, be- kinase)); NCK1 (NCK adaptor protein 1); NEK3 (NIMA 35 ta); PRKCA (, alpha); PRKCB1 (Protein (never in mitosis gene a)-related kinase); NME1 (Non- kinase C, beta 1); PRKCG (Protein kinase C, gamma); metastatic cells 1, protein (NM23A) expressed in); NME2 PRKCI (Protein kinase C, iota); PRKCL1 (Protein kinase (Non-metastatic cells 2, protein (NM23B) expressed in); C-like 1); PRKCL2 (Protein kinase C-like 2); PRKCM NOS2A (Nitric oxide synthase 2A (inducible, hepato- (Protein kinase C, mu); PRKCQ (Protein kinase C, theta); cytes)); NPM1 (Nucleophosmin (nucleolar phosphopro- 40 PRKCZ (Protein kinase C, zeta); PRKG1 (Protein kinase, tein B23, numatrin)); NTRK3 (Neurotrophic tyrosine ki- cGMP-dependent, type I); PRKG2 (Protein kinase, nase, receptor, type 3); OAS1 (2’,5’-oligoadenylate syn- cGMP-dependent, type II); PRKM1 (Protein kinase, mi- thetase 1); PA2G4 (Proliferation-associated 2G4, 38kD); togen-activated 1 (MAP kinase 1; p40, p41)); PRKM10 PCNA (Proliferating cell nuclear antigen); PCTK3 (Protein kinase mitogen-activated 10 (MAP kinase)); (PCTAIRE protein kinase 3); PDGFRB (Platelet-derived 45 PRKM11 (Protein kinase mitogen- activated 11); growth factor receptor, beta polypeptide); PDK2 (Pyru- PRKM13 (Protein kinase mitogen-activated 13); PRKM3 vate dehydrogenase kinase, isoenzyme 2); PDK4 (Pyru- (Protein kinase, mitogen-activated 3 (MAP kinase 3; vate dehydrogenase kinase, isoenzyme 4); PDPK1 (3- p44)); PRKM6 (Protein kinase, mitogen-activated 6 (ex- phosphoinositide dependent protein kinase-1); PHKA2 tracellular signal-regulated kinase, p97)); PRKM7 (Pro- (, alpha 2 (liver), glycogen storage 50 tein kinase mitogen-activated 7 (MAP kinase)); PRKM8 disease IX); PHKG2 (Phosphorylase kinase, gamma 2 (Protein kinase mitogen-activated 8 (MAP kinase)); (testis)); PIK3CA (Phosphoinositide-3-kinase, catalytic, PRKM9 (Protein kinase mitogen-activated 9 (MAP ki- alpha polypeptide); PIK3CG (Phosphoinositide-3-ki- nase)); PRKMK2 (Protein kinase, mitogen-activated, ki- nase, catalytic, gamma polypeptide); PIM1 (Pim-1 onco- nase 2, p45 (MAP kinase kinase 2)); PRKMK3 (Protein gene); POLB (Polymerase (DNA directed), beta); POLD1 55 kinase, mitogen-activated, kinase 3 (MAP kinase kinase (Polymerase (DNA directed), delta 1, catalytic subunit 3)); PRKMK5 (Protein kinase, mitogen-activated, kinase (125kD)); PPP1CA (Protein phosphatase 1, catalytic 5 (MAP kinase kinase 5)); PRKMK7 (Protein kinase, mi- subunit, alpha isoform); PPP1CB (Protein phosphatase togen-activated, kinase 7 (MAP kinase kinase 7)); PRKR

14 27 EP 1 364 069 B1 28

(Protein kinase, interferon-inducible double stranded perature sensitivity complementation, cell cycle specif- RNA dependent); PTEN (Phosphatase and tensin ho- ic,); TTK (TTK protein kinase); TXK (TXK tyrosine ki- molog (mutated in multiple advanced cancers 1)); PTK7 nase); TYK2 (Tyrosine kinase 2); TYRO3 (TYRO3 pro- (PTK7 protein tyrosine kinase 7); PTK9 (Protein tyrosine tein tyrosine kinase); VRK2 (Vaccinia related kinase 2); kinase 9); PTPN1 (Protein tyrosine phosphatase, non- 5 ZAP70 (Zeta-chain (TCR) associated protein kinase (70 receptor type 1); PTPN12 (Protein tyrosine phosphatase, kD)); and ZPK (Zipper () protein kinase). non-receptor type 12); PTPN 13 (Protein tyrosine phos- phatase, non-receptor type 13 (APO-1/CD95 (Fas)-as- sociated phosphatase)); PTPN2 (Protein tyrosine phos- phatase, non-receptor type 2); PTPN3 (Protein tyrosine 10 [0082] ABL1 (V-abl Abelson murine leukemia viral on- phosphatase, non-receptor type 3); PTPN4 (Protein ty- cogene homolog 1); ABL2 (V-abl Abelson murine leuke- rosine phosphatase, non-receptor type 4 (megakaryo- mia viral oncogene homolog 2 (arg, Abelson-related cyte)); PTPN6 (Protein tyrosine phosphatase, non-re- gene)); ABR (Active BCR-related gene); ACP1 (Acid ceptor type 6); PTPN7 (Protein tyrosine phosphatase, phosphatase 1, soluble); ACP2 (Acid phosphatase 2, lys- non-receptor type 7); PTPN9 (Protein tyrosine phos- 15 osomal); ACP5 (Acid phosphatase 5, tartrate resistant); phatase, non-receptor type 9); PTPRA (Protein tyrosine ACPP (Acid phosphatase, prostate); ACTG1 (, phosphatase, receptor type, alpha polypeptide); PTPRB gamma 1); ACVR1B (Activin A receptor, type IB); ADD3 (Protein tyrosine phosphatase, receptor type, beta (Adducin 3 (gamma)); ADK (Adenosine kinase); polypeptide); PTPRC (Protein tyrosine phosphatase, re- ADRBK1 (Adrenergic, beta, receptor kinase 1); AIF1 (Al- ceptor type, c polypeptide); PTPRD (Protein tyrosine 20 lograft inflammatory factor 1); AK1 (Adenylate kinase 1); phosphatase, receptor type, D); PTPRF (Protein tyrosine AK2 (Adenylate kinase 2); AK3 (Adenylate kinase 3); phosphatase, receptor type, F); PTPRG (Protein tyrosine AKT1 (V-akt murine thymoma viral oncogene homolog phosphatase, receptor type, gamma polypeptide); PT- 1); AKT2 (V-akt murine thymoma viral oncogene ho- PRH (Protein tyrosine phosphatase, receptor type, H); molog 2); ALCAM (Activated leucocyte cell adhesion PTPRK (Protein tyrosine phosphatase, receptor type, K); 25 molecule); ALOX12 (Arachidonate 12-lipoxygenase); PTPRM (Protein tyrosine phosphatase, receptor type, ALOX5 (Arachidonate 5-lipoxygenase); ALPI (Alkaline M); PTPRN (Protein tyrosine phosphatase, receptor phosphatase, intestinal); ALPL (Alkaline phosphatase, type, N); PTPRN2 (Protein tyrosine phosphatase, recep- liver/bone/kidney); ALPP (Alkaline phosphatase, placen- tor type, N polypeptide 2); PTX3 (Pentaxin-related gene, tal (Regan isozyme)); ANK1 (Ankyrin 1, erythrocytic); rapidly induced by IL-1 beta); RAB8IP (Rab8 interacting 30 ANT2 (Adenine nucleotide translocator 2 (fibroblast)); protein (GC kinase)); RAB8IP (Rab8 interacting protein ARAF1 (V-raf murine sarcoma 3611 viral oncogene ho- (GC kinase)); RAD9 (RAD9 (S. pombe) homolog); RAD9 molog 1); ARHA (Ras homolog gene family, member A); (RAD9 (S. pombe) homolog); RBL1 (Retinoblastoma-like ARHC (Ras homolog gene family, member C); ARHGDIB 1 (p107)); RET (Ret proto-oncogene (multiple endocrine (Rho GDP dissociation inhibitor (GDI) beta); BLK (B lym- neoplasia MEN2A, MEN2B and medullary thyroid carci- 35 phoid tyrosine kinase); BMPR2 (Bone morphogenetic noma 1, Hirschsprung disease)); RHOK (Rhodopsin ki- protein receptor, type II (serine/threonine kinase)); BMX nase); ROCK1 (Rho-associated, coiled-coil containing (BMX non-receptor tyrosine kinase); BRAF (V-raf murine protein kinase 1); RPS6KA2 (Ribosomal protein S6 ki- sarcoma viral oncogene homolog B1); BTK (Bruton ag- nase, 90kD, polypeptide 2); RPS6KB1 (Ribosomal pro- ammaglobulinemia tyrosine kinase); CAK (Cell adhesion tein S6 kinase, 70kD, polypeptide 1); RYK (RYK recep- 40 kinase); CALM1 (Calmodulin 1 (phosphorylase kinase, tor-like tyrosine kinase); SAPK3 (Stress-activated pro- delta)); CAMK4 (Calcium/calmodulin-dependent protein tein kinase 3); SERK1 (SAPK/Erk kinase 1); SRC (V-src kinase IV); CBLB (Cas-Br-M (murine) ectropic retroviral avian sarcoma (Schmidt-Ruppin A-2) viral oncogene ho- transforming sequence b); CD44 (CD44 antigen (homing molog); SRF ( (c-fos serum re- function and Indian blood group system)); CD47 (CD47 sponse element-binding transcription factor)); SRPK2 45 antigen (Rh-related antigen, integrin-associated signal (SFRS protein kinase 2); STK11 (Serine/threonine ki- transducer)); CD48 (CD48 antigen (B-cell membrane nase 11 (Peutz-Jeghers syndrome)); STK2 (Serine/thre- protein)); CD58 (CD58 antigen, (lymphocyte function-as- onine kinase 2); STK3 (Serine/threonine kinase 3 (Ste20, sociated antigen 3)); CD69 (CD69 antigen (p60, early T- yeast homolog)); STK4 (Serine/threonine kinase 4); SYK cell activation antigen)); CDC25A (Cell division cycle (Spleen tyrosine kinase); TCEB1L (Transcription elon- 50 25A); CDC25C (Cell division cycle 25C); CDC2L1 (Cell gation factor B (SIII), polypeptide 1-like); TESK1 (Testis- division cycle 2-like 1 (PITSLRE proteins)); CDC42 (Cell specific kinase 1); TFDP2 (Transcription factor Dp-2 division cycle 42 (GTP-binding protein, 25kD)); CDC42 (E2F dimerization partner 2)); TGFBI (Transforming (Cell division cycle 42 (GTP-binding protein, 25kD)); growth factor, beta-induced, 68kD); TIEG (TGFB induc- CDC7L1 (CDC7 (cell division cycle 7, S. cerevisiae, ho- ible early growth response); TK2 (Thymidine kinase 2, 55 molog)-like 1); CDH13 ( 13, H-cadherin (heart)); mitochondrial); TNFAIP1 (Tumor necrosis factor, alpha- CDH17 (Cadherin 17, LI cadherin (liver-intestine)); induced protein 1 (endothelial)); TNFSF5 (Tumor necro- CDH2 (Cadherin 2, N-cadherin (neuronal)); CDH4 (Cad- sis factor (ligand) superfamily, member 5); TS546 (Tem- herin 4, R-cadherin (retinal)); CDH5 (Cadherin 5, VE-

15 29 EP 1 364 069 B1 30 cadherin (vascular epithelium)); CDK2 (Cyclin-depend- beta 1, 32kD (connexin 32, Charcot-Marie-Tooth neu- ent kinase 2); CDK5 (Cyclin-dependent kinase 5); CDK6 ropathy, X-linked)); GLA (Galactosidase, alpha); GNAI1 (Cyclin-dependent kinase 6); CDK7 (Cyclin-dependent (Guanine nucleotide binding protein (G protein), alpha kinase 7 (homolog of Xenopus MO15 cdk-activating ki- inhibiting activity polypeptide 1); GNG 10 (Guanine nu- nase)); CDK8 (Cyclin-dependent kinase 8); CDKN2B 5 cleotide binding protein 10); GPRK6 (G protein-coupled (Cyclin-dependent kinase inhibitor 2B (p15, inhibits receptor kinase 6); GRB2 (Growth factor receptor-bound CDK4)); CHEK1 (CHUK1 (checkpoint, S.pombe) ho- protein 2); HMMR (Hyaluronan-mediated motility recep- molog); CHUK (Conserved helix-loop-helix ubiquitous ki- tor (RHAMM)); HMR ( (growth factor- nase); CKS1 (CDC28 protein kinase 1); CKS2 (CDC28 inducible nuclear protein N10)); ICAM1 (Intercellular ad- protein kinase 2); CLGN (Calmegin); CLK2 (CDC-like ki- 10 hesion molecule 1 (CD54), human rhinovirus receptor); nase 2); CLK3 (CDC-like kinase 3); CLTB (Clathrin, ICAM2 (Intercellular adhesion molecule 2); ICAM3 (Inter- polypeptide (Lcb)); CNK (-inducible kinase); cellular adhesion molecule 3); IFI16 (Interferon, gamma- COT (Cot (cancer Osaka thyroid) oncogene); CSNK1A1 inducible protein 16); IFI56 (Interferon-induced protein (Casein kinase 1, alpha 1); CSNK1D (Casein kinase 1, 56); IFIT4 (Interferon-induced protein with tetratricopep- delta); CSNK1E (Casein kinase 1, epsilon); CSNK2A2 15 tide repeats 4); IGFBP1 (Insulin-like growth factor binding (Casein kinase 2, alpha prime polypeptide); CSNK2B protein 1); ILK (Integrin-linked kinase); INP10 (Interferon (Casein kinase 2, beta polypeptide); CTNNA1 (Catenin (gamma)-induced cell line; protein 10 from); INPP5D (In- (cadherin-associated protein), alpha 1 (102kD)); ositol polyphosphate-5-phosphatase, 145kD); ISG20 CTNNB1 (Catenin (cadherin-associated protein), beta 1 (Interferon stimulated gene (20kD)); ITGA2 (Integrin, al- (88kD)); CTNND2 (Catenin (cadherin-associated pro- 20 pha 2 (CD49B, alpha 2 subunit of VLA-2 receptor)); tein), delta 2 (neural plakophilin-related arm-repeat pro- ITGA3 (Integrin, alpha 3 (antigen CD49C, alpha 3 subunit tein)); DAPK1 (Death-associated protein kinase 1); DG- of VLA-3 receptor)); ITGA4 (Integrin, alpha 4 (antigen KA (Diacylglycerol kinase, alpha (80kD)); DGKG (Dia- CD49D, alpha 4 subunit of VLA-4 receptor)); ITGA5 (In- cylglycerol kinase, gamma (90kD)); DGKQ (Diacylglyc- tegrin, alpha 5 (fibronectin receptor, alpha polypeptide)); erol kinase, theta (110kD)); DMPK (Dystrophia myotoni- 25 ITGA6 (Integrin, alpha 6); ITGA7 (Integrin, alpha 7); ca-protein kinase); DUSP3 (Dual specificity phosphatase ITGA9 (Integrin, alpha 9); ITGAE (Integrin, alpha E (an- 3 (vaccinia virus phosphatase VH1-related)); DUSP4 tigen CD103, human mucosal lymphocyte antigen 1; al- (Dual specificity phosphatase 4); DVL3 (Dishevelled 3 pha polypeptide)); ITGAL (Integrin, alpha L (antigen (homologous to Drosophila dsh)); DYRK1 (Dual-specif- CD11A (p180), lymphocyte function-associated antigen icity tyrosine-(Y)-phosphorylation regulated kinase 1); 30 1; alpha polypeptide)); ITGAM (Integrin, alpha M (com- EFNA1 (Ephrin-A1); EFNA5 (Ephrin-A5); EFNB1 plement component receptor 3, alpha; also known as (Ephrin-B1); EFNB2 (Ephrin-B2); EGR1 (Early growth re- CD11b (p170), antigen alpha polypeptide)); sponse 1); EGR3 (Early growth response 3); EGR4 (Ear- ITGAV (Integrin, alpha V (vitronectin receptor, alpha ly growth response 4); EPHA2 (EphA2); EPHA4 (EphA4); polypeptide, antigen CD51)); ITGAX (Integrin, alpha X EPHA5 (EphA5); EPHA7 (EphA7); EPHB3 (EphB3); 35 (antigen CD11C (p150), alpha polypeptide)); ITGB1 (In- EPHB4 (EphB4); EPHB6 (EphB6); ERBB3 (V-erb-b2 avi- tegrin, beta 1 (fibronectin receptor, beta polypeptide, an- an erythroblastic leukemia viral oncogene homolog 3); tigen CD29 includes MDF2, MSK12)); ITGB2 (Integrin, FAP (Fibroblast activation protein, alpha); FAT (FAT tu- beta 2 (antigen CD18 (p95), lymphocyte function-asso- mor suppressor (Drosophila) homolog); FBL (Fibrillarin); ciated antigen 1; macrophage antigen I (mac-1) beta sub- FES (Feline sarcoma (Snyder-Theilen) viral (v-fes)/Fuji- 40 unit)); ITGB3 (Integrin, beta 3 (platelet glycoprotein IIIa, nami avian sarcoma (PRCII) viral (v-fps) oncogene ho- antigen CD61)); ITGB4 (Integrin, beta 4); ITGB5 (In- molog); FGFR1 (Fibroblast growth factor receptor 1 (fms- tegrin, beta 5); ITGB7 (Integrin, beta 7); ITGB8 (Integrin, related tyrosine kinase 2, Pfeiffer syndrome)); FGFR2 beta 8); ITPKB (Inositol 1,4,5-trisphosphate 3-kinase B); (Fibroblast growth factor receptor 2 (bacteria-expressed JAK1 ( (a protein tyrosine kinase)); JAK3 kinase, keratinocyte growth factor receptor, craniofacial 45 (Janus kinase 3 (a protein tyrosine kinase, leukocyte)); dysostosis 1, Crouzon syndrome, Pfeiffer syndrome, KCNN3 (Potassium intermediate/small conductance cal- Jackson-Weiss syndrome)); FGR (Gardner-Rasheed fe- cium-activated channel, subfamily N, member 3); KDR line sarcoma viral (v-fgr) oncogene homolog); FLNA (Fil- (Kinase insert domain receptor (a type III receptor tyro- amin A, alpha (actin-binding protein-280)); FLT1 (Fms- sine kinase)); KPNB1 (Karyopherin () beta 1); related tyrosine kinase 1 (vascular endothelial growth 50 LCAT (Lecithin-cholesterol acyltransferase); LIMK1 (LIM factor/vascular permeability factor receptor)); FLT3LG domain kinase 1); LIMK2 (LIM domain kinase 2); LRP1 (Fms-related tyrosine kinase 3 ligand); FLT4 (Fms-relat- (Low density lipoprotein-related protein 1 (alpha-2-mac- ed tyrosine kinase 4); FN1 (Fibronectin 1); FRK (Fyn- roglobulin receptor)); LTK (Leukocyte tyrosine kinase); related kinase); FYB (FYN-binding protein (FYB- LY6E (Lymphocyte antigen 6 complex, locus E); MADH1 120/130)); G1P3 (Interferon, alpha-inducible protein 55 (MAD (mothers against decapentaplegic, Drosophila) (clone IFI-6-16)); GBP1 (Guanylate binding protein 1, in- homolog 1); MADH2 (MAD (mothers against decapen- terferon-inducible, 67kD); GBP2 (Guanylate binding pro- taplegic, Drosophila) homolog 2); MADH3 (MAD (moth- tein 2, interferon-inducible); GJB1 (Gap junction protein, ers against decapentaplegic, Drosophila) homolog 3);

16 31 EP 1 364 069 B1 32

MAP1B (Microtubule-associated protein 1B); MATK (B56), alpha isoform); PPP2R5B (Protein phosphatase (Megakaryocyte-associated tyrosine kinase); MCL 1 2, regulatory subunit B (B56), beta isoform); PPP2R5D (Myeloid cell leukemia sequence 1 (BCL2-related)); (Protein phosphatase 2, regulatory subunit B (B56), delta MEKK3 (MAP/ERK kinase kinase 3); MEKK5 (MAP/ERK isoform); PPP2R5E (Protein phosphatase 2, regulatory kinase kinase 5); MST1R (Macrophage stimulating 1 re- 5 subunit B (B56), epsilon isoform); PPP3CA (Protein ceptor (c-met-related tyrosine kinase)); MX1 (Myxovirus phosphatase 3 (formerly 2B), catalytic subunit, alpha iso- (influenza) resistance 1, homolog of murine (interferon- form (calcineurin A alpha)); PPP3CB (Protein phos- inducible protein p78)); MX2 (Myxovirus (influenza) re- phatase 3 (formerly 2B), catalytic subunit, beta isoform sistance 2, homolog of murine); MYL2 (Myosin, light (calcineurin A beta)); PPP4C (Protein phosphatase 4 polypeptide 2, regulatory, cardiac, slow); MYL3 (Myosin, 10 (formerly X), catalytic subunit); PRKAA2 (Protein kinase, light polypeptide 3, alkali; ventricular, skeletal, slow); AMP-activated, alpha 2 catalytic subunit); PRKACA (Pro- NCAM1 (Neural 1); NCK1 (NCK tein kinase, cAMP-dependent, catalytic, alpha); adaptor protein 1); NEK3 (NIMA (never in mitosis gene PRKACB (Protein kinase, cAMP-dependent, catalytic, a)-related kinase); NME1 (Non-metastatic cells 1, protein beta); PRKACG (Protein kinase, cAMP-dependent, cat- (NM23A) expressed in); NME2 (Non-metastatic cells 2, 15 alytic, gamma); PRKAG1 (Protein kinase, AMP-activat- protein (NM23B) expressed in); NOS2A (Nitric oxide syn- ed, gamma 1 non-catalytic subunit); PRKAR1A (Protein thase 2A (inducible, hepatocytes)); NPM1 (Nucleophos- kinase, cAMP-dependent, regulatory, type I, alpha (tis- min (nucleolar phosphoprotein B23, numatrin)); NTRK3 sue specific extinguisher 1)); PRKAR1B (Protein kinase, (Neurotrophic tyrosine kinase, receptor, type 3); OAS1 cAMP-dependent, regulatory, type I, beta); PRKAR2B (2’,5’-oligoadenylate synthetase 1); OCLN (Occludin); 20 (Protein kinase, cAMP-dependent, regulatory, type II, be- PCDH1 ( 1 (cadherin-like 1)); PCTK3 ta); PRKCA (Protein kinase C, alpha); PRKCB1 (Protein (PCTAIRE protein kinase 3); PDE4B (Phosphodieste- kinase C, beta 1); PRKCG (Protein kinase C, gamma); rase 4B, cAMP-specific (dunce (Drosophila)-homolog PRKCI (Protein kinase C, iota); PRKCL1 (Protein kinase phosphodiesterase E4)); PDGFRB (Platelet-derived C-like 1); PRKCL2 (Protein kinase C-like 2); PRKCM growth factor receptor, beta polypeptide); PDK2 (Pyru- 25 (Protein kinase C, mu); PRKCQ (Protein kinase C, theta); vate dehydrogenase kinase, isoenzyme 2); PDK4 (Pyru- PRKCZ (Protein kinase C, zeta); PRKG1 (Protein kinase, vate dehydrogenase kinase, isoenzyme 4); PDPK1 (3- cGMP-dependent, type I); PRKG2 (Protein kinase, phosphoinositide dependent protein kinase-1); PECAM1 cGMP-dependent, type II); PRKM1 (Protein kinase, mi- (Platelet/endothelial cell adhesion molecule (CD31 anti- togen-activated 1 (MAP kinase 1; p40, p41)); PRKM10 gen)); PGY3 (P glycoprotein 3/multiple drug resistance 30 (Protein kinase mitogen-activated 10 (MAP kinase)); 3); PHKA2 (Phosphorylase kinase, alpha 2 (liver), glyco- PRKM11 (Protein kinase mitogen- activated 11); PRKM gen storage disease IX); PHKG2 (Phosphorylase kinase, 13 (Protein kinase mitogen-activated 13); PRKM3 (Pro- gamma 2 (testis)); PIK3C3 (Phosphoinositide-3-kinase, tein kinase, mitogen-activated 3 (MAP kinase 3; p44)); class 3); PIK3CA (Phosphoinositide-3-kinase, catalytic, PRKM6 (Protein kinase, mitogen-activated 6 (extracel- alpha polypeptide); PIK3CA (Phosphoinositide-3-ki- 35 lular signal-regulated kinase, p97)); PRKM7 (Protein ki- nase, catalytic, alpha polypeptide); PIK3CG (Phosphoi- nase mitogen-activated 7 (MAP kinase)); PRKM8 (Pro- nositide-3-kinase, catalytic, gamma polypeptide); PIM1 tein kinase mitogen-activated 8 (MAP kinase)); PRKM9 (Pim-1 oncogene); PKD1 (Polycystic kidney disease 1 (Protein kinase mitogen-activated 9 (MAP kinase)); (autosomal dominant)); PLA2G2A (Phospholipase A2, PRKMK2 (Protein kinase, mitogen-activated, kinase 2, group IIA (, synovial fluid)); PLCB4 (Phospholi- 40 p45 (MAP kinase kinase 2)); PRKMK3 (Protein kinase, pase C, beta 4); PLCE (, epsilon); mitogen-activated, kinase 3 (MAP kinase kinase 3)); PLCG2 (Phospholipase C, gamma 2 (phosphatidylinosi- PRKMK5 (Protein kinase, mitogen-activated, kinase 5 tol-specific)); PPP1CA (Protein phosphatase 1, catalytic (MAP kinase kinase 5)); PRKMK7 (Protein kinase, mi- subunit, alpha isoform); PPP1CB (Protein phosphatase togen-activated, kinase 7 (MAP kinase kinase 7)); PRKR 1, catalytic subunit, beta isoform); PPP1CC (Protein 45 (Protein kinase, interferon-inducible double stranded phosphatase 1, catalytic subunit, gamma isoform); RNA dependent); PRKR (Protein kinase, interferon-in- PPP1R3 (Protein phosphatase 1, regulatory (inhibitor) ducible double stranded RNA dependent); PSME1 (Pro- subunit 3 (glycogen and sarcoplasmic reticulum binding teasome (prosome, macropain) activator subunit 1 subunit, skeletal muscle)); PPP2CA (Protein phos- (PA28 alpha)); PTEN (Phosphatase and tensin homolog phatase 2 (formerly 2A), catalytic subunit, alpha isoform); 50 (mutated in multiple advanced cancers 1)); PTK7 (PTK7 PPP2R1B (Protein phosphatase 2 (formerly 2A), regu- protein tyrosine kinase 7); PTK9 (Protein tyrosine kinase latory subunit A (PR 65), beta isoform); PPP2R2A (Pro- 9); PTPN1 (Protein tyrosine phosphatase, non-receptor tein phosphatase 2 (formerly 2A), regulatory subunit B type 1); PTPN12 (Protein tyrosine phosphatase, non-re- (PR 52), alpha isoform); PPP2R3 (Protein phosphatase ceptor type 12); PTPN13 (Protein tyrosine phosphatase, 2 (formerly 2A), regulatory subunit B" (PR 72), alpha iso- 55 non-receptor type 13 (APO-1/CD95 (Fas)-associated form and (PR 130), beta isoform); PPP2R4 (Protein phosphatase)); PTPN2 (Protein tyrosine phosphatase, phosphatase 2A, regulatory subunit B’ (PR 53)); non-receptor type 2); PTPN3 (Protein tyrosine phos- PPP2R5A (Protein phosphatase 2, regulatory subunit B phatase, non-receptor type 3); PTPN4 (Protein tyrosine

17 33 EP 1 364 069 B1 34 phosphatase, non-receptor type 4 (megakaryocyte)); growth response); TK2 (Thymidine kinase 2, mitochon- PTPN6 (Protein tyrosine phosphatase, non-receptor drial); TNFAIP1 (Tumor necrosis factor, alpha-induced type 6); PTPN7 (Protein tyrosine phosphatase, non-re- protein 1 (endothelial)); TNFAIP1 (Tumor necrosis factor, ceptor type 7); PTPN9 (Protein tyrosine phosphatase, alpha-induced protein 1 (endothelial)); TNFSF5 (Tumor non-receptor type 9); PTPRA (Protein tyrosine phos- 5 necrosis factor (ligand) superfamily, member 5); TTK phatase, receptor type, alpha polypeptide); PTPRB (Pro- (TTK protein kinase); TTN (); TUBA1 (, alpha tein tyrosine phosphatase, receptor type, beta polypep- I (testis specific)); TUBG (Tubulin, gamma polypeptide); tide); PTPRC (Protein tyrosine phosphatase, receptor TXK (TXK tyrosine kinase); TYK2 (Tyrosine kinase 2); type, c polypeptide); PTPRD (Protein tyrosine phos- TYRO3 (TYRO3 protein tyrosine kinase); UBE1L (Ubiq- phatase, receptor type, D); PTPRF (Protein tyrosine 10 uitin-activating enzyme E1, like); UBE2A (Ubiquitin-con- phosphatase, receptor type, F); PTPRG (Protein tyrosine jugating enzyme E2A (RAD6 homolog)); UBE2B (Ubiq- phosphatase, receptor type, gamma polypeptide); PT- uitin-conjugating enzyme E2B (RAD6 homolog)); VASP PRH (Protein tyrosine phosphatase, receptor type, H); (Vasodilator-stimulated phosphoprotein); VAV2 (Vav 2 PTPRK (Protein tyrosine phosphatase, receptor type, K); oncogene); VCAM1 (Vascular cell adhesion molecule 1); PTPRM (Protein tyrosine phosphatase, receptor type, 15 VCL (); VIM (Vimentin); VRK2 (Vaccinia related M); PTPRN (Protein tyrosine phosphatase, receptor kinase 2); WAS (Wiskott-Aldrich syndrome (ecezema- type, N); PTPRN2 (Protein tyrosine phosphatase, recep- thrombocytopenia)); ZAP70 (Zeta-chain (TCR) associat- tor type, N polypeptide 2); PTX3 (Pentaxin-related gene, ed protein kinase (70 kD)); and ZPK (Zipper (leucine) rapidly induced by IL-1 beta); RAB8IP (Rab8 interacting protein kinase). protein (GC kinase)); RAB8IP (Rab8 interacting protein 20 (GC kinase)); RAD9 (RAD9 (S. pombe) homolog); Development RASA1 (RAS p21 protein activator (GTPase activating protein) 1); RET (Ret proto-oncogene (multiple endo- [0083] ACCPN (Agenesis of corpus callosum and pe- crine neoplasia MEN2A, MEN2B and medullary thyroid ripheral neuropathy (Andermann); ACVR1 (Activin A re- carcinoma 1, Hirschsprung disease)); RGS1 (Regulator 25 ceptor, type I); ACVR1B (Activin A receptor, type IB); of G-protein signalling 1); RGS 16 (Regulator of G-protein ACVR2 (Activin A receptor, type II); ACVR2B (Activin A signalling 16); RGS7 (Regulator of G-protein signalling receptor, type IIB); ACVRL1 (Activin A receptor type II- 7); RHOK (Rhodopsin kinase); ROCK1 (Rho-associated, like 1); ADFN (Albinism-deafness syndrome); AES (Ami- coiled-coil containing protein kinase 1); RPS6KA2 (Ri- no-terminal enhancer of split); AFD1 (Acrofacial dysos- bosomal protein S6 kinase, 90kD, polypeptide 2); 30 tosis 1, Nager type); AGC1 (Aggrecan 1 (chondroitin sul- RPS6KB 1 (Ribosomal protein S6 kinase, 70kD, polypep- fate proteoglycan 1, large aggregating proteoglycan, an- tide 1); RSN (Restin (Reed-Steinberg cell-expressed in- tigen identified by monoclonal antibody A0122)); AHO2 termediate filament-associated protein)); RYK (RYK re- (Albright hereditary osteodystrophy-2); AIH3 (Amelogen- ceptor-like tyrosine kinase); SAPK3 (Stress-activated esis imperfecta 3, hypomaturation or hypoplastic type); protein kinase 3); SELE (Selectin E (endothelial adhesion 35 ALX3 (Aristaless-like 3); AMCD1 (Arthro- molecule 1)); SELL (Selectin L (lymphocyte adhesion gryposis multiplex congenital, distal, type 1); AMCD2B molecule 1)); SELP (Selectin P (granule membrane pro- (Arthrogryposis multiplex congenita, distal, type 2B); tein 140kD, antigen CD62)); SERK1 (SAPK/Erk kinase AMCN (Arthrogryposis multiplex congenita, neurogenic); 1); SFN (Stratifin); SH3D1B (SH3 domain protein 1B); AMCX1 (Arthrogryposis multiplex congenita, X-linked SLC2A3 (Solute carrier family 2 (facilitated glucose trans- 40 (spinal muscular atrophy,); AMDM (Acromesomelic dys- porter), member 3); SLC2A5 (Solute carrier family 2 (fa- plasia, Maroteaux type); AMH (Anti-Mullerian hormone); cilitated glucose transporter), member 5); SPTA1 (Spec- AMHR2 (Anti-Mullerian hormone receptor, type II); AM- trin, alpha, erythrocytic 1 (elliptocytosis 2)); SPTB (Spec- MECRI (Alport syndrome, mental retardation, midface trin, beta, erythrocytic (includes sperocytosis, clinical hypoplasia and elliptocytosis chromosomal region, gene type I)); SRC (V-src avian sarcoma (Schmidt-Ruppin A- 45 1); ANOP1 (Anophthalmos 1 (with mental retardation, 2) viral oncogene homolog); SRF (Serum response factor without limb anomalies or dental or urogenital abnormal- (c-fos serum response element-binding transcription fac- ities)); APC (Adenomatosis polyposis coli); ARIX (Arista- tor)); SRPK2 (SFRS protein kinase 2); STK11 (Serine/ less (Drosophila) homeobox); ARVCF (Armadillo repeat threonine kinase 11 (Peutz-Jeghers syndrome)); STK2 gene deletes in velocardiofacial syndrome); ASCL1 (Serine/threonine kinase 2); STK3 (Serine/threonine ki- 50 (Achaete-scute complex (Drosophila) homolog-like 1); nase 3 (Ste20, yeast homolog)); STK4 (Serine/threonine ASCL2 (Achaete-scute complex (Drosophila) homolog- kinase 4); SYK (Spleen tyrosine kinase); TAP1 (Trans- like 2); ASH2L (Ash2 (absent, small, or homeotic, Dro- porter 1, ABC (ATP binding cassette)); TAPBP (TAP sophila, homolog)-like); ASMD (Anterior segment mes- binding protein (tapasin)); TBCC (Tubulin-specific chap- enchymal dysgenesis); ATD (Asphixiating thoracic dys- erone c); TESK1 (Testis-specific kinase 1); TGFBI 55 trophy (chondroectodermal dysplasia-like syndrome)); (Transforming growth factor, beta-induced, 68kD); ATF4 (Activating transcription factor 4 (tax-responsive THBS1 (Thrombospondin 1); TIAM1 (T-cell lymphoma enhancer element B67)); AXIN1 (Axin); AXIN2 (Axin 2 invasion and metastasis 1); TIEG (TGFB inducible early (conductin, axil)); BAD (BCL2-antagonist of cell death);

18 35 EP 1 364 069 B1 36

BAPX1 (Bagpipe homeobox (Drosophila) homolog 1); FKHL7 (Forkhead (Drosophila)-like 7); (Frizzled- BARD1 (BRCA1 associated RING domain 1); BARX2 related protein); FZD 1 (Frizzled (Drosophila) homolog (BarH-like homeobox 2); BAX (BCL2-associated X pro- 1); FZD2 (Frizzled (Drosophila) homolog 2); FZD3 (Friz- tein); BDB 1 (Brachydactyly type B1); BDC (); BDE zled (Drosophila) homolog 3); FZD4 (Frizzled (Drosophi- (Brachydactyly type E); BDMR (Brachydactyly-mental 5 la) homolog 4); FZD5 (Frizzled (Drosophila) homolog 5); retardation syndrome); BDNF (Brain-derived neuro- FZD6 (Frizzled (Drosophila) homolog 6); FZD7 (Frizzled trophic factor); BMP1 (Bone morphogenetic protein 1); (Drosophila) homolog 7); FZD8 (Frizzled (Drosophila) BMP2 (Bone morphogenetic protein 2); BMP3 (Bone homolog 8); FZD9 (Frizzled (Drosophila) homolog 9); morphogenetic protein 3 (osteogenic)); BMP4 (Bone GDF5 (Growth differentiation factor 5 (cartilage-derived morphogenetic protein 4); BMP5 (Bone morphogenetic 10 morphogenetic protein-1)); GLI (Glioma-associated on- protein 5); BMP6 (Bone morphogenetic protein 6); BMP7 cogene homolog (zinc finger protein)); GLI2 (GLI-Krup- (Bone morphogenetic protein 7 (osteogenic protein 1)); pel family member GLI2); GLI3 (GLI-Kruppel family mem- BMPR1A (Bone morphogenetic protein receptor, type ber GLI3 (Greig cephalopolysyndactyly syndrome)); IA); BMPR1B (Bone morphogenetic protein receptor, GLI4 (GLI-Kruppel family member GLI4); GSC (Goose- type IB); BMPR2 (Bone morphogenetic protein receptor, 15 coid); GSCL (Goosecoid-like); HESX1 (Homeo box gene type II (serine/threonine kinase)); CBFA1 (Core-binding expressed in ES cells; Rathke pouch homeo box); factor, runt domain, alpha subunit 1); CBFA2 (Core-bind- HLXB9 (Homeo box HB9); HNF3A (Hepatocyte nuclear ing factor, runt domain, alpha subunit 2 (acute myeloid factor 3, alpha); HNF3B (Hepatocyte nuclear factor 3, leukemia 1; aml1 oncogene)); CBFA3 (Core-binding fac- beta); HNF3G (Hepatocyte nuclear factor 3, gamma); tor, runt domain, alpha subunit 3); CER1 (Cerberus 1 20 HNF4A (Hepatocyte nuclear factor 4, alpha); HNF4B (Xenopus laevis) homolog (cysteine knot superfamily)); (Hepatocyte nuclear factor 4, beta); HNF4G (Hepatocyte CHH (Cartilage-hair hypoplasia); CHRD (Chordin); nuclear factor 4, gamma); HNF6A (Hepatocyte nuclear CHX10 (C elegans ceh-10 homeo domain-containing ho- factor 6, alpha); HOX11 (Homeo box 11 (T-cell lympho- molog); CREB2 (CAMP responsive element binding pro- ma 3-associated breakpoint)); HOXA1 (Homeo box A1); tein 2); CSH2 (Chorionic somatomammotropin hormone 25 HOXA10 (Homeo box A10); HOXA11 (Homeo box A11); 2); DLK1 (Delta (Drosophila)-like 1); EBAF (Endometrial HOXA13 (Homeo box A 13); HOXA2 (Homeo box A2); bleeding associated factor (left-right determination, fac- HOXA3 (Homeo box A3); HOXA4 (Homeo box A4); tor A; transforming growth factor beta superfamily)); HOXA5 (Homeo box A5); HOXA6 (Homeo box A6); EDN1 ( 1); EDN2 (); EDN3 (En- HOXA7 (Homeo box A7); HOXA9 (Homeo box A9); dothelin 3); EDNRA ( type A); ED- 30 HOXA@ (Homeo box A cluster); HOXB1 (Homeo box NRB (Endothelin receptor type B); EDR2 (Early devel- B1); HOXB2 (Homeo box B2); HOXB3 (Homeo box B3); opment regulator 2 (homolog of polyhomeotic 2)); EED HOXB4 (Homeo box B4); HOXB5 (Homeo box B5); (Embryonic ectoderm development protein); EFNA5 HOXB6 (Homeo box B6); HOXB7 (Homeo box B7); (Ephrin-A5); EN1 ( homolog 1); EN2 (Engrailed HOXB8 (Homeo box B8); HOXB9 (Homeo box B9); homolog 2); ENG (Endoglin (Osler-Rendu-Weber syn- 35 HOXC10 (Homeo box C10); HOXC11 (Homeo box C11); drome 1)); EOMES ( (Xenopus laevis) HOXC12 (Homeo box C12); HOXC13 (Homeo box C13); homology); EPHA2 (EphA2); EPHB2 (EphB2); FAST-1 HOXC4 (Homeo box C4); HOXC5 (Homeo box C5); (Human homolog of Xenopus forkhead activin signal HOXC6 (Homeo box C6); HOXC8 (Homeo box C8); transducer-1); FGD1 (Faciogenital dysplasia (Aarskog- HOXC9 (Homeo box C9); HOXD1 (Homeo box D1); Scott syndrome)); FGF1 (Fibroblast growth factor 1 (acid- 40 HOXD10 (Homeo box D10); HOXD11 (Homeo box D11); ic)); FGF10 (Fibroblast growth factor 10); FGF13 (Fibrob- HOXD12 (Homeo box D12); HOXD13 (Homeo box D13); last growth factor 13); FGF14 (Fibroblast growth factor HOXD3 (Homeo box D3); HOXD4 (Homeo box D4); 14); FGF16 (Fibroblast growth factor 16); FGF2 (Fibrob- HOXD8 (Homeo box D8); HOXD9 (Homeo box D9); IHH last growth factor 2 (basic)); FGF3 (Fibroblast growth fac- (Indian hedgehog (Drosophila) homolog); INHBA (Inhib- tor 3 (murine mammary tumor virus integration site (v- 45 in, beta A (activin A, activin AB alpha polypeptide)); IN- int-2) oncogene homolog)); FGF4 (Fibroblast growth fac- HBB (Inhibin, beta B (activin AB beta polypeptide)); ISL1 tor 4 (heparin secretory transforming protein 1, Kaposi (ISL1 transcription factor, LIM/homeodomain, (islet-1)); sarcoma oncogene)); FGF7 (Fibroblast growth factor 7 JAG1 (Jagged1 (Alagille syndrome)); JAG2 (Jagged 2); (keratinocyte growth factor)); FGF8 (Fibroblast growth LEF1 (Lymphoid enhancer-binding factor 1); LHX1 (LIM factor 8 (androgen-induced)); FGFR1 (Fibroblast growth 50 homeobox protein 1); LHX2 (LIM HOX gene 2); LHX3 factor receptor 1 (fms-related tyrosine kinase 2, Pfeiffer (LIM/homeodomain protein LHX3); LMX1A (LIM home- syndrome)); FGFR2 (Fibroblast growth factor receptor 2 obox transcription factor 1, alpha); LMX1B (LIM home- (bacteria-expressed kinase, keratinocyte growth factor obox transcription factor 1, beta); MADH1 (MAD (moth- receptor, craniofacial dysostosis 1, Crouzon syndrome, ers against decapentaplegic, Drosophila) homolog 1); Pfeiffer syndrome, Jackson-Weiss syndrome)); FGFR3 55 MADH2 (MAD (mothers against decapentaplegic, Dro- (Fibroblast growth factor receptor 3 (achondroplasia, sophila) homolog 2); MADH3 (MAD (mothers against de- thanatophoric dwarfism)); FGFR4 (Fibroblast growth fac- capentaplegic, Drosophila) homolog 3); MADH4 (MAD tor receptor 4); FKHL16 (Forkhead (Drosophila)-like 16); (mothers against decapentaplegic, Drosophila) homolog

19 37 EP 1 364 069 B1 38

4); MADH5 (MAD (mothers against decapentaplegic, (Drosophila) homolog); SOX1 (SRY (sex determining re- Drosophila) homolog 5); MADH6 (MAD (mothers against gion Y)-box 1); SOX10 (SRY (sex-determining region decapentaplegic, Drosophila) homolog 6); MADH7 (MAD Y)-box 10); (SRY (sex determining region Y)-box (mothers against decapentaplegic, Drosophila) homolog 2); SOX9 (SRY (sex-determining region Y)-box 9 (cam- 7); MADH9 (MAD (mothers against decapentaplegic, 5 pomelic dysplasia, autosomal sex-reversal)); SRF (Se- Drosophila) homolog 9); MEIS1 (Meis1 (mouse) ho- rum response factor (c-fos serum response element- molog); MEIS2 (Meis (mouse) homolog 2); MEIS3 (Meis binding transcription factor)); STAT3 (Signal transducer (mouse) homolog 3); MEKK5 (MAP/ERK kinase kinase and activator of transcription 3 (acute-phase response 5); MLLT1 (Myeloid/lymphoid or mixed-lineage leukemia factor)); T (T (mouse) homolog); TBX1 (T-box (trithorax (Drosophila) homolog); translocated to, 1); 10 1); TBX10 (T-box 10); TBX10 (T-box 10); TBX15 (T-box MSX1 (Msh (Drosophila) homeo box homolog 1 (formerly 15); TBX18 (T-box 18); TBX19 (T-box 19); TBX2 (T-box homeo box 7)); MSX2 (Msh (Drosophila) homeo box ho- 2); TBX3 (T-box 3 (ulnar mammary syndrome)); TBX4 molog 2); NOG (Noggin); ORW2 (Osler-Rendu-Weber (T-box 4); TBX5 (T-box 5); TBX6 (T-box 6); TBX7 (T-box syndrome 2); PAX1 (Paired box gene 1); PAX1 (Paired 7); TFAP2A (Transcription factor AP-2 alpha (activating box gene 1); PAX2 (Paired box gene 2); PAX3 (Paired 15 enhancer-binding protein 2 alpha)); TFAP2B (Transcrip- box gene 3 (Waardenburg syndrome 1)); PAX4 (Paired tion factor AP-2 beta (activating enhancer-binding pro- box gene 4); PAX5 (Paired box gene 5 (B-cell lineage tein 2 beta)); TFCOUP2 (Transcription factor COUP 2 specific activator protein)); PAX6 (Paired box gene 6 (an- (chicken ovalbumin upstream promoter 2, apolipoprotein iridia, keratitis)); PAX7 (Paired box gene 7); PAX8 regulatory protein)); TGFBR1 (Transforming growth fac- (Paired box gene 8); PAX9 (Paired box gene 9); PBX1 20 tor, beta receptor I (activin A receptor type II-like kinase, (Pre-B-cell leukemia transcription factor 1); PBX2 (Pre- 53kD)); TWIST (Twist (Drosophila) homolog); WNT1 B-cell leukemia transcription factor 2); PBX3 (Pre-B-cell (Wingless-type MMTV integration site family, member 1); leukemia transcription factor 3); PITX2 (Paired-like WNT10B (Wingless-type MMTV integration site family, homeodomain transcription factor 2); PKHD1 (Polycystic member 10B); WNT11 (Wingless-type MMTV integration kidney and hepatic disease 1 (autosomal recessive)); 25 site family, member 11); WNT14 (Wingless-type MMTV PROP1 (Prophet of Pit1, paired-like homeodomain tran- integration site family, member 14); WNT15 (Wingless- scription factor); PTCH (Patched (Drosophila) homolog); type MMTV integration site family, member 15); WNT2 PTCH2 (Patched (Drosophila) homolog 2); RARA (Retin- (Wingless-type MMTV integration site family member 2); oic acid receptor, alpha); RARB (, WNT2B (Wingless-type MMTV integration site family, beta); RARG (Retinoic acid receptor, gamma); RET (Ret 30 member 2B); WNT3 (Wingless-type MMTV integration proto-oncogene (multiple endocrine neoplasia MEN2A, site family, member 3); WNT5A (Wingless-type MMTV MEN2B and medullary thyroid carcinoma 1, Hirschs- integration site family, member 5A); WNT6 (Wingless- prung disease)); RIEG2 (Rieger syndrome 2); RXRA type MMTV integration site family, member 6); WNT7A (, alpha); RXRB (Retinoid X receptor, (Wingless-type MMTV integration site family, member beta); RXRG (Retinoid X receptor, gamma); SFRP1 (Se- 35 7A); WNT7B (Wingless-type MMTV integration site fam- creted frizzled-related protein 1); SFRP2 (Secreted friz- ily, member 7B); WNT8A (Wingless-type MMTV integra- zled-related protein 2); SFRP4 (Secreted frizzled-related tion site family, member 8A); WNT8B (Wingless-type protein 4); SFRP5 (Secreted frizzled-related protein 5); MMTV integration site family, member 8B); ZIC3 (Zic SHH (Sonic hedgehog (Drosophila) homolog); family member 3 (odd-paired Drosophila homolog, het- SMARCA2 (SWI/SNF related, matrix associated, actin 40 erotaxy 1)); and ZIC3 (Zic family member 3 (odd-paired dependent regulator of chromatin, subfamily a, member Drosophila homolog, heterotaxy 1)). 2); SMARCA4 (SWI/SNF related, matrix associated, ac- tin dependent regulator of chromatin, subfamily a, mem- DNA adducts ber 4); SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, 45 [0084] DFFA (DNA fragmentation factor, 45 kD, alpha member 1); SMARCC1 (SWI/SNF related, matrix asso- subunit); DNMT1 (DNA (cytosine-5-)-methyltransferase ciated, actin dependent regulator of chromatin, subfamily 1); DNMT2 (DNA (cytosine-5-)-methyltransferase 2); c, member 1); SMARCC2 (SWI/SNF related, matrix as- IGHMBP2 (Immunoglobulin mu binding protein 2); LIG1 sociated, actin dependent regulator of chromatin, sub- ( I, DNA, ATP-dependent); LIG3 (Ligase III, DNA, family c, member 2); SMARCD1 (SWI/SNF related, ma- 50 ATP-dependent); LIG4 (Ligase IV, DNA, ATP-depend- trix associated, actin dependent regulator of chromatin, ent); MGMT (O-6-methylguanine-DNA methyltrans- subfamily d, member 1); SMARCD2 (SWI/SNF related, ferase); NTHL1 (Nth (E.coli endonuclease III)-like 1); matrix associated, actin dependent regulator of chroma- PRIM1 (Primase, polypeptide 1 (49kD)); RAG1 (Recom- tin, subfamily d, member 2); SMARCD3 (SWI/SNF relat- bination activating gene 1); RFC3 (Replication factor C ed, matrix associated, actin dependent regulator of chro- 55 (activator 1) 3 (38kD)); RFC4 (Replication factor C (ac- matin, subfamily d, member 3); SMARCE1 (SWI/SNF tivator 1) 4 (37kD)); TERT (Telomerase reverse tran- related, matrix associated, actin dependent regulator of scriptase); TOP1 ( (DNA) I); TOP2A chromatin, subfamily e, member 1); SMOH ( (Topoisomerase (DNA) II alpha (170kD)); TOP2B

20 39 EP 1 364 069 B1 40

(Topoisomerase (DNA) II beta (180kD)); TOP3 (Topoi- meiotic segregation increased 2-like 2); PMS2L3 (Post- somerase (DNA) III); and TOP3B (Topoisomerase (DNA) meiotic segregation increased 2-like 3); PMS2L4 (Post- III beta). meiotic segregation increased 2-like 4); PMS2L5 (Post- meiotic segregation increased 2-like 5); PMS2L6 DNA damage 5 (Postmeiotic segregation increased 2-like 6); PMS2L8 (Postmeiotic segregation increased 2-like 8); PMS2L9 [0085] ADPRT (ADP-ribosyltransferase (NAD+; poly (Postmeiotic segregation increased 2-like 9); POLB (ADP-ribose) polymerase)); APEX (APEX nuclease (Polymerase (DNA directed), beta); PRIM1 (Primase, (multifunctional DNA repair enzyme)); ATM (Ataxia tel- polypeptide 1 (49kD)); PRKDC (Protein kinase, DNA-ac- angiectasia mutated (includes complementation groups 10 tivated, catalytic polypeptide); RAD1 (RAD1 (S. pombe) A, C and D)); BLM (Bloom syndrome); BRCA1 (Breast homolog); RAD17 (RAD17 (S. pombe) homolog); RAD21 cancer 1, early onset); BRCA2 (Breast cancer 2, early (RAD21 (S. pombe) homolog); RAD23A (RAD23 (S. cer- onset); CKN1 (Cockayne syndrome 1 (classical)); DDB1 evisiae) homolog A); RAD23B (RAD23 (S. cerevisiae) (Damage-specific DNA binding protein 1 (127kD)); DDB2 homolog B); RAD51 (RAD51 (S. cerevisiae) homolog (E (Damage-specific DNA binding protein 2 (48kD)); DDIT1 15 coli RecA homolog)); RAD51C (RAD51 (S. cerevisiae) (DNA-damage-inducible transcript 1); DDIT1L (DNA- homolog C); RAD51L1 (RAD51 (S. cerevisiae)-like 1); damage-inducible transcript 1-like); DDIT3 (DNA-dam- RAD51L3 (RAD51 (S. cerevisiae)-like 3); RAD52 age-inducible transcript 3); DFFA (DNA fragmentation (RAD52 (S. cerevisiae) homolog); RAD54L (RAD54 factor, 45 kD, alpha subunit); DNMT1 (DNA (cytosine- (S.cerevisiae)-like); RAG1 (Recombination activating 5-)-methyltransferase 1); DNMT2 (DNA (cytosine- 20 gene 1); RFC3 (Replication factor C (activator 1) 3 5-)-methyltransferase 2); ERCC1 (Excision repair cross- (38kD)); RFC4 (Replication factor C (activator 1) 4 complementing rodent repair deficiency, complementa- (37kD)); TDG (Thymine-DNA glycosylase); TERT (Tel- tion group 1 (includes overlapping antisense sequence)); omerase reverse transcriptase); TOP1 (Topoisomerase ERCC2 (Excision repair cross-complementing rodent re- (DNA) I); TOP2A (Topoisomerase (DNA) II alpha pair deficiency, complementation group 2 (xeroderma 25 (170kD)); TOP2B (Topoisomerase (DNA) II beta pigmentosum D)); ERCC3 (Excision repair cross-com- (180kD)); TOP3 (Topoisomerase (DNA) III); TOP3B plementing rodent repair deficiency, complementation (Topoisomerase (DNA) III beta); TP53 (Tumor protein group 3 (xeroderma pigmentosum group B complement- p53 (Li-Fraumeni syndrome)); TRLP1 (TRNA leucine ing)); ERCC5 (Excision repair cross-complementing ro- (AAG) pseudogene 1); UNG (Uracil-DNA glycosylase); dent repair deficiency, complementation group 5 (xero- 30 WRN (Werner syndrome); XPA (Xeroderma pigmento- derma pigmentosum, complementation group G sum, complementation group A); XPC (Xeroderma pig- (Cockayne syndrome))); ERCC6 (Excision repair cross- mentosum, complementation group C); XRCC1 (X-ray complementing rodent repair deficiency, complementa- repair complementing defective repair in Chinese ham- tion group 6); FANCA (Fanconi anemia, complementa- ster cells 1); XRCC2 (X-ray repair complementing defec- tion group A); FANCB (Fanconi anemia, complementa- 35 tive repair in Chinese hamster cells 2); XRCC3 (X-ray tion group B); FANCC (Fanconi anemia, complementa- repair complementing defective repair in Chinese ham- tion group C); FANCG (Fanconi anemia, complementa- ster cells 3); XRCC4 (X-ray repair complementing defec- tion group G); G22P1 (Thyroid autoantigen 70kD (Ku an- tive repair in Chinese hamster cells 4); XRCC5 (X-ray tigen)); GTBP (G/T mismatch-binding protein); repair complementing defective repair in Chinese ham- IGHMBP2 (Immunoglobulin mu binding protein 2); 40 ster cells 5 (double-strand-break rejoining; Ku autoanti- INPPL1 (Inositol polyphosphate phosphatase-like 1); gen, 80kD)); and XRCC8 (X-ray repair complementing LIG1 (Ligase I, DNA, ATP-dependent); LIG3 (Ligase III, defective repair in Chinese hamster cells 8). DNA, ATP-dependent); LIG3 (Ligase III, DNA, ATP-de- pendent); LIG4 (Ligase IV, DNA, ATP-dependent); MG- DNA replication MT (O-6-methylguanine-DNA methyltransferase); MLH1 45 (MutL (E. coli) homolog 1 (colon cancer, nonpolyposis [0086] ADAR (Adenosine deaminase, RNA-specific); type 2)); MPG (N-methylpurine-DNA glycosylase); ADPRT (ADP-ribosyltransferase (NAD+; poly (ADP-ri- MSH2 (MutS (E. coli) homolog 2 (colon cancer, nonpoly- bose) polymerase)); ATM (Ataxia telangiectasia mutated posis type 1)); MSH3 (MutS (E. coli) homolog 3); MSH4 (includes complementation groups A, C and D)); ATR (MutS (E. coli) homolog 4); MSH5 (MutS (E. coli) homolog 50 (Ataxia telangiectasia and Rad3 related); ATRX (Alpha 5); MTH1 (MutT (E. coli) human homolog (8-oxo-7,8-di- thalassemia/mental retardation syndrome X-linked); hydroguanosine triphosphatase)); NTHL1 (Nth (E.coli BLM (Bloom syndrome); CENPB ( protein B endonuclease III)-like 1); PMS1 (Postmeiotic segrega- (80kD)); CENPC1 (Centromere 1); CHD4 tion increased (S. cerevisiae) 1); PMS2 (Postmeiotic seg- (Chromodomain DNA binding protein 4); CHDL regation increased (S. cerevisiae) 2); PMS2L1 (Postmei- 55 (Chromodomain-helicase-DNA-binding protein); CKN1 otic segregation increased 2-like 1); PMS2L11 (Postmei- (Cockayne syndrome 1 (classical)); DNA2L (DNA2 (DNA otic segregation increased 2-like 11); PMS2L12 (Post- replication helicase, yeast, homolog)-like); DNASE1 (De- meiotic segregation increased 2-like 12); PMS2L2 (Post- oxyribonuclease I); DNASE1L1 (Deoxyribonuclease I-

21 41 EP 1 364 069 B1 42 like 1); DNASE1L2 (Deoxyribonuclease I-like 2); ERCC1 box-binding transcription factor); CBFA2 (Core-binding (Excision repair cross-complementing rodent repair de- factor, runt domain, alpha subunit 2 (acute myeloid leuke- ficiency, complementation group 1 (includes overlapping mia 1; aml1 oncogene)); CBFA3 (Core-binding factor, antisense sequence)); ERCC2 (Excision repair cross- runt domain, alpha subunit 3); CBFB (Core-binding fac- complementing rodent repair deficiency, complementa- 5 tor, beta subunit); CEBPA (CCAAT/enhancer binding tion group 2 (xeroderma pigmentosum D)); ERCC3 (Ex- protein (C/EBP), alpha); CEBPB (CCAAT/enhancer cision repair cross-complementing rodent repair defi- binding protein (C/EBP), beta); CEBPD (CCAAT/en- ciency, complementation group 3 (xeroderma pigmento- hancer binding protein (C/EBP), delta); CEBPE (CCAAT/ sum group B complementing)); ERCC4 (Excision repair enhancer binding protein (C/EBP), epsilon); CEBPG cross-complementing rodent repair deficiency, comple- 10 (CCAAT/enhancer binding protein (C/EBP), gamma); mentation group 4); ERCC5 (Excision repair cross-com- CENPE (Centromere protein E (312kD)); CHD1 (Chro- plementing rodent repair deficiency, complementation modomain helicase DNA binding protein 1); CHD2 (Chro- group 5 (xeroderma pigmentosum, complementation modomain helicase DNA binding protein 2); CHD3 (Chro- group G (Cockayne syndrome))); ERCC6 (Excision re- modomain helicase DNA binding protein 3); CHDL (Chro- pair cross-complementing rodent repair deficiency, com- 15 modomain-helicase-DNA-binding protein); CREB2 plementation group 6); EXO1 (Exonuclease 1); FEN1 (CAMP responsive element binding protein 2); CREBBP (Flap structure-specific endonuclease 1); G22P1 (Thy- (CREB binding protein (Rubinstein-Taybi syndrome)); roid autoantigen 70kD (Ku antigen)); HMGIY (High-mo- CSE1L (Chromosome segregation 1 (yeast ho- bility group (nonhistone chromosomal) protein isoforms molog)-like); CSTF3 (Cleavage stimulation factor, 3’ pre- I and Y); HUS1 (HUS1 (S. pombe) checkpoint homolog); 20 RNA, subunit 3, 77kD); CTPS (CTP synthase); DCK (De- LIG2 (Ligase II, DNA, ATP-dependent); MLH 1 (MutL (E. oxycytidine kinase); DCTD (DCMP deaminase); DGUOK coli) homolog 1 (colon cancer, nonpolyposis type 2)); (Deoxyguanosine kinase); DNASE1 (Deoxyribonucle- MSH5 (MutS (E. coli) homolog 5); POLA (Polymerase ase I); DNASE1L3 (Deoxyribonuclease I-like 3); DUT (DNA directed), alpha); POLB (Polymerase (DNA direct- (DUTP pyrophosphatase); DXS423E (Segregation of mi- ed), beta); POLD1 (Polymerase (DNA directed), delta 1, 25 totic chromosomes 1 (SMC1, yeast human homolog of;); catalytic subunit (125kD)); RAD1 (RAD1 (S. pombe) ho- E2F2 (E2F transcription factor 2); E2F5 (E2F transcrip- molog); RAD50 (RAD50 (S. cerevisiae) homolog); tion factor 5, p130-binding); EEF1A1 (Eukaryotic trans- RAD51 (RAD51 (S. cerevisiae) homolog (E coli RecA lation elongation factor 1 alpha 1); EEF2 (Eukaryotic homolog)); RAD51C (RAD51 (S. cerevisiae) homolog C); translation elongation factor 2); EGR1 (Early growth re- RAD52 (RAD52 (S. cerevisiae) homolog); RPA1 (Repli- 30 sponse 1); EIF2B1 (Eukaryotic translation initiation factor cation protein A1 (70kD)); RPA2 (Replication protein A2 2B, subunit 1 (alpha, 26kD)); EIF3S6 (Eukaryotic trans- (32kD)); RPA3 (Replication protein A3 (14kD)); RPA40 lation initiation factor 3, subunit 6 (48kD)); EIF4E (Eu- (RNA polymerase I subunit); SNRPA (Small nuclear ri- karyotic translation initiation factor 4E); EIF4G2 (Eukary- bonucleoprotein polypeptide A); SNRPA1 (Small nuclear otic translation initiation factor 4 gamma, 2); ELF1 (E74- ribonucleoprotein polypeptide A’); TOP1 (Topoisomer- 35 like factor 1 (ets domain transcription factor)); ELF3 (E74- ase (DNA) I); TOP2A (Topoisomerase (DNA) II alpha like factor 3 (ets domain transcription factor)); ELK4 (170kD)); TOP3 (Topoisomerase (DNA) III); TOP3B (ELK4, ETS-domain protein (SRF accessory protein 1) (Topoisomerase (DNA) III beta); TR4 (TR4 nuclear hor- NOTE: Symbol and name provisional); EP300 (E1A bind- mone receptor); WRN (Werner syndrome); XPA (Xero- ing protein p300); ESR1 ( 1); ETV3 (Ets derma pigmentosum, complementation group A); 40 variant gene 3); ETV4 (Ets variant gene 4 (E1A enhancer- XRCC1 (X-ray repair complementing defective repair in binding protein, E1AF)); ETV5 (Ets variant gene 5 (ets- Chinese hamster cells 1); XRCC2 (X-ray repair comple- related molecule)); FKHR (Forkhead (Drosophila) ho- menting defective repair in Chinese hamster cells 2); molog 1 (rhabdomyosarcoma)); FLI1 (Friend leukemia XRCC3 (X-ray repair complementing defective repair in virus integration 1); GART (Phosphoribosylglycinamide Chinese hamster cells 3); XRCC4 (X-ray repair comple- 45 formyltransferase, phosphoribosylglycinamide syn- menting defective repair in Chinese hamster cells 4); and thetase, phosphoribosylaminoimidazole synthetase); XRCC5 (X-ray repair complementing defective repair in GATA1 (GATA-binding protein 1 (globin transcription Chinese hamster cells 5 (double-strand-break rejoining; factor 1)); GATA2 (GATA-binding protein 2); GATA3 Ku autoantigen, 80kD)). (GATA-binding protein 3); GATA4 (GATA-binding pro- 50 tein 4); GLI (Glioma-associated oncogene homolog (zinc Gene regulation finger protein)); GRSF1 (G-rich RNA sequence binding factor 1); H4FI (H4 histone family, member I); HIF1A (Hy- [0087] ADA (Adenosine deaminase); ADPRT (ADP- poxia-inducible factor 1, alpha subunit (basic helix-loop- ribosyltransferase (NAD+; poly (ADP-ribose) polymer- helix transcription factor)); HIVEP1 (Human immunode- ase)); ADSS (Adenylosuccinate synthase); AHR (Aryl 55 ficiency virus type I enhancer-binding protein 1); HLF hydrocarbon receptor); ATBF1 (AT-binding transcription (Hepatic leukemia factor); HMG17 (High-mobility group factor 1); ATF3 (Activating transcription factor 3); BARD1 (nonhistone chromosomal) protein 17); HMG2 (High-mo- (BRCA1 associated RING domain 1); CBF2 (CCAAT- bility group (nonhistone chromosomal) protein 2); HN-

22 43 EP 1 364 069 B1 44

RPK (Heterogeneous nuclear ribonucleoprotein K); SMARCA2 (SWI/SNF related, matrix associated, actin ICSBP1 (Interferon consensus sequence binding protein dependent regulator of chromatin, subfamily a, member 1); ID1 (Inhibitor of DNA binding 1, dominant negative 2); SOX4 (SRY (sex determining region Y)-box 4); SP100 helix-loop-helix protein); ID2 (Inhibitor of DNA binding 2, (Nuclear antigen Sp100); SPIB (Spi-B transcription factor dominant negative helix-loop-helix protein); ID3 (Inhibitor 5 (Spi-1/PU.1 related)); SRF (Serum response factor (c- of DNA binding 3, dominant negative helix-loop-helix pro- fos serum response element-binding transcription fac- tein); ID4 (Inhibitor of DNA binding 4, dominant negative tor)); STAT3 (Signal transducer and activator of tran- helix-loop-helix protein); IRF1 (Interferon regulatory fac- scription 3 (acute-phase response factor)); STAT4 (Sig- tor 1); IRF2 (Interferon regulatory factor 2); IRF4 (Inter- nal transducer and activator of transcription 4); STAT5A feron regulatory factor 4); IRF5 (Interferon regulatory fac- 10 (Signal transducer and activator of transcription 5A); tor 5); IRF7 (Interferon regulatory factor 7); JUN (V-jun TAF2C2 (TATA box binding protein (TBP)-associated avian sarcoma virus 17 oncogene homolog); JUND (Jun factor, RNA polymerase II, C2, 105kD); TAL2 (T-cell D proto-oncogene); LAF4 (Lymphoid nuclear protein re- acute lymphocytic leukemia 2); TCEB1L (Transcription lated to AF4); LYL1 (Lymphoblastic leukemia derived se- elongation factor B (SIII), polypeptide 1-like); TCF12 quence 1); MAFG (V- musculoaponeurotic fibrosar- 15 (Transcription factor 12 (HTF4, helix-loop-helix transcrip- coma (avian) oncogene family, protein G); MAX (MAX tion factors 4)); TCF3 (Transcription factor 3 (E2A immu- protein); MDM2 (Mouse double minute 2, human ho- noglobulin enhancer binding factors E12/E47)); TCF7 molog of; p53-binding protein); MHC2TA (MHC class II (Transcription factor 7 (T-cell specific, HMG-box)); transactivator); MKI67 (Antigen identified by monoclonal TFAP2B (Transcription factor AP-2 beta (activating en- antibody Ki-67); MNDA (Myeloid cell nuclear differentia- 20 hancer-binding protein 2 beta)); TFAP4 (Transcription tion antigen); MSX1 (Msh (Drosophila) homeo box ho- factor AP-4 (activating enhancer-binding protein 4)); molog 1 (formerly homeo box 7)); MTHFD (5,10-methyl- TFDP2 (Transcription factor Dp-2 (E2F dimerization part- enetetrahydrofolate dehydrogenase, 5,10-methylenetet- ner 2)); THRA (, alpha (avian rahydrofolate cyclohydrolase, 10-formyltetrahydrofolate erythroblastic leukemia viral (v-erb-a) oncogene ho- synthetase); MYC (V-myc avian myelocytomatosis viral 25 molog)); TIAL1 (TIA1 cytotoxic granule-associated RNA- oncogene homolog); NCBP (Nuclear cap binding protein, binding protein-like 1); TK1 (Thymidine kinase 1, solu- 80kD); NCBP (Nuclear cap binding protein, 80kD); ble); TOP1 (Topoisomerase (DNA) I); TOP2B (Topoi- NDP52 (Nuclear domain 10 protein); NFE2 (Nuclear fac- somerase (DNA) II beta (180kD)); TP53 (Tumor protein tor (erythroid-derived 2), 45kD); NFKB1 (Nuclear factor p53 (Li-Fraumeni syndrome)); UBL1 (Ubiquitin-like 1 of kappa light polypeptide gene enhancer in B-cells 1 30 (sentrin)); WT1 (Wilms tumor 1); XPO1 (Exportin 1 (p105)); NFKB2 (Nuclear factor of kappa light polypep- (CRM1, yeast, homolog)); ZFP36 (Zinc finger protein ho- tide gene enhancer in B-cells 2 (p49/p100)); NFYA (Nu- mologous to Zfp-36 in mouse); ZNF173 (Zinc finger pro- clear transcription factor Y, alpha); NP (Nucleoside phos- tein 173); ZNF200 (Zinc finger protein 200); ZNF42 (Zinc phorylase); NUMA1 (Nuclear mitotic apparatus protein finger protein 42 (myeloid-specific retinoic acid- respon- 1); ODC 1 (Ornithine decarboxylase 1); PAX3 (Paired 35 sive)); box gene 3 (Waardenburg syndrome 1)); PBX1 (Pre-B- cell leukemia transcription factor 1); PBX3 (Pre-B-cell Immunology leukemia transcription factor 3); PCNA (Proliferating cell nuclear antigen); PEX6 (Peroxisomal biogenesis factor [0088] A1BG (Alpha-1-B glycoprotein); A2M (Alpha-2- 6); PML (Promyelocytic leukemia); POU2AF1 (POU do- 40 macroglobulin); AAA (Achalasia-addisonianism-alacrim- main, class 2, associating factor 1); POU2F1 (POU do- ia syndrome (Allgrove syndrome); AABT (Beta-amino ac- main, class 2, transcription factor 1); POU2F2 (POU do- ids, renal transport of); AACT (Alpha-1-antichymot- main, class 2, transcription factor 2); PPAT (Phosphori- rypsin); AARS (Alanyl-tRNA synthetase); ABAT (4-ami- bosyl pyrophosphate amidotransferase); PRPS1 (Phos- nobutyrate aminotransferase); ABC7 (ATP-binding cas- phoribosyl pyrophosphate synthetase 1); PTB (Polypy- 45 sette 7); ABO (ABO blood group ( A, alpha); rimidine tract binding protein (heterogeneous nuclear ri- 1-3-N-acetylgalactosaminyltransferase; transferase B, bonucleoprotein I)); RANBP2 (RAN binding protein 2); alpha 1-3-);ACADL (Acyl-Coen- RARB (Retinoic acid receptor, beta); RARG (Retinoic ac- zyme A dehydrogenase, long chain); ACADM (Acyl- id receptor, gamma); RECQL (RecQ protein-like (DNA Coenzyme A dehydrogenase, C-4 to C-12 straight helicase Q1-like)); RENBP (Renin-binding protein); 50 chain); ACADS (Acyl-Coenzyme A dehydrogenase, C-2 RPL27 (Ribosomal protein L27); RPL32 (Ribosomal pro- to C-3 short chain); ACAT2 (Acetyl-Coenzyme A acetyl- tein L32); RPL5 (Ribosomal protein L5); RPS16 (Ribos- transferase 2 (acetoacetyl Coenzyme A thiolase)); ACHE omal protein S16); RPS21 (Ribosomal protein S21); (Acetylcholinesterase (YT blood group)); ACLS (Acrocal- RPS5 (Ribosomal protein S5); RPS9 (Ribosomal protein losal syndrome); ACO1 (Aconitase 1, soluble); ACO2 S9); RXRA (Retinoid X receptor, alpha); SATB1 (Special 55 (Aconitase 2, mitochondrial); ACP1 (Acid phosphatase AT-rich sequence binding protein 1 (binds to nuclear ma- 1, soluble); ACP5 (Acid phosphatase 5, tartrate resist- trix/scaffold-associating DNA’s)); SFRS7 (Splicing fac- ant); ACTC (Actin, alpha, ); ACTG2 (Actin, tor, arginine/serine-rich 7 (35kD)); SKIL (SKI-like); gamma 2, smooth muscle, enteric); ACTN2 (Actinin, al-

23 45 EP 1 364 069 B1 46 pha 2); ACUG (Arthrocutaneouveal granulomatosis (membrane) aminopeptidase (aminopeptidase N, ami- (Blau syndrome)); ACY1 (Aminoacylase 1); ADA (Ade- nopeptidase M, microsomal aminopeptidase, CD13, nosine deaminase); ADAM10 (A disintegrin and metal- p150)); ANX11 ( XI (56kD autoantigen)); ANX3 loprotease domain 10); ADAM8 (A disintegrin and met- (Annexin III (lipocortin III, 1,2-cyclic-inositol-phosphate alloprotease domain 8); ADCYAP1 (Adenylate cyclase 5 phosphodiesterase, placental protein III, activating polypeptide 1 (pituitary)); ADD1 (Adducin 1 (al- calcimedin 35-alpha)); ANX4 (Annexin IV (placental an- pha)); ADH1 (Alcohol dehydrogenase 1 (class I), alpha ticoagulant protein II)); ANX5 (Annexin V (endonexin II)); polypeptide); ADH2 (Alcohol dehydrogenase 2 (class I), ANX8 (Annexin VIII); APAF1 (Apoptotic protease acti- beta polypeptide); ADH3 (Alcohol dehydrogenase 3 vating factor); APBA2 (Amyloid beta (A4) precursor pro- (class I), gamma polypeptide); ADH4 (Alcohol dehydro- 10 tein-binding, family A, member 2 (X11-like)); APBB1 genase 4 (class II), pi polypeptide); ADH5 (Alcohol de- (Amyloid beta (A4) precursor protein-binding, family B, hydrogenase 5 (class III), chi polypeptide); ADH5 (Alco- member 1 (Fe65)); APC (Adenomatosis polyposis coli); hol dehydrogenase 5 (class III), chi polypeptide); ADK APCS (Amyloid P component, serum); APEH (N- (Adenosine kinase); ADORA1 (); acylaminoacyl-peptide ); API1 (Apoptosis in- ADORA2A (); ADORA2A (Ade- 15 hibitor 1); API2 (Apoptosis inhibitor 2); API3 (Apoptosis nosine A2a receptor); ADPRT (ADP-ribosyltransferase inhibitor 3); API4 (Apoptosis inhibitor 4 (survivin)); (NAD+; poly (ADP-ribose) polymerase)); ADRA2A APOA1 (Apolipoprotein A-I); APOA2 (Apolipoprotein A- (Adrenergic, alpha-2A-, receptor); ADRA2B (Adrenergic, II); APOA4 (Apolipoprotein A-IV); APOB (Apolipoprotein alpha-2B-, receptor); ADRA2C (Adrenergic, alpha-2C-, B (including Ag(x) antigen)); APOC2 (Apolipoprotein C- receptor); ADRB 1 (Adrenergic, beta-1-, receptor); 20 II); APOC3 (Apolipoprotein C-III); APOD (Apolipoprotein ADRB2 (Adrenergic, beta-2-, receptor, surface); ADRB3 D); APOE (Apolipoprotein E); APOH ( (Adrenergic, beta-3-, receptor); ADSS (Adenylosucci- (beta-2-glycoprotein I)); APP (Amyloid beta (A4) precur- nate synthase); AFP (Alpha-fetoprotein); AGA (Aspar- sor protein (protease nexin-II, Alzheimer disease)); tylglucosaminidase); AGMX2 (Agammaglobulinemia, X- APRT (Adenine phosphoribosyltransferase); AQP1 (Aq- linked 2 (with growth hormone deficiency)); AGT (Angi- 25 uaporin 1 (channel-forming integral protein, 28kD)); otensinogen); AGTR1 (Angiotensin receptor 1); AGTR2 AQP2 (Aquaporin 2 (collecting duct)); AR (Androgen re- (Angiotensin receptor 2); AGXT (Alanine-glyoxylate ami- ceptor (dihydrotestosterone receptor; testicular femini- notransferase (oxalosis I; hyperoxaluria I; glycolicaci- zation; spinal and bulbar muscular atrophy; Kennedy dis- duria; serine-pyruvate aminotransferase)); AHCY (S-ad- ease)); AREG ( (schwannoma-derived enosylhomocysteine hydrolase); AHR (Aryl hydrocarbon 30 growth factor)); ARHE (Ras homolog gene family, mem- receptor); AHSG (Alpha-2-HS-glycoprotein); AIH2 ber E); ARHGAP1 (Rho GTPase activating protein 1); (Amelogenesis imperfecta 2, hypocalcification (auto- ARHGAP5 (Rho GTPase activating protein 5); ARNT (Ar- somal dominant)); AIRE ( (auto- yl hydrocarbon receptor nuclear translocator); ARNTL mimmune) polyendocrinopathy candidiasis ectodermal (Aryl hydrocarbon receptor nuclear translocator-like); dystrophy)); AK1 (Adenylate kinase 1); AKT1 (V-akt 35 ARSA (Arylsulfatase A); ART1 (ADP-ribosyltransferase murine thymoma viral oncogene homolog 1); ALAD (Ami- 1); ARVD2 (Arrhythmogenic right ventricular dysplasia nolevulinate, delta-, dehydratase); ALAS2 (Aminolevuli- 2); ASL (Argininosuccinate ); ASNS (Asparagine nate, delta-, synthase 2) (sideroblastic/hypochromic ane- synthetase); ASPH (Aspartate beta-hydroxylase); AT3 mia)); ALB (Albumin); ALD (Adrenoleukodystrophy/ ( III); ATCAY (Ataxia, cerebellar, Cayman adrenomyeloneuropathy); ALDH1 (Aldehyde dehydro- 40 type); ATM (Ataxia telangiectasia mutated (includes genase 1, soluble); ALDH2 (Aldehyde dehydrogenase complementation) groups A, C and D)); ATOX1 (ATX1 2, mitochondrial); ALDH6 (Aldehyde dehydrogenase 6); (antioxidant protein 1, yeast) homolog 1); ATP1A1 (AT- ALDH9 (Aldehyde dehydrogenase 9 (gamma-aminobu- Pase, Na+/K+ transporting, alpha 1 polypeptide); tyraldehyde dehydrogenase, E3 isozyme)); ALDOA (Al- ATP2B2 (ATPase, Ca++ transporting, plasma mem- dolase A, fructose-bisphosphate); ALDOB (Aldolase B, 45 brane 2); ATP4B (ATPase, H+/K+ exchanging, beta fructose-bisphosphate); ALOX12 (Arachidonate 12- polypeptide); ATP7B (ATPase, Cu++ transporting, beta lipoxygenase); ALOX5 (Arachidonate 5-lipoxygenase); polypeptide (Wilson disease)); ATR (Ataxia telangiecta- ALPL (Alkaline phosphatase, liver/bone/kidney); ALPP sia and Rad3 related); ATRN (Attractin (with dipepti- (Alkaline phosphatase, placental (Regan isozyme)); dylpeptidase IV activity)); ATRX (Alpha thalassemia/ ALPPL2 (Alkaline phosphatase, placental-like 2); AMBP 50 mental retardation syndrome X-linked); ATSV (Axonal (Alpha-1-microglobulin/bikunin precursor); AMCN (Ar- transport of synaptic vesicles); AUH (AU RNA-binding throgryposis multiplex congenita, neurogenic); AMELX protein/enoyl-Coenzyme A hydratase); AVP (Arginine (Amelogenin (, amelogenesis imperfecta (neurophysin II, antidiuretic hormone, dia- 1)); AMH (Anti-Mullerian hormone); AMPH (Amphiphysin betes insipidus, neurohypophyseal)); AVPR1A (Arginine (Stiff-Mann syndrome with breast cancer 128kD autoan- 55 1A); AVPR2 (Arginine vasopressin tigen)); AMPHL (Amphiphysin-like); AMY1A (Amylase, receptor 2 (nephrogenic )); AXL (AXL alpha 1A; salivary); AMY2A (Amylase, alpha 2A; pancre- receptor tyrosine kinase); AZGP1 (Alpha-2-glycoprotein atic); ANK1 (Ankyrin 1, erythrocytic); ANPEP (Alanyl 1, zinc); AZU1 (Azurocidin 1 (cationic antimicrobial pro-

24 47 EP 1 364 069 B1 48 tein 37)); B120 (Brain protein 120); B2M (Beta-2-mi- receptor); CAMP (Cathelicidin antimicrobial peptide); croglobulin); BAG1 (BCL2-associated athanogene); CAPG (Capping protein (actin filament), -like); BAK1 (BCL2-antagonist/killer 1); BAX (BCL2-associated CAPN3 (, large polypeptide L3); CASP1 (Cas- X protein); BCHE (Butyrylcholinesterase); BCKDHA pase 1, apoptosis-related cysteine protease (interleukin (Branched chain keto acid dehydrogenase E1, alpha 5 1, beta, convertase)); CASP10 (Caspase 10, apoptosis- polypeptide (maple syrup urine disease)); BCL1 (B-cell related cysteine protease); CASP2 (Caspase 2, apopto- CLL/lymphoma 1); BCL2 (B-cell CLL/lymphoma 2); sis-related cysteine protease (neural precursor cell ex- BCL2A1 (BCL2-related protein A1); BCL2L1; BCL2L2 pressed, developmentally down-regulated 2)); CASP3 (BCL2-like 2); BCL7 (B-cell CLL/lymphoma 7); BCPM (Caspase 3, apoptosis-related cysteine protease); (Benign chronic pemphigus (Hailey-Hailey disease)); 10 CASP4 (Caspase 4, apoptosis-related cysteine pro- BCPR (Breast cancer-related regulator of TP53); BCR tease); CASP5 (Caspase 5, apoptosis-related cysteine (Breakpoint cluster region); BDKRB1 (Bradykinin recep- protease); CASP6 (Caspase 6, apoptosis-related tor B1); BDKRB2 ( B2); BENE (BENE cysteine protease); CASP7 (Caspase 7, apoptosis-relat- protein); BF (B-factor, ); BGLAP (Bone gamma- ed cysteine protease); CASP8 (Caspase 8, apoptosis- carboxyglutamate (gla) protein ()); BGP (Bil- 15 related cysteine protease); CASP9 (Caspase 9, apopto- iary glycoprotein); BHR1 (Bronchial hyperresponsive- sis-related cysteine protease); CASR (Calcium-sensing ness-1 (bronchial asthma)); BID (BH3 interacting domain receptor (hypocalciuric hypercalcemia 1, severe neona- death ); BLK (B lymphoid tyrosine kinase); BLM tal hyperparathyroidism)); CAT (Catalase); CAV3 (Cave- (Bloom syndrome); BLMH (Bleomycin hydrolase); BMI1 olin 3); CBBM (Blue-monochromatic colorblindness (blue (Murine leukemia viral (bmi-1) oncogene homolog); 20 cone monochromacy)); CBFA2 (Core-binding factor, runt BN51T (BN51 (BHK21) temperature sensitivity comple- domain, alpha subunit 2 ( 1; aml1 menting); BPAG1 (Bullous pemphigoid antigen 1 oncogene)); CBFA2T1 (Core-binding factor, runt do- (230/240kD)); BPI (Bactericidal/permeability-increasing main, alpha subunit 2; translocated to, 1; cyclin D-relat- protein); BRAF (V-raf murine sarcoma viral oncogene ed); CBFA2T2 (Core-binding factor, runt domain, alpha homolog B1); BRAK (CXC chemokine in breast and kid- 25 subunit 2; translocated to, 2); CBFA2T3 (Core-binding ney); BRCA1 (Breast cancer 1, early onset); BRCA2 factor, runt domain, alpha subunit 2; translocated to, 3); (Breast cancer 2, early onset); BSEP (Bile salt export CBFB (Core-binding factor, beta subunit); CBLN1 (Cer- pump (ABC member 16, MDR/TAP subfamily)); BST1 ebellin 1 precursor); CBR1 (Carbonyl reductase 1); CBS (Bone marrow stromal cell antigen 1); BTD (Biotinidase); (Cystathionine-beta-synthase); CBX4 (Chromobox ho- BTK (Bruton agammaglobulinemia tyrosine kinase); 30 molog 4 (Drosophila Pc class)); CCAL1 (Chondrocalci- BUB1 (Budding uninhibited by benzimidazoles 1 (yeast nosis 1 (calcium pyrophosphate-deposition disease, ear- homolog)); C1NH (Complement component 1 inhibitor ly onset osteoarthritis)); CCR1 (Chemokine (C-C motif) (angioedema, hereditary)); C1QA (Complement compo- receptor 1); CCR1 (Chemokine (C-C motif) receptor 1); nent 1, q subcomponent, alpha polypeptide); C1QB CCR2 (Chemokine (C-C motif) receptor 2); CCR3 (Complement component 1, q subcomponent, beta 35 (Chemokine (C-C motif) receptor 3); CCR3 (Chemokine Polypeptide); C1QBP (Complement component 1, q sub- (C-C motif) receptor 3); CCR4 (Chemokine (C-C motif) component binding protein); C1QG (Complement com- receptor 4); CCR5 (Chemokine (C-C motif) receptor 5); ponent 1, q subcomponent, gamma polypeptide); C1R CCR5 (Chemokine (C-C motif) receptor 5); CCR6 (Complement component 1, r subcomponent); C1S (Chemokine (C-C motif) receptor 6); CCR7 (Chemokine (Complement component 1, s subcomponent); C2 (Com- 40 (C-C motif) receptor 7); CCR7 (Chemokine (C-C motif) plement component 2); C3 (); receptor 7); CCR8 (Chemokine (C-C motif) receptor 8); C3AR1 (Complement component 3a receptor 1); CD 14 (CD 14 antigen); CD 151 (CD151 antigen); CD 19 (Complement component 4A); C4B (Complement com- (CD 19 antigen); CD1A (CD1A antigen, a polypeptide); ponent 4B); C4BPA (-binding CD1B (CD1B antigen, b polypeptide); CD2 (CD2 antigen protein, alpha); C4BPAL2 (Complement component 4- 45 (p50), sheep red blood cell receptor); CD20 (CD20 anti- binding protein, alpha-like 2); C4BPB (Complement com- gen); CD22 (CD22 antigen); CD36 (CD36 antigen (col- ponent 4-binding protein, beta); C5 (Complement com- lagen type I receptor, thrombospondin receptor)); ponent 5); C5R1 ( receptor 1 CD36L1 (CD36 antigen (collagen type I receptor, throm- (C5a ligand)); C6 (); C7 (Com- bospondin receptor)-like 1); CD39 (CD39 antigen); plement component 7); C8A (Complement component 50 CD3E (CD3E antigen, epsilon polypeptide (TiT3 com- 8, alpha polypeptide); C8B (Complement component 8, plex)); CD3G (CD3G antigen, gamma polypeptide (TiT3 beta polypeptide); C8G (Complement component 8, complex)); CD3Z (CD3Z antigen, zeta polypeptide (TiT3 gamma polypeptide); C9 (); complex)); CD4 (CD4 antigen (p55)); CD44 (CD44 anti- CA1 (Carbonic anhydrase I); CA2 (Carbonic anhydrase gen (homing function and Indian blood group system)); II); CACNA1S (Calcium channel, voltage-dependent, L 55 CD47 (CD47 antigen (Rh-related antigen, integrin-asso- type, alpha 1S subunit); CACNB2 (Calcium channel, volt- ciated signal transducer)); CD5 (CD5 antigen (p56-62)); age-dependent, beta 2 subunit); CALCA (Calcitonin/cal- CD53 (CD53 antigen); CD58 (CD58 antigen, (lym- citonin-related polypeptide, alpha); CALCR (Calcitonin phocyte function-associated antigen 3)); CD59 (CD59

25 49 EP 1 364 069 B1 50 antigen p18-20 (antigen identified by monoclonal anti- (Clusterin (complement lysis inhibitor, SP-40,40, sulfated bodies 16.3A5, EJ16, EJ30, EL32 and G344)); CD5L glycoprotein 2, -repressed prostate mes- (CD5 antigen-like (scavenger receptor cysteine rich fam- sage 2, apolipoprotein J)); CMA1 (Chymase 1, mast cell); ily)); CD6 (CD6 antigen); CD63 (CD63 antigen (melano- CMAR (Cell matrix adhesion regulator); CMD1A (Cardi- ma 1 antigen)); CD68 (CD68 antigen); CD69 (CD69 an- 5 omyopathy, dilated 1A (autosomal dominant)); CMKBR9 tigen (p60, early T-cell activation antigen)); CD7 (CD7 (Chemokine (C-C motif) receptor 9); CMKBR9 (Chem- antigen (p41)); CD74 (CD74 antigen (invariant polypep- okine (C-C motif) receptor 9); CMKLR1 (Chemokine-like tide of major histocompatibility complex, class II antigen- receptor 1); CNC (, multiple neoplasia associated)); CD79A (CD79A antigen (immunoglobulin- and lentiginosis); CNGA1 (Cyclic nucleotide gated chan- associated alpha)); CD79B (CD79B antigen (immu- 10 nel alpha 1); CNK (Cytokine-inducible kinase); CNP (2’, noglobulin-associated beta)); CD80 (CD80 antigen 3’-cyclic nucleotide 3’ phosphodiesterase); CNTF (Ciliary (CD28 antigen ligand 1, B7-1 antigen)); CD81 (CD81 an- neurotrophic factor); CNTFR (Ciliary neurotrophic factor tigen (target of antiproliferative antibody 1)); CD86 (CD86 receptor); COIL (Coilin p80); COL11A2 (Collagen, type antigen (CD28 antigen ligand 2, B7-2 antigen)); CD8A XI, alpha 2); COL17A1 (Collagen, type XVII, alpha 1); (CD8 antigen, alpha polypeptide (p32)); CDA (Cytidine 15 COL1A1 (Collagen, type I, alpha 1); COL1A2 (Collagen, deaminase); CDAN1 (Congenital dyserythropoietic ane- type I, alpha 2); COL2A1 (Collagen, type II, alpha 1 (pri- mia, type I); CDAN2 (Congenital dyserythropoietic ane- mary osteoarthritis, spondyloepiphyseal dysplasia, con- mia, type II); CDC2L1 (Cell division cycle 2-like 1 (PIT- genital)); COL3A1 (Collagen, type III, alpha 1 (Ehlers- SLRE proteins)); CDH12 (Cadherin 12 (N-cadherin 2)); Danlos syndrome type IV, autosomal dominant)); CDK2 (Cyclin-dependent kinase 2); CDK4 (Cyclin-de- 20 COL4A1 (Collagen, type IV, alpha 1); COL4A3 (Colla- pendent kinase 4); CDKN1A (Cyclin-dependent kinase gen, type IV, alpha 3 (Goodpasture antigen)); COL5A1 inhibitor 1A (p21, Cip1)); CDKN1B (Cyclin-dependent ki- (Collagen, type V, alpha 1); COL7A1 (Collagen, type VII, nase inhibitor 1B (p27, Kip 1)); CDKN1C (Cyclin-depend- alpha 1 (epidermolysis bullosa, dystrophic, dominant and ent kinase inhibitor 1C (p57, Kip2)); CDKN2A (Cyclin- recessive)); COL9A2 (Collagen, type IX, alpha 2); COMT dependent kinase inhibitor 2A (melanoma, p16, inhibits 25 (Catechol-O-methyltransferase); COX4 (Cytochrome c CDK4)); CDKN2C (Cyclin-dependent kinase inhibitor 2C oxidase subunit IV); CP ( (ferroxidase)); (p18, inhibits CDK4)); CDR1 (Cerebellar degeneration- CP20 (Lymphocyte cytosolic protein, molecular weight related protein (34kD)); CDR2 (Cerebellar degeneration- 20kD); CPE (Carboxypeptidase E); CPM (Carboxypepti- related protein (62kD)); CDSN (Corneodesmosin); dase M); CPO (Coproporphyrinogen oxidase (copropor- CDW52 (CDW52 antigen (CAMPATH-1 antigen)); CEB- 30 phyria, harderoporphyria)); CPS1 (Carbamoyl-phos- PB (CCAAT/enhancer binding protein (C/EBP), beta); phate synthetase 1, mitochondrial); CR1 (Complement CEBPE (CCAAT/enhancer binding protein (C/EBP), ep- component (3b/4b) receptor 1, including Knops blood silon); CEL (Carboxyl ester lipase (bile salt-stimulated group system); CR1L (Complement component (3b/4b) lipase)); CELL (Carboxyl ester lipase-like (bile salt-stim- receptor 1-like); CR2 (Complement component (3d/Ep- ulated lipase-like)); CENPB (Centromere protein B 35 stein Barr virus) receptor 2); CREB1 (CAMP responsive (80kD)); CENPC1 (Centromere protein C 1); CES1 (Car- element binding protein 1); CREBL1 (CAMP responsive boxylesterase 1 (monocyte/macrophage serine esterase element binding protein-like 1); CREM (CAMP respon- 1)); CETP (Cholesteryl ester transfer protein, plasma); sive element modulator); CRP (C-reactive protein, pen- CFTR (Cystic fibrosis transmembrane conductance reg- traxin-related); CRS1C (Cryptidin-related sequence- ulator); CGA (Glycoprotein , alpha polypep- 40 1C); CRX (Cone-rod homeobox); CRYAB (, al- tide); CHC1 (Chromosome condensation 1); CHE2 pha B); CSBP1 (Cytokine suppressive antiinflammatory (Cholinesterase (serum) 2); CHGA (Chromogranin A drug binding protein 1 (p38 MAP kinase)); CSE1L (Chro- (parathyroid secretory protein 1)); CHH (Cartilage-hair mosome segregation 1 (yeast homolog)-like); CSF1 hypoplasia); CHIT1 (Chitinase 1); CHM (Choroideremia (Colony stimulating factor 1 (macrophage)); CSF1 (Col- ()); CHML (Choroideremia-like (Rab 45 ony stimulating factor 1 (macrophage)); CSF1R (Colony escort protein 2)); CHRM4 ( receptor, mus- stimulating factor 1 receptor, formerly McDonough feline carinic 4); CHRNA1 (Cholinergic receptor, nicotinic, al- sarcoma viral (v-fms) oncogene homolog); CSF2 (Colo- pha polypeptide 1 (muscle)); CHRNA7 (Cholinergic re- ny stimulating factor 2 (granulocyte-macrophage)); ceptor, nicotinic, alpha polypeptide 7); CHS1 (Chediak- CSF2RA (Colony stimulating factor 2 receptor, alpha, Higashi syndrome 1); CISH (Cytokine inducible SH2- 50 low-affinity (granulocyte-macrophage)); CSF2RB (Colo- containing protein); CKB (Creatine kinase, brain); CKM ny stimulating factor 2 receptor, beta, low-affinity (gran- (Creatine kinase, muscle); CKN1 (Cockayne syndrome ulocyte-macrophage)); CSF2RY (Granulocyte-macro- 1 (classical)); CLA1 (Cerebellar ataxia 1 (autosomal re- phage colony-stimulating factor receptor, alpha); CSF3 cessive)); CLCN1 (Chloride channel 1 , skeletal muscle); (Colony stimulating factor 3 (granulocyte)); CSF3R (Col- CLCN4 (Chloride channel 4); CLCNKB (Chloride chan- 55 ony stimulating factor 3 receptor (granulocyte)); CSF3R nel Kb); CLDN3 (Claudin 3); CLN3 (Ceroid-lipofuscino- (Colony stimulating factor 3 receptor (granulocyte)); sis, neuronal 3, juvenile (Batten, Spielmeyer-Vogt dis- CSH1 (Chorionic somatomammotropin hormone 1 (pla- ease)); CLTA (Clathrin, light polypeptide (Lca)); CLU cental lactogen)); CSMF (Chondrosarcoma, extraskele-

26 51 EP 1 364 069 B1 52 tal myxoid, fused to EWS in); CSN1 (Casein, alpha); dase 1 (angiotensin I converting enzyme)); DCX (Dou- CSN2 (Casein, beta); CSNU3 (Cystinuria type 3); blecortex; lissencephaly, X-linked (doublecortin)); CSPG2 (Chondroitin sulfate proteoglycan 2 (versican)); DDX10 (DEAD/H (Asp-Glu-Ala-Asp/His) box polypep- CSPG3 (Chondroitin sulfate proteoglycan 3 (neurocan)); tide 10 (RNA helicase)); DDX11 (DEAD/H (Asp-Glu-Ala- CSRP1 (Cysteine and glycine-rich protein 1); CSRP2 5 Asp/His) box polypeptide 11 (S.cerevisiae CHL1-like (Cysteine and glycine-rich protein 2 (LIM domain only, helicase) ); DEFA1 (Defensin, alpha 1, myeloid-related smooth muscle)); CST3 (Cystatin C (amyloid angiopathy sequence); DEFA4 (Defensin, alpha 4, corticostatin); and cerebral hemorrhage)); CSTB (Cystatin B (stefin B)); DEFA5 (Defensin, alpha 5, Paneth cell-specific); DEFA6 CTF1 (Cardiotrophin 1); CTGF (Connective tissue (Defensin, alpha 6, Paneth cell-specific); DEFB1 (De- growth factor); CTLA4 (Cytotoxic T-lymphocyte-associ- 10 fensin, beta 1); DF (D component of complement (ad- ated protein 4); CTNS (Cystinosis, nephropathic); CTSB ipsin)); DFFA (DNA fragmentation factor, 45 kD, alpha (Cathepsin B); CTSC (Cathepsin C); CTSF (Cathepsin subunit); DFFB (DNA fragmentation factor, 40 kD, beta F); CTSG (Cathepsin G); CTSK (Cathepsin K (pycnod- subunit); DGCR (DiGeorge syndrome chromosome re- ysostosis)); CTSL (Cathepsin L); CTSS (Cathepsin S); gion); DGI1 (Dentinogenesis imperfecta 1); DHFR (Di- CUBN (Cubilin (intrinsic factor-cobalamin receptor)); 15 hydrofolate reductase); DI (Diego blood group); DIA1 (Di- CX3CR1 (Chemokine (C-X3-C) receptor 1); CXCR4 aphorase (NADH) (cytochrome b-5 reductase)); DM (Chemokine (C-X-C motif), receptor 4 (fusin)); CYBA (Dystrophia myotonica (includes dystrophia myotonia (Cytochrome b-245, alpha polypeptide); CYBB (Cyto- protein kinase)); DMD (Dystrophin (muscular dystrophy, chrome b-245, beta polypeptide (chronic granulomatous Duchenne and Becker types), includes DXS142, disease)); CYP11A (Cytochrome P450, subfamily XIA 20 DXS164, DXS206, DXS230, DXS239, DXS268, (cholesterol side chain cleavage)); CYP11B2 (Cyto- DXS269, DXS270, DXS272); DMP1 (Dentin matrix acid- chrome P450, subfamily XIB (steroid 11-beta-hydroxy- ic phosphoprotein); DNASE1 (Deoxyribonuclease I); lase), polypeptide 2); CYP17 (Cytochrome P450, sub- DNASE1L1 (Deoxyribonuclease I-like 1); DNASE1L2 family XVII (steroid 17-alpha-hydroxylase), adrenal hy- (Deoxyribonuclease I-like 2); DNASE1L3 (Deoxyribonu- perplasia); CYP19 (Cytochrome P450, subfamily XIX (ar- 25 clease I-like 3); DNASE2 (Deoxyribonuclease II, lyso- omatization of androgens)); CYP1A2 (Cytochrome somal); DNTT (Deoxynucleotidyltransferase, terminal); P450, subfamily I (aromatic compound-inducible), DOCK1 (Dedicator of cyto-kinesis 1); DPP4 (Dipepti- polypeptide 2); CYP1B1 (Cytochrome P450, subfamily I dylpeptidase IV (CD26, adenosine deaminase complex- (dioxin-inducible), polypeptide 1 (glaucoma 3, primary in- ing protein 2) ); DPYD (Dihydropyrimidine dehydroge- fantile)); CYP21 (Cytochrome P450, subfamily XXI (ster- 30 nase); DRA (Down-regulated in adenoma); DRD2 oid 21-hydroxylase, congenital adrenal hyperplasia)); (); DRD3 (Dopamine receptor CYP27A1 (Cytochrome P450, subfamily XXVIIA (steroid D3); DRD4 (); DSG1 ( 27-hydroxylase, cerebrotendinous xanthomatosis), 1); DSG3 (Desmoglein 3 (pemphigus vulgaris antigen)); polypeptide 1); CYP2A (Cytochrome P450, subfamily IIA DSP (Desmoplakin (DPI, DPII)); DTD (Diastrophic dys- (phenobarbital-inducible)); CYP2A6 (Cytochrome P450, 35 plasia); DTNA (Dystrobrevin, alpha); DTR (Diphtheria subfamily IIA (phenobarbital-inducible), polypeptide 6); toxin receptor (heparin-binding - CYP2C9 (Cytochrome P450, subfamily IIC (mepheny- like growth factor)); DXS423E (Segregation of mitotic toin 4-hydroxylase), polypeptide 9); CYP2D@ (Cyto- chromosomes 1 (SMC1, yeast human homolog of;); chrome P450, subfamily IID (debrisoquine, sparteine, DXS435E (A-11 gene); DYS (Dysautonomia (Riley-Day etc., -metabolizing) cluster); CYP2E (Cytochrome P450, 40 syndrome, hereditary sensory autonomic neuropathy subfamily IIE (ethanol-inducible)); CYP7A1 (Cytochrome type III)); DYX2 (Dyslexia 2); (E2F transcription P450, subfamily VIIA (cholesterol 7 alpha-monooxygen- factor 1); EBF (Early B-cell factor); ECB2); ECGF1 (En- ase), polypeptide 1); D2S69E (T-lymphocyte activation dothelial cell growth factor 1 (platelet-derived)); ED1 (Ec- gene 519); D6S207E (Minor histocompatibility antigen todermal dysplasia 1, anhidrotic); EDG1 (Endothelial dif- HA-2); D6S2244E (Ke4 gene, mouse, human homolog 45 ferentiation, sphingolipid G-protein-coupled receptor, 1); of); D6S231E (DEK gene); D6S51E (HLA-B associated EDN1 (); EEC2 (Ectrodactyly, ectodermal transcript-2); D6S52E (HLA-B associated transcript-3); dysplasia and cleft lip/palate syndrome 2); EGR1 (Early D6S54E (HLA-B associated transcript-4); D6S81E (HLA- growth response 1); EGR2 (Early growth response 2 B associated transcript-1); D6S82E (HLA-B associated (Krox-20 (Drosophila) homolog)); EIF3S6 (Eukaryotic transcript-5); DAD1 (Defender against cell death 1); DAF 50 translation initiation factor 3, subunit 6 (48kD)); EIF4G1 (Decay accelerating factor for complement (CD55, (Eukaryotic translation initiation factor 4 gamma, 1); Cromer blood group system)); DAG1 (Dystroglycan I EIF4G2 (Eukaryotic translation initiation factor 4 gamma, (dystrophin-associated glycoprotein 1)); DAO (D-amino- 2); EIF5A (Eukaryotic translation initiation factor 5A); acid oxidase); DAP (Death-associated protein); DAPK1 EJM1 (Epilepsy, juvenile myoclonic 1); ELA2 (Elastase (Death-associated protein kinase 1); DAPK3 (Death-as- 55 2, ); ELANH2 (Protease inhibitor 2 (anti- sociated protein kinase 3); DBH (Dopamine beta-hydrox- elastase), monocyte/neutrophil); ELAVL2 (ELAV (em- ylase (dopamine beta-monooxygenase)); DCC (Deleted bryonic lethal, abnormal vision, Drosophila)-like 2); in colorectal carcinoma); DCP1 (Dipeptidyl carboxypepti- ELAVL4 (ELAV (embryonic lethal, abnormal vision, Dro-

27 53 EP 1 364 069 B1 54 sophila)-like 4 (Hu antigen D)); ELN (Elastin (supraval- homolog); FBLN1 ( 1); FBN1 (Fibrillin 1 (Marfan vular aortic stenosis, Williams-Beuren syndrome)); ENG syndrome)); FBP1 (Fructose-bisphosphatase 1); FCAR (Endoglin (Osler-Rendu-Weber syndrome 1)); ENPEP (Fc fragment of IgA, receptor for); FCER1A (Fc fragment ( (aminopeptidase A)); EPB41 of IgE, high affinity I, receptor for; alpha polypeptide); (Erythrocyte membrane protein band 4.1 (elliptocytosis 5 FCER1B (Fc fragment of IgE, high affinity I, receptor for; 1, RH-linked)); EPB42 (Erythrocyte membrane protein beta polypeptide); FCER2 (Fc fragment of IgE, low affin- band 4.2); EPHA3 (EphA3); EPHX1 (Epoxide hydrolase ity II, receptor for (CD23A)); FCGR1A (Fc fragment of 1, microsomal (xenobiotic)); EPHX2 (Epoxide hydrolase IgG, high affinity Ia, receptor for (CD64)); FCGR1B (Fc 2, cytoplasmic); EPO (); EPOR (Erythro- fragment of IgG, high affinity Ib, receptor for (CD64)); poietin receptor); EPOR (); EPOR 10 FCGR1B (Fc fragment of IgG, high affinity Ib, receptor (Erythropoietin receptor); EPS 15 (Epidermal growth fac- for (CD64)); FCGR2A (Fc fragment of IgG, low affinity tor receptor pathway substrate 15); EPT (Epilepsy, par- IIa, receptor for (CD32)); FCGR2B (Fc fragment of IgG, tial); ERBB2 (V-erb-b2 avian erythroblastic leukemia viral low affinity IIb, receptor for (CD32)); FCGR2C (Fc frag- oncogene homolog 2 (neuro/glioblastoma derived onco- ment of IgG, low affinity IIb, receptor for (CD32)); gene homolog)); ERCC1 (Excision repair cross-comple- 15 FCGR3A (Fc fragment of IgG, low affinity IIIa, receptor menting rodent repair deficiency, complementation for (CD16)); FCGR3B (Fc fragment of IgG, low affinity group 1 (includes overlapping antisense sequence)); IIIb, receptor for (CD 16)); FCN1 ( (collagen/- ERCC2 (Excision repair cross-complementing rodent re- ogen domain-containing) 1); FDH (Formaldehyde dehy- pair deficiency, complementation group 2 (xeroderma drogenase); FEA (F9 embryonic antigen); FEB1 (Febrile pigmentosum D)); ERCC3 (Excision repair cross-com- 20 convulsions 1febrile convulsions 1); FECH (Ferroche- plementing rodent repair deficiency, complementation latase (protoporphyria)); FES (Feline sarcoma (Snyder- group 3 (xeroderma pigmentosum group B complement- Theilen) viral (v-fes)/Fujinami avian sarcoma (PRCII) vi- ing)); ERCC4 (Excision repair cross-complementing ro- ral (v-fps) oncogene homolog); FGA (, A alpha dent repair deficiency, complementation group 4); polypeptide); FGB (Fibrinogen, B beta polypeptide); ERCC5 (Excision repair cross-complementing rodent re- 25 FGF1 (Fibroblast growth factor 1 (acidic)); FGF9 (Fibrob- pair deficiency, complementation group 5 (xeroderma last growth factor 9 (glia-activating factor)); FGFR1 (Fi- pigmentosum, complementation group G (Cockayne broblast growth factor receptor 1 (fms-related tyrosine syndrome))); ES1 (ES1 (zebrafish) protein, human ho- kinase 2, Pfeiffer syndrome)); FGFR3 (Fibroblast growth molog of); ESB3 (Esterase B3); ESD (Esterase D/ factor receptor 3 (achondroplasia, thanatophoric dwarf- formylglutathione hydrolase); ESR1 (Estrogen receptor 30 ism)); FGG (Fibrinogen, gamma polypeptide); FGR 1); ESR2 (Estrogen receptor 2 (ER beta)); ETV4 (Ets (Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene variant gene 4 (E1A enhancer-binding protein, E1AF)); homolog); FHR2 (-related gene 2); FKHR (Fork- ETV6 (Ets variant gene 6 (TEL oncogene)); EYCL3 (Eye head (Drosophila) homolog 1 (rhabdomyosarcoma)); color 3 (brown)); F10 (Coagulation ); F11 (Coag- FLG (); FLNB (Filamin B, beta (actin-binding ulation factor XI (plasma thromboplastin antecedent)); 35 protein-278)); FLT3 (Fms-related tyrosine kinase 3); F12 (Coagulation factor XII (Hageman factor)); F13A1 FLT3LG (Fms-related tyrosine kinase 3 ligand); FMO1 (Coagulation factor XIII, A1 polypeptide); F13B (Coagu- (Flavin containing monooxygenase 1); FMO3 (Flavin lation factor XIII, B polypeptide); F2 (Coagulation factor containing monooxygenase 3); FN1 (Fibronectin 1); II ()); F2R (Coagulation factor II (thrombin) re- FOLR1 (Folate receptor 1 (adult)); FOS (V-fos FBJ ceptor); F2RL2 (Coagulation factor II (thrombin) recep- 40 murine osteosarcoma viral oncogene homolog); FOSB tor-like 2); F3 (Coagulation factor III (thromboplastin, tis- (FBJ murine osteosarcoma viral oncogene homolog B); sue factor)); F5 (Coagulation (proaccelerin, labile FPDMM); FPR1 ( 1); FPRL1 factor)); F7 (Coagulation factor VII (serum prothrombin (Formyl peptide receptor-like 1); FR (Froese blood conversion accelerator)); F7R (Coagulation factor VII group); FRAP1 (FRK506 binding protein 12-rapamycin regulator); F8A (Factor VIII associated gene); F8C (Co- 45 associated protein 1); FRDA (Friedreich ataxia); FRG1 agulation factor VIIIc, procoagulant component (hemo- (FSHD region gene 1); FSHMD1A (Facioscapulohumer- philia A)); F9 (Coagulation factor IX (plasma thrombo- al muscular dystrophy 1A); FTL (Ferritin, light polypep- plastic component, Christmas disease, hemophilia B)); tide); FTNB (Fertilin beta (a disintegrin and metallopro- FABP1 (Fatty acid binding protein 1, liver); FABP2 (Fatty teinase domain 2)); FUCA1 (Fucosidase, alpha-L- 1, tis- acid binding protein 2, intestinal); FABP6 (Fatty acid bind- 50 sue); FUCA2 (Fucosidase, alpha-L- 2, plasma); FUT2 ing protein 6, ileal (gastrotropin)); FADD (Fas ( 2 ( included)); FUT3 (TNFRSF6)-associated via death domain); FAH (Fumar- ( (galactoside 3(4)-L-fucosyltrans- ylacetoacetate); FANCA (Fanconi anemia, complemen- ferase, Lewis blood group included)); FXR1 (Fragile X tation group A); FANCB (Fanconi anemia, complemen- mental retardation, autosomal homolog); DAD1 (Defend- tation group B); FANCC (Fanconi anemia, complemen- 55 er against cell death 1); DAF (Decay accelerating factor tation group C); FANCE (Fanconi anemia, complemen- for complement (CD55, Cromer blood group system)); tation group E); FANCG (Fanconi anemia, complemen- DAG1 (Dystroglycan 1 (dystrophin-associated glycopro- tation group G); FAT (FAT tumor suppressor (Drosophila) tein 1)); DAO (D-amino-acid oxidase); DAP (Death-as-

28 55 EP 1 364 069 B1 56 sociated protein); DAPK1 (Death-associated protein ki- 2, neutrophil); ELANH2 (Protease inhibitor 2 (anti- nase 1); DAPK3 (Death-associated protein kinase 3); elastase), monocyte/neutrophil); ELAVL2 (ELAV (em- DBH (Dopamine beta-hydroxylase (dopamine beta-mo- bryonic lethal, abnormal vision, Drosophila)-like 2); nooxygenase)); DCC (Deleted in colorectal carcinoma); ELAVL4 (ELAV (embryonic lethal, abnormal vision, Dro- DCP1 (Dipeptidyl carboxypeptidase 1 (angiotensin I con- 5 sophila)-like 4 (Hu antigen D)); ELN (Elastin (supraval- verting enzyme)); DCX (Doublecortex; lissencephaly, X- vular aortic stenosis, Williams-Beuren syndrome) ); ENG linked (doublecortin)); DDX10 (DEAD/H (Asp-Glu-Ala- (Endoglin (Osler-Rendu-Weber syndrome 1)); ENPEP Asp/His) box polypeptide 10 (RNA helicase)); DDX11 (Glutamyl aminopeptidase (aminopeptidase A)); EPB41 (DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 11 (Erythrocyte membrane protein band 4.1 (elliptocytosis (S.cerevisiae CHL1-like helicase)); DEFA1 (Defensin, al- 10 1, RH-linked)); EPB42 (Erythrocyte membrane protein pha 1, myeloid-related sequence); DEFA4 (Defensin, al- band 4.2); EPHA3 (EphA3); EPHX1 (Epoxide hydrolase pha 4, corticostatin); DEFA5 (Defensin, alpha 5, Paneth 1, microsomal (xenobiotic)); EPHX2 (Epoxide hydrolase cell-specific); DEFA6 (Defensin, alpha 6, Paneth cell- 2, cytoplasmic); EPO (Erythropoietin); EPOR (Erythro- specific); DEFB1 (Defensin, beta 1); DF (D component poietin receptor); EPOR (Erythropoietin receptor); EPOR of complement (adipsin)); DFFA (DNA fragmentation fac- 15 (Erythropoietin receptor); EPS 15 (Epidermal growth fac- tor, 45 kD, alpha subunit); DFFB (DNA fragmentation fac- tor receptor pathway substrate 15); EPT (Epilepsy, par- tor, 40 kD, beta subunit); DGCR (DiGeorge syndrome tial); ERBB2 (V-erb-b2 avian erythroblastic leukemia viral chromosome region); DGI1 (Dentinogenesis imperfecta oncogene homolog 2 (neuro/glioblastoma derived onco- 1); DHFR (Dihydrofolate reductase); DI (Diego blood gene homolog)); ERCC1 (Excision repair cross-comple- group); DIA1 (Diaphorase (NADH) (cytochrome b-5 re- 20 menting rodent repair deficiency, complementation ductase)); DM (Dystrophia myotonica (includes dys- group 1 (includes overlapping antisense sequence)); trophia myotonia protein kinase)); DMD (Dystrophin ERCC2 (Excision repair cross-complementing rodent re- (muscular dystrophy, Duchenne and Becker types), in- pair deficiency, complementation group 2 (xeroderma cludes DXS142, DXS164, DXS206, DXS230, DXS239, pigmentosum D)); ERCC3 (Excision repair cross-com- DXS268, DXS269, DXS270, DXS272); DMP1 (Dentin 25 plementing rodent repair deficiency, complementation matrix acidic phosphoprotein); DNASE1 (Deoxyribonu- group 3 (xeroderma pigmentosum group B complement- clease I); DNASE1L1 (Deoxyribonuclease I-like 1); ing)); ERCC4 (Excision repair cross-complementing ro- DNASE1L2 (Deoxyribonuclease I-like 2); DNASE1L3 dent repair deficiency, complementation group 4); (Deoxyribonuclease I-like 3); DNASE2 (Deoxyribonucle- ERCC5 (Excision repair cross-complementing rodent re- ase II, lysosomal); DNTT (Deoxynucleotidyltransferase, 30 pair deficiency, complementation group 5 (xeroderma terminal); DOCK1 (Dedicator of cyto-kinesis 1); DPP4 pigmentosum, complementation group G (Cockayne (Dipeptidylpeptidase IV (CD26, adenosine deaminase syndrome))); ES1 (ES1 (zebrafish) protein, human ho- complexing protein 2)); DPYD (Dihydropyrimidine dehy- molog of); ESB3 (Esterase B3); ESD (Esterase D/ drogenase); DRA (Down-regulated in adenoma); DRD2 formylglutathione hydrolase); ESR1 (Estrogen receptor (Dopamine receptor D2); DRD3 (Dopamine receptor 35 1); ESR2 (Estrogen receptor 2 (ER beta)); ETV4 (Ets D3); DRD4 (Dopamine receptor D4); DSG1 (Desmoglein variant gene 4 (E1A enhancer-binding protein, E1AF) ); 1); DSG3 (Desmoglein 3 (pemphigus vulgaris antigen)); ETV6 (Ets variant gene 6 (TEL oncogene)); EYCL3 (Eye DSP (Desmoplakin (DPI, DPII)); DTD (Diastrophic dys- color 3 (brown)); F10 (Coagulation factor X); F11 (Coag- plasia); DTNA (Dystrobrevin, alpha); DTR (Diphtheria ulation factor XI (plasma thromboplastin antecedent)); toxin receptor (heparin-binding epidermal growth factor- 40 F12 (Coagulation factor XII (Hageman factor)); F13A1 like growth factor)); DXS423E (Segregation of mitotic (Coagulation factor XIII, A1 polypeptide); F13B (Coagu- chromosomes 1 (SMC1, yeast human homolog of;); lation factor XIII, B polypeptide); F2 (Coagulation factor DXS435E (A-11 gene); DYS (Dysautonomia (Riley-Day II (thrombin)); F2R (Coagulation factor II (thrombin) re- syndrome, hereditary sensory autonomic neuropathy ceptor); F2RL2 (Coagulation factor II (thrombin) recep- type III)); DYX2 (Dyslexia 2); E2F1 (E2F transcription 45 tor-like 2); F3 (Coagulation factor III (thromboplastin, tis- factor 1); EBF (Early B-cell factor ECB2); ECGF1 En- sue factor)); F5 (Coagulation factor V (proaccelerin, labile dothelial cell growth factor 1 (platelet-derived)); ED1 (Ec- factor)); F7 (Coagulation factor VII (serum prothrombin todermal dysplasia 1, anhidrotic); EDG1 (Endothelial dif- conversion accelerator)); F7R (Coagulation factor VII ferentiation, sphingolipid); G-protein-coupled receptor, regulator); F8A (Factor VIII associated gene); F8C (Co- 1); EDN1 (Endothelin 1); EEC2 (Ectrodactyly, ectoder- 50 agulation factor VIIIc, procoagulant component (hemo- mal dysplasia and cleft lip/palate syndrome 2); EGR1 philia A)); F9 (Coagulation factor IX (plasma thrombo- (Early growth response 1); EGR2 (Early growth response plastic component, Christmas disease, hemophilia B)); 2 (Krox-20 (Drosophila) homolog)); EIF3S6 (Eukaryotic FABP1 (Fatty acid binding protein 1, liver); FABP2 (Fatty translation initiation factor 3, subunit 6 (48kD)); EIF4G1 acid binding protein 2, intestinal); FABP6 (Fatty acid bind- (Eukaryotic translation initiation factor 4 gamma, 1); 55 ing protein 6, ileal (gastrotropin)); FADD (Fas EIF4G2 (Eukaryotic translation initiation factor 4 gamma, (TNFRSF6)-associated via death domain); FAH (Fumar- 2); EIF5A (Eukaryotic translation initiation factor 5A); ylacetoacetate); FANCA (Fanconi anemia, complemen- EJM1 (Epilepsy, juvenile myoclonic 1); ELA2 (Elastase tation group A); FANCB (Fanconi anemia, complemen-

29 57 EP 1 364 069 B1 58 tation group B); FANCC (Fanconi anemia, complemen- group); FYB (FYN-binding protein (FYB-120/130)); tation group C); FANCE (Fanconi anemia, complemen- G22P1 (Thyroid autoantigen 70kD (Ku antigen)); G6PD tation group E); FANCG (Fanconi anemia, complemen- (Glucose-6-phosphate dehydrogenase); GAA (Glucosi- tation group G); FAT (FAT tumor suppressor (Drosophila) dase, alpha; acid (Pompe disease, glycogen storage dis- homolog); FBLN1 (Fibulin 1); FBN1 (Fibrillin 1 (Marfan 5 ease type II)); GABRA5 (Gamma-aminobutyric acid syndrome)); FBP1 (Fructose-bisphosphatase 1); FCAR (GABA) A receptor, alpha 5); GABRA6 (Gamma-ami- (Fc fragment of IgA, receptor for); FCER1A (Fc fragment nobutyric acid (GABA) A receptor, alpha 6); GABRB1 of IgE, high affinity I, receptor for; alpha polypeptide); (Gamma-aminobutyric acid (GABA) A receptor, beta 1); FCER1B (Fc fragment of IgE, high affinity I, receptor for; GAD2 (Glutamate decarboxylase 2 (pancreatic islets and beta polypeptide); FCER2 (Fc fragment of IgE, low affin- 10 brain, 65kD)); GALC (Galactosylceramidase (Krabbe ity II, receptor for (CD23A)); FCGR1A (Fc fragment of disease)); GALK1 (Galactokinase 1); GALT (Galactose- IgG, high affinity Ia, receptor for (CD64)); FCGR1B (Fc 1-phosphate uridylyltransferase); GANC (Glucosidase, fragment of IgG, high affinity Ib, receptor for (CD64)); alpha; neutral C); GAS (Gastrin); GAS6 (Growth arrest- FCGR1B (Fc fragment of IgG, high affinity Ib, receptor specific 6); GATA3 (GATA-binding protein 3); GBA (Glu- for (CD64)); FCGR2A (Fc fragment of IgG, low affinity 15 cosidase, beta; acid (includes glucosyl-ceramidase)); IIa, receptor for (CD32)); FCGR2B (Fc fragment of IgG, GC (Group-specific component (vitamin D binding pro- low affinity IIb, receptor for (CD32)); FCGR2C (Fc frag- tein)); GCDH (Glutaryl-Coenzyme A dehydrogenase); ment of IgG, low affinity IIb, receptor for (CD32)); GCGR (); GCK (Glucokinase (hexoki- FCGR3A (Fc fragment of IgG, low affinity IIIa, receptor nase 4, maturity onset diabetes of the young 2)); GCP for (CD16)); FCGR3B (Fc fragment of IgG, low affinity 20 (Green cone pigment (color blindness, deutan)); GDH IIIb, receptor for (CD16)); FCN1 (Ficolin (collagen/fibrin- (Glucose dehydrogenase); GEM (GTP-binding protein ogen domain-containing) 1); FDH (Formaldehyde dehy- overexpressed in skeletal muscle); GFI1 (Growth factor drogenase); FEA (F9 embryonic antigen); FEB1 (Febrile independent 1); GGCX (Gamma-glutamyl carboxylase); convulsions 1febrile convulsions 1); FECH (Ferroche- GGT1 (Gamma-glutamyltransferase 1); GGTA1 (Glyco- latase (protoporphyria)); FES (Feline sarcoma (Snyder- 25 protein, alpha-galactosyltransferase 1); GH1 (Growth Theilen) viral (v-fes)/Fujinami avian sarcoma (PRCII) vi- hormone 1); GH2 (Growth hormone 2); GHR (Growth ral (v-fps) oncogene homolog); FGA (Fibrinogen, A alpha hormone receptor); GIF (Gastric intrinsic factor (vitamin polypeptide); FGB (Fibrinogen, B beta polypeptide); B synthesis)); GLA (Galactosidase, alpha); GLC1B FGF1 (Fibroblast growth factor 1 (acidic)); FGF9 (Fibrob- (Glaucoma 1, open angle, B (adult-onset)); GLCLC last growth factor 9 (glia-activating factor)); FGFR1 (Fi- 30 (Glutamate-cysteine ligase (gamma-glutamylcysteine broblast growth factor receptor 1 (fms-related tyrosine synthetase), catalytic (72.8kD)); GLO1 (Glyoxalase I); kinase 2, Pfeiffer syndrome)); FGFR3 (Fibroblast growth GLP1R (Glucagon-like peptide 1 receptor); GLRB (Gly- factor receptor 3 (achondroplasia, thanatophoric dwarf- cine receptor, beta); GLS (Glutaminase); GLUD1 (Gluta- ism)); FGG (Fibrinogen, gamma polypeptide); FGR mate dehydrogenase 1); GLYB (Glycine B complement- (Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene 35 ing); GLYS1 (Glycosuria 1, renal); GNAQ (Guanine nu- homolog); FHR2 (Factor H-related gene 2); FKHR (Fork- cleotide binding protein (G protein), q polypeptide); head (Drosophila) homolog 1 (rhabdomyosarcoma)); GNAS1 (Guanine nucleotide binding protein (G protein), FLG (Filaggrin); FLNB (Filamin B, beta (actin-binding alpha stimulating activity polypeptide 1); GNB3 (Guanine protein-278)); FLT3 (Fms-related tyrosine kinase 3); nucleotide binding protein (G protein), beta polypeptide FLT3LG (Fms-related tyrosine kinase 3 ligand); FMO1 40 3); GNL1 (Guanine nucleotide binding protein-like 1); (Flavin containing monooxygenase 1); FMO3 (Flavin GOT2 (Glutamic-oxaloacetic transaminase 2, mitochon- containing monooxygenase 3); FN1 (Fibronectin 1); drial (aspartate aminotransferase 2)); GP1BA (Glycopro- FOLR1 (Folate receptor 1 (adult)); FOS (V-fos FBJ tein Ib (platelet), alpha polypeptide); GP1BB (Glycopro- murine osteosarcoma viral oncogene homolog); FOSB tein Ib (platelet), beta polypeptide); GP9 (Glycoprotein (FBJ murine osteosarcoma viral oncogene homolog B); 45 IX (platelet)); GPD2 (Glycerol-3-phosphate dehydroge- FPDMM); FPR1 (Formyl peptide receptor 1); FPRL1 nase 2 (mitochondrial)); GPR10 (G protein-coupled re- (Formyl peptide receptor-like 1); FR (Froese blood ceptor 10); GPR13 (G protein-coupled receptor 13); group); FRAP1 (FK506 binding protein 12-rapamycin as- GPR15 (G protein-coupled receptor 15); GPR2 (G pro- sociated protein); FRDA (Friedreich ataxia); FRG1); tein-coupled receptor 2); GPR30 (G protein-coupled re- FSHD region gene 1); FSHMD1A (Facioscapulohumeral 50 ceptor 30); GPR4 (G protein-coupled receptor 4); GPR5 muscular dystrophy 1A); FTL (Ferritin, light polypeptide); (G protein-coupled receptor 5); GPR9 (G protein-coupled FTNB (Fertilin beta (a disintegrin and metalloproteinase receptor 9); GPT (Glutamic-pyruvate transaminase domain 2)); FUCA1 (Fucosidase, alpha-L- 1, tissue); (alanine aminotransferase)); GPX1 (Glutathione peroxi- FUCA2 (Fucosidase, alpha-L- 2, plasma); FUT2 (Fuco- dase 1); GPX2 (Glutathione peroxidase 2 (gastrointesti- syltransferase 2 (secretor status included)); FUT3 (Fuc- 55 nal)); GRB10 (Growth factor receptor-bound protein 10); osyltransferase 3 (galactoside); 3(4)-L-fucosyltrans- GRB14 (Growth factor receptor-bound protein 14); ferase, Lewis blood group included)); FXR1 (Fragile X GRIK1 (, ionotropic, kainate 1); mental retardation, autosomal homolog); FY (Duffy blood GRIK2 (Glutamate receptor, ionotropic, kainate 2); GRL

30 59 EP 1 364 069 B1 60

(); GRO1 (GRO1 oncogene DQ beta 1); HLA-DRA (Major histocompatibility complex, (melanoma growth stimulating activity, alpha)); GRO2 class II, DR alpha); HLA-DRB1 (Major histocompatibility (GRO2 oncogene); GRO3 (GRO3 oncogene); GRPR complex, class II, DR beta 1); HLA-E (Major histocom- (Gastrin-releasing peptide receptor); GSN (Gelsolin patibility complex, class I, E); HLA-F (Major histocompat- (amyloidosis, Finnish type)); GSPT1 (G1 to S phase tran- 5 ibility complex, class I, F); HLA-G (HLA-G histocompat- sition 1); GSR (Glutathione reductase); GSS (Glutath- ibility antigen, class I, G); HLALS (Major histocompatibil- ione synthetase); GSTA1 (Glutathione S-transferase ity complex, class I-like sequence (NOTE: symbol provi- A1); GSTA2 (Glutathione S-transferase A2); GSTA4 sional)); HLCS (Holocarboxylase synthetase (bi- (Glutathione S-transferase A4); GSTM1 (Glutathione S- otin-[proprionyl-Coenzyme A-carboxylase (ATP-hydro- transferase M1); GSTM2 (Glutathione S-transferase M2 10 lysing)] ligase)); HLX1 (H2.0 (Drosophila)-like homeo (muscle)); GSTM3 (Glutathione S-transferase M3 box 1); HM74 (Putative ; GTP-bind- (brain)); GSTP1 (Glutathione S-transferase pi); GSTT1 ing protein); HMAB (Monocyte antigen B); HMBS (Hy- (Glutathione S-transferase theta 1); GTF2H2 (General droxymethylbilane synthase); HMGCL (3-hydroxyme- transcription factor IIH, polypeptide 2 (44kD subunit)); thyl-3-methylglutaryl-Coenzyme A lyase ((hydroxymeth- GTS (Gilles de la Tourette syndrome); GUCY1A3 (Gua- 15 ylglutaricaciduria)); HMGIC (High-mobility group (non- nylate cyclase 1, soluble, alpha 3); GUCY2D (Guanylate histone chromosomal) protein isoform I-C); HMSNL ); cyclase 2D, membrane (retina-specific)); GUSB (Glu- HMX1 (Homeo box (H6 family) 1); HNRPD (Heteroge- curonidase, beta); GYPA ( (includes MN neous nuclear ribonucleoprotein D); HOXB5 (Homeo box blood group)); GYPB (Glycophorin B (includes Ss blood B5); HOXD13 (Homeo box D13); HOXD8 (Homeo box group)); GYS1 ( I (muscle)); GZMA 20 D8); HP (Haptoglobin); HPE1 (Holoprosencephaly 1, alo- (Granzyme A (granzyme 1, cytotoxic T-lymphocyte-as- bar); HPN (Hepsin (transmembrane protease, serine 1)); sociated serine esterase 3)); GZMB (Granzyme B HPR (Haptoglobin-related protein); HPRT1 (Hypoxan- (granzyme 2, cytotoxic T-lymphocyte-associated serine thine phosphoribosyltransferase 1 (Lesch-Nyhan syn- esterase 1)); GZMM (Granzyme M (lymphocyte met-ase drome)); HPS (Hermansky-Pudlak syndrome); HPX (He- 1)); H142T (Temperature sensitivity complementation, 25 mopexin); HR (Hairless (mouse) homolog); HRAS (V- H142); HADHA (Hydroxyacyl-Coenzyme A dehydroge- Ha-ras Harvey sarcoma viral oncogene homolog); nase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme HRG (-rich glycoprotein); HRMT1L1 (HMT1 (hn- A hydratase (trifunctional protein), alpha subunit); RNP methyltransferase, S. cerevisiae)-like 1); HRMT1L2 HADHSC (L-3-hydroxyacyl-Coenzyme A dehydroge- (HMT1 (hnRNP methyltransferase, S. cerevisiae)-like 2); nase, short chain); HAGH (Hydroxyacyl glutathione hy- 30 HRY (Hairy (Drosophila)-homolog); HSD17B3 (Hy- drolase; glyoxalase 2); HAL (Histidine ammonia-lyase); droxysteroid (17-beta) dehydrogenase 3); HSD3B1 (Hy- HBA1 (Hemoglobin, alpha 1); HBB (Hemoglobin, beta); droxy-delta-5-steroid dehydrogenase, 3 beta- and ster- HBG1 (Hemoglobin, gamma A); HBZ (Hemoglobin, ze- oid delta- 1); HSD3B2 (Hydroxy-delta-5-ster- ta); HCF2 (Heparin II); HCFC1 (Host cell factor oid dehydrogenase, 3 beta- and steroid delta-isomerase C1 (VP16-accessory protein)); HCR (Chemokine recep- 35 2); HSPA1A (Heat shock 70kD protein 1); HSPA1L (Heat tor); HD (Huntingtin (Huntington disease)); HDAC1 (His- shock 70kD protein-like 1); HSPA2 (Heat shock 70kD tone deacetylase 1); HEXA (Hexosaminidase A (alpha protein 2); HSPA6 (Heat shock 70kD protein 6 polypeptide)); HEXB (Hexosaminidase B (beta polypep- (HSP70B’)); HSPG2 (Heparan sulfate proteoglycan 2 tide)); HF1 (H factor 1 (complement)); HFE (Hemochro- (perlecan)); HTLVR (Human T-cell leukemia virus (I and matosis); HFL1 (H factor (complement)-like 1); HGF 40 II) receptor); HTN1 (Histatin 1); HTN3 (Histatin 3); (Hepatocyte growth factor (hepapoietin A; scatter fac- HTR2A (5-hydroxytryptamine (serotonin) receptor 2A); tor)); HGL (Heregulin, alpha (45kD, ERBB2 p185-activa- HTR2C (5-hydroxytryptamine (serotonin) receptor 2C); tor)); HIP1 (Huntingtin interacting protein 1); HIVEP1 HTR6 (5-hydroxytryptamine (serotonin) receptor 6); (Human immunodeficiency virus type I enhancer-binding HTR7 (5-hydroxytryptamine (serotonin) receptor 7 (ade- protein 1); HK1 (Hexokinase 1); HK2 (Hexokinase 2); 45 nylate cyclase-coupled)); HVBS6 (Hepatitis B virus inte- HK3 (Hexokinase 3 (white cell)); HLA-A (Major histocom- gration site 6); HY (Histocompatibility Y antigen); IARS patibility complex, class I, A); HLA-B (Major histocom- (Isoleucine-tRNA synthetase); IBD1 (Inflammatory bow- patibility complex, class I, B); HLA-C (Major histocom- el disease 1); IBSP (Integrin-binding sialoprotein (bone patibility complex, class I, C); HLA-DMA (Major histo- sialoprotein, bone sialoprotein II)); ICAM1 (Intercellular compatibility complex, class II, DM alpha); HLA-DMB 50 adhesion molecule 1 (CD54), human rhinovirus recep- (Major histocompatibility complex, class II, DM beta); tor); ICAM2 (Intercellular adhesion molecule 2); ICAM3 HLA-DNA (Major histocompatibility complex, class II, DN (Intercellular adhesion molecule 3); ICAM4 (Intercellular alpha); HLA-DOB (Major histocompatibility complex, adhesion molecule 4, Landsteiner-Wiener blood group); class II, DO beta); HLA-DPA1 (Major histocompatibility ICAM5 (Intercellular adhesion molecule 5, telencepha- complex, class II, DP alpha 1); HLA-DPB1 (Major histo- 55 lin); ICR5 (Ichthyosis congenita V, Sjogren-Larsson-like); compatibility complex, class II, DP beta 1); HLA-DQA1 ICS1 (Immotile cilia syndrome 1); ICTI (Immature colon (Major histocompatibility complex, class II, DQ alpha 1); carcinoma transcript 1); IDDM10 (Insulin-dependent di- HLA-DQB1 (Major histocompatibility complex, class II, abetes mellitus 10); IDDM11 (Insulin-dependent diabe-

31 61 EP 1 364 069 B1 62 tes mellitus 11); IDDM15 (Insulin-dependent diabetes ma-inducing factor)); IL18BP (Interleukin 18 binding pro- mellitus 15); IDDM17 (Insulin-dependent diabetes melli- tein); IL18R1 (Interleukin 18 receptor 1); IL18RAP (Inter- tus 17); IDDM4 (Insulin-dependent diabetes mellitus 4); leukin 18 receptor accessory protein); IL1A (Interleukin IDDM6 (Insulin-dependent diabetes mellitus 6); IDDM7 1, alpha); IL1B (Interleukin 1, beta); IL1R1 (Interleukin 1 (Insulin-dependent diabetes mellitus 7); IDDMX (Diabe- 5 receptor, type I); IL1R1 (Interleukin 1 receptor, type I); tes mellitus, insulin-dependent, X-linked, susceptibility IL1R2 (Interleukin 1 receptor, type II); IL1RAP (Inter- to); IDH1 (Isocitrate dehydrogenase 1 (NADP+), solu- leukin 1 receptor accessory protein); IL1RL2 (Interleukin ble); IDS (Iduronate 2-sulfatase (Hunter syndrome)); ID- 1 receptor-like 2); IL1RN (Interleukin 1 receptor antago- UA (Iduronidase, alpha-L-); IF (I factor (complement)); nist); IL2 (); IL2RA (Interleukin 2 receptor, IFNA1 (Interferon, alpha 1); IFNA10 (Interferon, alpha 10 alpha); IL2RA (Interleukin 2 receptor, alpha); IL2RB (In- 10); IFNA13 (Interferon, alpha 13); IFNA2 (Interferon, al- terleukin 2 receptor, beta); IL2RB (Interleukin 2 receptor, pha 2); IFNAR1 (Interferon (alpha, beta and omega) re- beta); IL2RG (Interleukin 2 receptor, gamma (severe ceptor 1); IFNAR2 (Interferon (alpha, beta and omega) combined immunodeficiency) ); IL2RG (Interleukin 2 re- receptor 2); IFNG (Interferon, gamma); IFNGR1 (Inter- ceptor, gamma (severe combined immunodeficiency)); feron gamma receptor 1); IFNGR2 ( 15 IL3 (Interleukin 3 (colony-stimulating factor, multiple)); receptor 2 (interferon gamma transducer 1)); IFNR (In- IL3RA (Interleukin 3 receptor, alpha (low affinity)); IL4 terferon production regulator); IGAT (Immune response (Interleukin 4); IL4R (Interleukin 4 receptor); IL4R (Inter- to synthetic polypeptide--IRGAT); IGER (IgE responsive- leukin 4 receptor); IL5 (Interleukin 5 (colony-stimulating ness (atopic)); IGES (Immunoglobulin E concentration, factor, eosinophil)); IL5RA (Interleukin 5 receptor, alpha); serum); IGF1 (Insulin-like growth factor 1 (somatomedin 20 IL5RA (Interleukin 5 receptor, alpha); IL6 ( C)); IGF1R (Insulin-like growth factor 1 receptor); IGF2 (interferon, beta 2)); IL6R (Interleukin 6 receptor); IL6ST (Insulin-like growth factor 2 (somatomedin A)); IGF2R (Interleukin 6 signal transducer (gp130, oncostatin M re- (Insulin-like growth factor 2 receptor); IGFBP1 (Insulin- ceptor)); IL6ST (Interleukin 6 signal transducer (gp130, like growth factor binding protein 1); IGFBP10 (Insulin- oncostatin M receptor)); IL7 (Interleukin 7); IL7R (Inter- like growth factor binding protein 10); IGFBP2 (Insulin- 25 leukin 7 receptor); IL8 (Interleukin 8); IL8RA (Interleukin like growth factor binding protein 2 (36kD)); IGFBP3 (In- 8 receptor, alpha); IL8RB (Interleukin 8 receptor, beta); sulin-like growth factor binding protein 3); IGHA1 (Immu- IL8RB (Interleukin 8 receptor, beta); IL9 (Interleukin 9); noglobulin alpha 1); IGHA2 (Immunoglobulin alpha 2 IL9R (Interleukin 9 receptor); IL9R (Interleukin 9 recep- (A2M marker)); IGHE (Immunoglobulin epsilon); IGHG1 tor); ILF1 (Interleukin enhancer binding factor 1); ILF2 (Immunoglobulin gamma 1 (Gm marker)); IGHG2 (Im- 30 (Interleukin enhancer binding factor 2, 45kD); ILF3 (In- munoglobulin gamma 2 (Gm marker)); IGHV@ (Immu- terleukin enhancer binding factor 3, 90kD); IMPA1 (In- noglobulin heavy polypeptide, variable region (cluster)); ositol(myo)-1(or 4)-monophosphatase 1); IMPT1 (Im- IGJ (Immunoglobulin J polypeptide, linker protein for im- printed polyspecific membrane transporter 1); INLU (Lu- munoglobulin alpha and mu polypeptides); IGKC (Immu- theran inhibitor, dominant (monoclonal antibody A3D8) ); noglobulin kappa constant region); IGKV (Immunoglob- 35 INP10 (Interferon (gamma)-induced cell line; protein 10 ulin kappa variable region); IGLP1 (Immune response to from INPP5D Inositol polyphosphate-5-phosphatase, synthetic polypeptides-1); IGLP2 (Immune response to 145kD); INS (Insulin); INSR (); IPF1 (In- synthetic polypeptides-2); IL10 (Interleukin 10); IL10RA sulin promoter factor 1, homeodomain transcription fac- (Interleukin 10 receptor, alpha); IL10RA (Interleukin 10 tor); IPOX (Intestinal pseudoobstruction, neuronal, pri- receptor, alpha); IL10RB (Interleukin 10 receptor, beta); 40 mary idiopathic); IRAK1 (Interleukin-1 receptor-associ- IL10RB (Interleukin 10 receptor, beta); IL11 (Interleukin ated kinase 1); IRAK2 (Interleukin-1 receptor-associated 11); IL11RA (Interleukin 11 receptor, alpha); IL11RA (In- kinase 2); IRF4 (Interferon regulatory factor 4); IRS1 (In- terleukin 11 receptor, alpha); IL11RB (Interleukin 11 re- sulin receptor substrate 1); ITGA1 (Integrin, alpha 1); ceptor, beta); IL12A (Interleukin 12A ( ITGA2 (Integrin, alpha 2 (CD49B, alpha 2 subunit of VLA- stimulatory factor 1, cytotoxic lymphocyte maturation fac- 45 2 receptor)); ITGA2B (Integrin, alpha 2b (platelet glyco- tor 1, p35)); IL12B (Interleukin 12B (natural killer cell stim- protein IIb of IIb/IIIa complex, antigen CD41B)); ITGA4 ulatory factor 2, cytotoxic lymphocyte maturation factor (Integrin, alpha 4 (antigen CD49D, alpha 4 subunit of 2, p40)); IL12RB1 ( receptor, beta 1); VLA-4 receptor) ); ITGA5 (Integrin, alpha 5 (fibronectin IL12RB2 (Interleukin 12 receptor, beta 2); IL12RB2 (In- receptor, alpha polypeptide)); ITGA6 (Integrin, alpha 6); terleukin 12 receptor, beta 2); IL13 (Interleukin 13); 50 ITGA7 (Integrin, alpha 7); ITGAD (Integrin, alpha D); IT- IL13RA1 (Interleukin 13 receptor, alpha 1); IL13RA2 (In- GAL (Integrin, alpha L (antigen CD11A (p180), lym- terleukin 13 receptor, alpha 2); IL13RA2 (Interleukin 13 phocyte function-associated antigen 1; alpha polypep- receptor, alpha 2); IL15 (Interleukin 15); IL15RA (Inter- tide)); ITGAM (Integrin, alpha M (complement compo- leukin 15 receptor, alpha); IL15RA (Interleukin 15 recep- nent receptor 3, alpha; also known as CD11b (p170), tor, alpha); IL15RB (Interleukin 15 receptor, beta); IL16 55 macrophage antigen alpha polypeptide)); ITGAV (In- (Interleukin 16 (lymphocyte chemoattractant factor)); tegrin, alpha V (vitronectin receptor, alpha polypeptide, IL17 (Interleukin 17 (cytotoxic T-lymphocyte-associated antigen CD51)); ITGAX (Integrin, alpha X (antigen serine esterase 8)); IL18 (Interleukin 18 (interferon-gam- CD11C (p150), alpha polypeptide)); ITGB1 (Integrin, be-

32 63 EP 1 364 069 B1 64 ta 1 (fibronectin receptor, beta polypeptide, antigen CD29 (Lymphocyte-specific protein tyrosine kinase); LCN1 includes MDF2, MSK12)); ITGB2 (Integrin, beta 2 (anti- ( 1 (protein migrating faster than albumin, tear gen CD18 (p95), lymphocyte function-associated anti- prealbumin)); LCN2 (Lipocalin 2 (oncogene 24p3)); gen 1; macrophage antigen 1 (mac-1) beta subunit)); LCP1 (Lymphocyte cytosolic protein 1 (L-plastin)); LCP2 ITGB3 (Integrin, beta 3 (platelet glycoprotein IIIa, antigen 5 (Lymphocyte cytosolic protein 2 (SH2 domain-containing CD61)); ITGB4 (Integrin, beta 4); ITGB4BP (Integrin beta leukocyte protein of 76kD)); LDHA (Lactate dehydroge- 4 binding protein); ITGB5 (Integrin, beta 5); ITGB6 (In- nase A); LDLR (Low density lipoprotein receptor (familia tegrin, beta 6); ITGB7 (Integrin, beta 7); ITIH1 (Inter-al- X02152); LDLR (Low density lipoprotein receptor (famil- pha (globulin) inhibitor, H1 polypeptide); ITIH4 (Inter-al- ial hypercholesterolemia)); LECT2 (Leukocyte cell-de- pha (globulin) inhibitor H4 (plasma -sensitive 10 rived chemotaxin 2); LEP (Leptin (murine obesity ho- glycoprotein)); ITK (IL2-inducible T-cell kinase); IVL (In- molog)); LEPR (); LGALS1 (Lectin, galac- volucrin); JAK1 (Janus kinase 1 (a protein tyrosine ki- toside-binding, soluble, 1 (galectin 1)); LGALS3 (Lectin, nase)); JAK2 ( (a protein tyrosine kinase)); galactoside-binding, soluble, 3 (galectin 3)); LGALS3BP JAK3 (Janus kinase 3 (a protein tyrosine kinase, leuko- (Lectin, galactoside-binding, soluble, 3 binding protein cyte)); JPD (Juvenile periodontitis); JUP (Junction pla- 15 (galectin 6 binding protein)); LGALS9 (Lectin, galactos- koglobin); KAL1 (Kallmann syndrome 1 sequence); ide-binding, soluble, 9 (galectin 9)); LHB (Luteinizing hor- KARS (Lysyl-tRNA synthetase); KCNA1 (Potassium volt- mone beta polypeptide); LHCGR (Luteinizing hormone/ age-gated channel, shaker-related subfamily, member 1 choriogonadotropin receptor); LIF (Leukemia inhibitory (episodic ataxia with myokymia)); KCNA2 (Potassium factor (cholinergic differentiation factor)); LIFR (Leuke- voltage-gated channel, shaker-related subfamily, mem- 20 mia inhibitory factor receptor); LIFR (Leukemia inhibitory ber 2); KCNA3 (Potassium voltage-gated channel, shak- factor receptor); LIG1 (Ligase I, DNA, ATP-dependent); er-related subfamily, member 3); KCNA5 (Potassium LKN-1 (Chemokine CC-2,); LMAN1 (Lectin, mannose- voltage-gated channel, shaker-related subfamily, mem- binding, 1); LMO4 (LIM domain only 4); LNPEP (Leucyl/ ber 5); KCNE1 (Potassium voltage-gated channel, Isk- cystinyl aminopeptidase); LOX (Lysyl oxidase); LPA (Li- related family, member 1); KCNJ12 (Potassium inwardly- 25 poprotein, Lp(a)); LPL (Lipoprotein lipase); LQT2 (Long rectifying channel, subfamily J, member 12); KCNJ3 (Po- (electrocardiographic) QT syndrome 2); LRP1 (Low den- tassium inwardly-rectifying channel, subfamily J, mem- sity lipoprotein-related protein 1 (alpha-2-macroglobulin ber 3); KCNQ1 (Potassium voltage-gated channel, KQT- receptor)); LRP2 (Low density lipoprotein-related protein like subfamily, member 1); KCNQ2 (Potassium voltage- 2); LSL (Leptin, serum levels of); LSP1 (Lymphocyte- gated channel, KQT-like subfamily, member 2); KDR (Ki- 30 specific protein 1); LTA (Lymphotoxin alpha (TNF super- nase insert domain receptor (a type III receptor tyrosine family, member 1)); LTB4R ( kinase)); KEL (Kell blood group); KHK (Ketohexokinase (chemokine receptor-like 1)); LTB4R (Leukotriene b4 re- (fructokinase)); KIR2DL4 (Killer cell immunoglobulin-like ceptor (chemokine receptor-like 1)); LTC4S (, two domains, long cytoplasmic tail, 4); KIT (V- C4 synthase); LTF (Lactotransferrin); LTK (Leukocyte ty- Hardy-Zuckerman 4 feline sarcoma viral oncogene 35 rosine kinase); LU (Lutheran blood group (Auberger b homolog); KLKB1 (Kallikrein B plasma, (Fletcher factor) antigen included)); LY64 (Lymphocyte antigen 64 1); KLRC2 (Killer cell lectin-like receptor subfamily C, (mouse) homolog, radioprotective, 105kD); LY9 (Lym- member 2); KLRC3 (Killer cell lectin-like receptor sub- phocyte antigen 9); LYN (V-yes-1 Yamaguchi sarcoma family C, member 3); KLRC4 (Killer cell lectin-like recep- viral related oncogene homolog); LYZ (Lysozyme (renal tor subfamily C, member 4); KLRD1 (Killer cell lectin-like 40 amyloidosis)); M1S1 (Membrane component, chromo- receptor subfamily D, member 1); KNG (); some 1, surface marker 1 (40kD glycoprotein, identified KPNA1 (Karyopherin alpha 1 (importin alpha 5)); KRAS2 by monoclonal antibody GA733)); MAB21L1 (Mab-21 (C. (V-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene ho- elegans)-like 1); MACAM1 (Mucosal addressin cell ad- molog); KRT4 (Keratin 4); KRT9 (Keratin 9 (epidermolytic hesion molecule-1); MADH1 (MAD (mothers against de- palmoplantar keratoderma)); KRTHA4 (Keratin, hair, 45 capentaplegic, Drosophila) homolog 1); MADH2 (MAD acidic, 4); KRTHB4 (Keratin, hair, basic, 4); KSR (Kinase (mothers against decapentaplegic, Drosophila) homolog suppressor of ras); L1CAM ( cell adhesion molecule 2); MADH4 (MAD (mothers against decapentaplegic, (hydrocephalus, stenosis of queduct of Sylvius 1, MASA Drosophila) homolog 4); MAGEA1 (Melanoma antigen, (mental retardation, aphasia, shuffling gait and adducted family A, 1 (directs expression of antigen MZ2-E)); thumbs) syndrome, spastic paraplegia 1)); LAG3 (Lym- 50 MAGEB1 (Melanoma antigen, family B, 1); MAL (Mal, T- phocyte-activation gene 3); LAG5 (Leukocyte antigen cell differentiation protein); MALL (Mal, T-cell differenti- group 5); LAKL (Lymphokine-activated killer cell ligand); ation protein-like); MANB (Mannosidase, alpha B, lyso- LALBA (Lactalbumin, alpha-); LAMA3 (Laminin, alpha 3 somal); MAP1B (Microtubule-associated protein 1B); (nicein (150kD), kalinin (165kD), BM600 (150kD), epi- MAPKAPK3 (Mitogen-activated protein kinase-activated legrin)); LAMC1 (Laminin, gamma 1 (formerly LAMB2)); 55 protein kinase 3); MASP1 (Mannan-binding lectin serine LAMP2 (Lysosomal-associated membrane protein 2); protease 1 (C4/C2 activating component of Ra-reactive LAMR1 (Laminin receptor 1 (67kD); Ribosomal protein factor)); MAT2A (Methionine adenosyltransferase II, al- SA); LBP (-binding protein); pha); MATN1 (Matrilin 1, cartilage matrix protein);

33 65 EP 1 364 069 B1 66

MATN3 (Matrilin 3); MBL2 (Mannose-binding lectin (pro- self-healing squamous epithelioma); MST1 (Macro- tein C) 2, soluble (opsonic defect)); MC1R (Melanocortin phage stimulating 1 (hepatocyte growth factor-like)); 1 receptor (alpha melanocyte stimulating hormone re- MST1R (Macrophage stimulating 1 receptor (c-met-re- ceptor)); MC2R (Melanocortin 2 receptor (adrenocortico- lated tyrosine kinase)); MSX2 (Msh (Drosophila) homeo tropic hormone)); MCC (Mutated in colorectal cancers); 5 box homolog 2); MTCO1 (Cytochrome c oxidase I); MTH- MCF2 (MCF.2 cell line derived transforming sequence); FD (5,10-methylenetetrahydrofolate dehydrogenase, MCP (Membrane cofactor protein (CD46, trophoblast- 5,10-methylenetetrahydrofolate cyclohydrolase, 10- lymphocyte cross-reactive antigen)); MDF1 (Antigen formyltetrahydrofolate synthetase); MTHFR (5,10-meth- identified by monoclonal antibody A-3A4); MDH2 (Malate ylenetetrahydrofolate reductase (NADPH)); MTND2 dehydrogenase 2, NAD (mitochondrial)); MDU1 (Antigen 10 (NADH dehydrogenase 2); MTP (Microsomal triglyceride identified by monoclonal antibodies 4F2, TRA1.10, transfer protein (large polypeptide, 88kD)); MTR (5- TROP4, and T43); ME1 (Malic enzyme 1, soluble); ME2 methyltetrahydrofolate-homocysteine methyltrans- (Malic enzyme 2, mitochondrial); MEKK1 (MAP/ERK ki- ferase); MTRR (5-methyltetrahydrofolate-homocysteine nase kinase 1); MEKK3 (MAP/ERK kinase kinase 3); methyltransferase reductase); MUC1 (Mucin 1, trans- MEMO1 (Methylation modifier for class I HLA); MEN1 15 membrane); MUC2 (Mucin 2, intestinal/tracheal); MUC4 (Multiple endocrine neoplasia I); MEP1A (Meprin A, al- (Mucin 4, tracheobronchial); MUL (Mulibrey nanism); pha (PABA peptide hydrolase)); MER2 (Antigen identi- MUT (Methylmalonyl Coenzyme A mutase); MX1 (Myxo- fied by monoclonal antibodies 1D12, 2F7); MFAP2 (Mi- virus (influenza) resistance 1, homolog of murine (inter- crofibrillar-associated protein 2); MFAP4 (Microfibrillar- feron-inducible protein p78)); MXI1 (MAX-interacting associated protein 4); MFTS (Migraine, familial typical, 20 protein 1); MYB (V- avian myeloblastosis viral onco- susceptibility to); MGCT ( MGI); MGP (Matrix Gla pro- gene homolog); MYBPC3 (Myosin-binding protein C, tein); MHC2TA (MHC class II transactivator); MIC2 (An- cardiac); MYC (V-myc avian myelocytomatosis viral on- tigen identified by monoclonal antibodies 12E7, F21 and cogene homolog); MYCL1 (V-myc avian myelocytoma- O13); MIC5 (Antigen identified by monoclonal antibody tosis viral oncogene homolog 1, lung carcinoma derived); R1); MIC7 (Antigen identified by monoclonal antibody 25 MYD88 (Myeloid differentiation primary response gene 28.3.7); MICA (MHC class I polypeptide-related se- (88)); MYF5 (Myogenic factor 5); MYF6 (Myogenic factor quence A); MIF (Macrophage migration inhibitory factor 6 (herculin)); MYO5A (Myosin VA (heavy polypeptide 12, (glycosylation-inhibiting factor)); MIG (Monokine induced myoxin)); MYO9B (Myosin IXB); NAB1 (NGFI-A binding by gamma interferon); MIR-10 (Leukocyte immunoglob- protein 1 (ERG1 binding protein 1)); NAGA (N-acetylga- ulin-like receptor); MITF (Microphthalmia-associated 30 lactosaminidase, alpha-); NAIP (Neuronal apoptosis in- transcription factor); MLLT2 (Myeloid/lymphoid or mixed- hibitory protein); NAPA (N-ethylmaleimide-sensitive fac- lineage leukemia (trithorax (Drosophila) homolog); trans- tor attachment protein, alpha); NAPB ); NAPG (N-ethyl- located to, 2); MLN (Motilin); MLR (Mineralocorticoid re- maleimide-sensitive factor attachment protein, gamma); ceptor (aldosterone receptor)); MMP12 (Matrix metallo- NAT1 (N-acetyltransferase 1 (arylamine N-acetyltrans- proteinase 12 (macrophage elastase)); MMP13 (Matrix 35 ferase)); NAT2 (N-acetyltransferase 2 (arylamine N- metalloproteinase 13 (collagenase 3)); MMP14 (Matrix acetyltransferase)); NB (Neuroblastoma (neuroblastoma metalloproteinase 14 (membrane-inserted)); MMP15 suppressor)); NCAM1 (Neural cell adhesion molecule 1); (Matrix metalloproteinase 15 (membrane-inserted)); NCF1 (Neutrophil cytosolic factor 1 (47kD, chronic gran- MMP16 (Matrix metalloproteinase 16 (membrane-insert- ulomatous disease, autosomal 1)); NCF2 (Neutrophil cy- ed)); MMP17 (Matrix metalloproteinase 17 (membrane- 40 tosolic factor 2 (65kD, chronic granulomatous disease, inserted)); MMP18 (Matrix metalloproteinase 18); MMP autosomal 2)); NCF4 (Neutrophil cytosolic factor 4 19 (Matrix metalloproteinase 19); MMP2 (Matrix metal- (40kD)); NDP (Norrie disease (pseudoglioma)); NDUFS2 loproteinase 2 (gelatinase A, 72kD gelatinase, 72kD type (NADH dehydrogenase (ubiquinone) Fe-S protein 2 IV collagenase)); MMP20 (Matrix metalloproteinase 20); (49kD) (NADH-coenzyme Q reductase)); NEB (Nebulin); MMP21 (Matrix metalloproteinase 21); MMP3 (Matrix 45 NEU (Neuraminidase); NF1 ( (neurofi- metalloproteinase 3 (stromelysin 1, progelatinase)); bromatosis, von Recklinghausen disease, Watson dis- MMP7 (Matrix metalloproteinase 7 (matrilysin, uterine)); ease)); NF2 (Neurofibromin 2 (bilateral acoustic neuro- MMP8 (Matrix metalloproteinase 8 (neutrophil colla- ma)); NFATC1 (Nuclear factor of activated T-cells, cyto- genase)); MMP9 (Matrix metalloproteinase 9 (gelatinase plasmic 1); NFATC3 (Nuclear factor of activated T-cells, B, 92kD gelatinase, 92kD type IV collagenase)); MNG1 50 cytoplasmic 3); NFATC4 (Nuclear factor of activated T- (Multinodular goitre 1); MOG (Myelin oligodendrocyte cells, cytoplasmic 4); NFE2 (Nuclear factor (erythroid- glycoprotein); MPL (Myeloproliferative leukemia virus derived 2), 45kD); NFE2L2 (Nuclear factor (erythroid-de- oncogene); MPO (Myeloperoxidase); MRBC (Monkey rived 2)-like 2); NFIL3 (Nuclear factor, interleukin 3 reg- RBC receptor); MRC1 (, C type 1); ulated); NFKB1 (Nuclear factor of kappa light polypeptide MRX20 (Mental retardation, X-linked 20); MSH3 (MutS 55 gene enhancer in B-cells 1 (p105)); NFKB2 (Nuclear fac- (E. coli) homolog 3); MSLR1 (Macrophage scavenger tor of kappa light polypeptide gene enhancer in B-cells receptor-like 1); MSR1 (Macrophage scavenger receptor 2 (p49/p100)); NFKBIA (Nuclear factor of kappa light 1); MSS (Marinesco-Sjogren syndrome); MSSE (Multiple polypeptide gene enhancer in B-cells inhibitor, alpha);

34 67 EP 1 364 069 B1 68

NFRKB (Nuclear factor related to kappa B binding pro- (40kD)); PAH (Phenylalanine hydroxylase); PAI1 (Plas- tein); NFYA (Nuclear transcription factor Y, alpha); NGFB minogen activator inhibitor, type I); PAPPA (Pregnancy- (, beta polypeptide); NKS1 (Natural associated plasma protein A); PAR4 (Protease-activated killer cell susceptibility 1); NM (Neutrophil migration); receptor-4 PAWR); PRKC, apoptosis, WT1, regulator); NME1 (Non-metastatic cells 1, protein (NM23A) ex- 5 PAX2 (Paired box gene 2); PAX3 (Paired box gene 3 pressed in); NMOR2 (NAD(P)H menadione oxidoreduct- (Waardenburg syndrome 1)); PAX8 (Paired box gene 8); ase 2, dioxin-inducible); NNMT (Nicotinamide N-methyl- PCBD (6-pyruvoyl-tetrahydropterin synthase/dimeriza- transferase); NOS1 (Nitric oxide synthase 1 (neuronal)); tion cofactor of hepatocyte nuclear factor 1 alpha NOS2A (Nitric oxide synthase 2A (inducible, hepato- (TCF1)); PCCA (Propionyl Coenzyme A carboxylase, al- cytes)); NOS2B (Nitric oxide synthase 2B); NOS2C (Ni- 10 pha polypeptide); PCCB (Propionyl Coenzyme A carbox- tric oxide synthase 2C); NOS3 (Nitric oxide synthase 3 ylase, beta polypeptide); PCI (Protein C inhibitor (plas- (endothelial cell)); NOTCH1 (Notch (Drosophila) ho- minogen activator inhibitor III)); PCK1 (Phosphoe- molog 1 (translocation-associated)); NOTCH4 (Notch nolpyruvate carboxykinase 1 (soluble)); PCM1 (Pericen- (Drosophila) homolog 4); NP (Nucleoside phosphoryla- triolar material 1); PCNT (Pericentrin); PCTK1 (PCTAIRE se); NPC1 (Niemann-Pick disease, type C1); NPHP1 15 protein kinase 1); PCYT2 (Phosphate cytidylyltrans- (Nephronophthisis 1 (juvenile)); NPY1R (Neuropeptide ferase 2, ethanolamine); PDB2); PDCD2 (Programmed Y receptor Y1); NRAMP1 (Natural resistance-associated cell death 2); PDE3B (Phosphodiesterase 3B, cGMP- macrophage protein 1 (might include Leishmaniasis)); inhibited); PDE4A (Phosphodiesterase 4A, cAMP-spe- NRAMP2 (Natural resistance-associated macrophage cific (dunce (Drosophila)-homolog phosphodiesterase protein 2); NRAS (Neuroblastoma RAS viral (v-ras) on- 20 E2)); PDE4B (Phosphodiesterase 4B, cAMP-specific cogene homolog); NRL (Neural retina ); (dunce (Drosophila)-homolog phosphodiesterase E4)); NT5 (5’ nucleotidase (CD73)); NTF3 ( 3); PDE7A (Phosphodiesterase 7A); PDES 1 B (Phosphodi- NUCB1 (Nucleobindin 1); NUMA1 (Nuclear mitotic ap- esterase IB); PDGFA (Platelet-derived growth factor al- paratus protein 1); NURR1 ( related 1 pha polypeptide); PDGFB (Platelet-derived growth factor (transcriptionally inducible)); OA1 (Ocular albinism 1 25 beta polypeptide (simian sarcoma viral (v-sis) oncogene (Nettleship-Falls)); OAS1 (2’,5’-oligoadenylate syn- homolog)); PDGFRA (Platelet-derived growth factor re- thetase 1); OAS2 (2’-5’oligoadenylate synthetase 2); ceptor, alpha polypeptide); PDGFRB (Platelet-derived OAT (Ornithine aminotransferase (gyrate atrophy)); growth factor receptor, beta polypeptide); PDHA1 (Pyru- OCRL (Oculocerebrorenal syndrome of Lowe); ODC1 vate dehydrogenase (lipoamide) alpha 1); PDX1 (Pyru- (Ornithine decarboxylase 1); OGG1 (8-oxoguanine DNA 30 vate dehydrogenase complex, lipoyl-containing compo- glycosylase); OLFR2 ( 2); OMG (Oli- nent X; E3-binding protein); PECAM1 (Platelet/endothe- godendrocyte myelin glycoprotein); OPA1 (Optic atrophy lial cell adhesion molecule (CD31 antigen)); PEPC 1 (autosomal dominant)); OPA3 (Iraqi-Jewish optic atro- (Peptidase C); PEPD (Peptidase D); PEX10 (Peroxi- phy plus (3-methylglutaconicaciduria type 3)); OPLL ); some biogenesis factor 10); PF4 (Platelet factor 4); OPRM1 (Opioid receptor, mu 1); OPTA2 (Osteopetrosis, 35 PF4V1 (Platelet factor 4 variant 1); PFBI (Plasmodium autosomal dominant, type II); OPTB1 (Osteopetrosis, au- falciparum blood infection levels); PFC (Properdin P fac- tosomal recessive); OR1D2 (Olfactory receptor, family tor, complement); PFKL (Phosphofructokinase, liver); 1, subfamily D, member 2); ORCTL2 (Beckwith-Wiede- PFKM (Phosphofructokinase, muscle); PFKP (Phos- mann syndrome chromosome region 1, candidate A; Or- phofructokinase, platelet); PFN1 (Profilin 1); PGA3 (Pep- ganic cation transporter-like 2; Imprinted polyspecific 40 sinogen 3, group I (pepsinogen A)); PGC (Progastricsin membrane transporter 1); ORM1 (Orosomucoid 1); (pepsinogen C)); PGD (Phosphogluconate dehydroge- ORM2 (Orosomucoid 2); OSM (Oncostatin M); OTC (Or- nase); PGF (, vascular endothe- nithine carbamoyltransferase); OXT (, prepro- lial growth factor-related protein); PGK1 (Phosphoglyc- ()); P (P blood group ); P1 (P erate kinase 1); PGK2 (Phosphoglycerate kinase 2); blood group (P one antigen)); P2RX1 (Purinergic recep- 45 PGL1 (Paraganglioma or familial glomus tumors 1); tor P2X, ligand-gated ion channel, 1); P2RY1 (Purinergic PGM1 (Phosphoglucomutase 1); PGM3 (Phosphogluco- receptor P2Y, G-protein coupled, 1); PA2G4 (Prolifera- mutase 3); PGP (Phosphoglycolate phosphatase); tion-associated 2G4, 38kD); PAC1 (Prostate adenocar- PGY1 (P glycoprotein 1/multiple drug resistance 1); cinoma-1); PACE (Paired basic amino acid cleaving en- PHAP1 (Putative human HLA class II associated protein zyme (furin, membrane associated receptor protein)); 50 I); PHB (Prohibitin); PI (Protease inhibitor 1 (anti- PAEP (Progestagen-associated endometrial protein elastase), alpha-1-antitrypsin); PI3 (Protease inhibitor 3, (placental protein 14, pregnancy-associated endometrial skin-derived (SKALP)); PI6 (Protease inhibitor 6 (placen- alpha-2-globulin, alpha uterine protein)); PAFAH (Plate- tal thrombin inhibitor)); PI8 (Protease inhibitor 8 (ovalbu- let-activating factor acetylhydrolase); PAFAH1B1 (Plate- min type)); PI9 (Protease inhibitor 9 (ovalbumin type)); let-activating factor acetylhydrolase, isoform Ib, alpha 55 PIGA (Phosphatidylinositol glycan, class A (paroxysmal subunit (45kD)); PAFAH1B2 (Platelet-activating factor nocturnal hemoglobinuria)); PIGF (Phosphatidylinositol acetylhydrolase, isoform Ib, beta subunit (30kD)); glycan, class F); PIGR (Polymeric immunoglobulin re- PAFAH2 (Platelet-activating factor acetylhydrolase 2 ceptor); PIK3CA (Phosphoinositide-3-kinase, catalytic,

35 69 EP 1 364 069 B1 70 alpha polypeptide); PIK3CB (Phosphoinositide-3-ki- achromatic leukodystrophy)); PSD (Pleckstrin and Sec7 nase, catalytic, beta polypeptide); PIK3R1 (Phosphoi- domain protein); PSMB8 (Proteasome (prosome, mac- nositide-3-kinase, regulatory subunit, polypeptide 1 (p85 ropain) subunit, beta type, 8 (large multifunctional pro- alpha)); PIL (Protease inhibitor 1 (alpha-1-antit- tease 7)); PSORS1 (Psoriasis susceptibility 1); PSORS2 rypsin)-like); PIN (Dynein, cytoplasmic, light polypep- 5 (Psoriasis susceptibility 2); PSORS3 (Psoriasis suscep- tide); PKLR (Pyruvate kinase, liver and RBC); PLAGL1 tibility 3); PTAFR (Platelet-activating factor receptor); (Pleomorphic adenoma gene-like 1); PLAT (Plasmino- PTC (Phenylthiocarbamide tasting); PTCH (Patched gen activator, tissue); PLCD1 (Phospholipase C, delta (Drosophila) homolog); PTEN (Phosphatase and tensin 1); PLCG1 (Phospholipase C, gamma 1 (formerly sub- homolog (mutated in multiple advanced cancers 1)); PT- type 148)); PLEK (Pleckstrin); PLG (Plasminogen); 10 GDS (Prostaglandin D2 synthase (21 kD, brain)); PLOD (Procollagen-lysine, 2-oxoglutarate 5-dioxygen- PTGER3 (Prostaglandin E receptor 3 (subtype EP3)); ase (lysine hydroxylase, Ehlers-Danlos syndrome type PTGIR (Prostaglandin I2 (prostacyclin) receptor (IP)); VI)); PLP (Proteolipid protein (Pelizaeus-Merzbacher PTGS1 (Prostaglandin-endoperoxide synthase 1 (pros- disease, spastic paraplegia 2, uncomplicated)); PLT1 taglandin G/H synthase and cyclooxygenase)); PTGS2 (Primed lymphocyte test-1); PML (Promyelocytic leuke- 15 (Prostaglandin-endoperoxide synthase 2 (prostaglandin mia); PMP22 (Peripheral myelin protein 22); PMS2 (Post- G/H synthase and cyclooxygenase)); PTK2B (Protein ty- meiotic segregation increased (S. cerevisiae) 2); PNMT rosine kinase 2 beta); PTN ( (heparin binding (Phenylethanolamine N-methyltransferase); PNUTL1 growth factor 8, neurite growth-promoting factor 1)); (Peanut (Drosophila)-like 1); POLB (Polymerase (DNA PTPN 13 (Protein tyrosine phosphatase, non-receptor directed), beta); POMC (Proopiomelanocortin (adreno- 20 type 13 (APO-1/CD95 (Fas)-associated phosphatase)); corticotropin/beta-lipotropin/ alpha-melanocyte stimulat- PTPN6 (Protein tyrosine phosphatase, non-receptor ing hormone/beta-melanocyte stimulating hormone/ be- type 6); PTPRC (Protein tyrosine phosphatase, receptor ta-endorphin)); PON1 (Paraoxonase 1); PON2 (Paraox- type, c polypeptide); PTPRCAP (Protein tyrosine phos- onase 2); PORC (Porphyria, acute; Chester type); phatase, receptor type, c polypeptide-associated pro- POU2AF1 (POU domain, class 2, associating factor 1); 25 tein); PTPRD (Protein tyrosine phosphatase, receptor POU5F1 (POU domain, class 5, transcription factor 1); type, D); PTPRF (Protein tyrosine phosphatase, receptor PPBP (Pro-platelet basic protein (includes platelet basic type, F); PTPRG (Protein tyrosine phosphatase, receptor protein, beta-thromboglobulin, connective tissue-activat- type, gamma polypeptide); PTX3 (Pentaxin-related ing peptide III, neutrophil-activating peptide-2)); PPCD gene, rapidly induced by IL-1 beta PUJO ); PVR (Polio- (Posterior polymorphous corneal dystrophy); PPH1 (Pri- 30 virus receptor); PVRL1 (Poliovirus receptor-like 1); mary pulmonary hypertension 1); PPIB (Peptidylprolyl PVRL2 (Poliovirus receptor-like 2); PXE (Pseudoxantho- isomerase B (cyclophilin B)); PPOX (Protoporphyrinogen ma elasticum); PXMP1 (Peroxisomal membrane protein oxidase); PPP1R8 (Protein phosphatase 1, regulatory 1 (70kD, Zellweger syndrome)); PXN (Paxillin); PYCR1 (inhibitor) subunit 8); PRB1 (-rich protein BstNI (Pyrroline-5-carboxylate reductase 1); PYGM (Phospho- subfamily 1); PRB2 (Proline-rich protein BstNI subfamily 35 rylase, glycogen; muscle (McArdle syndrome, glycogen 2); PRB3 (Proline-rich protein BstNI subfamily 3); PRB4 storage disease type V)); QDPR (Quinoid dihydropteri- (Proline-rich protein BstNI subfamily 4); PREP (Prolyl en- dine reductase); RAC2 (Ras-related C3 botulinum toxin dopeptidase); PRF1 (Perforin 1 (preforming protein)); substrate 2 (rho family, small GTP binding protein Rac2)); PRG1 (Proteoglycan 1, secretory granule); PRH1 (Pro- RAC3 (Ras-related C3 botulinum toxin substrate 3 (rho line-rich protein HaeIII subfamily 1); PRH2 (Proline-rich 40 family, small GTP binding protein Rac3)); RAD17 protein HaeIII subfamily 2); PRKCQ (Protein kinase C, (RAD17 (S. pombe) homolog); RAD51L3 (RAD51 (S. theta); PRKDC (Protein kinase, DNA-activated, catalytic cerevisiae)-like 3); RAF1 (V-raf-1 murine leukemia viral polypeptide); PRKG1 (Protein kinase, cGMP-depend- oncogene homolog 1); RAG1 (Recombination activating ent, type I); PRKM10 (Protein kinase mitogen-activated gene 1); RAG2 (Recombination activating gene 2); 10 (MAP kinase)); PRKM9 (Protein kinase mitogen-ac- 45 RANBP3 (RAN binding protein 3); RAP1A (RAP1A, tivated 9 (MAP kinase)); PRL (); PRLR (Prolac- member of RAS oncogene family); RB1 (Retinoblastoma tin receptor); PRNP (Prion protein (p27-30) (Creutzfeld- 1 (including osteosarcoma)); RBP4 (Retinol-binding pro- Jakob disease, Gerstmann-Strausler-Scheinker syn- tein 4, interstitial); RBS (Roberts syndrome); RCN2 (Re- drome, fatal familial insomnia)); PROC (Protein C (inac- ticulocalbin 2, EF-hand calcium binding domain); RCP tivator of coagulation factors Va and VIIIa) ); PROP1 50 (Red cone pigment (color blindness, protan)); RCV1 (Re- (Prophet of Pit1, paired-like homeodomain transcription coverin); RDBP (RD RNA-binding protein); RDS (Retinal factor); PROS1 ( (alpha)); PRPH (Peripherin); degeneration, slow (retinitis pigmentosa 7)); RELA (V- PRSS1 (Protease, serine, 1 (trypsin 1)); PRSS2 (Pro- avian reticuloendotheliosis viral oncogene homolog tease, serine, 2 (trypsin 2)); PRSS7 (Protease, serine, 7 A (nuclear factor of kappa light polypeptide gene enhanc- (enterokinase)); PRSS8 (Protease, serine, 8 (prosta- 55 er in B-cells 3 (p65))); REN (Renin); RENBP (Renin-bind- sin)); PRTN3 (Proteinase 3 (serine proteinase, neu- ing protein); REQ (Requiem, apoptosis response zinc trophil, Wegener granulomatosis autoantigen)); PSAP finger gene); RFX1 (Regulatory factor X, 1 (influences (Prosaposin (variant Gaucher disease and variant met- HLA class II expression)); RFX2 (Regulatory factor X, 2

36 71 EP 1 364 069 B1 72

(influences HLA class II expression)); RFX3 (Regulatory 1a)); SCYA3L1 (Small inducible cytokine A3-like 1); factor X, 3 (influences HLA class II expression)); RFX4 SCYA4 (Small inducible cytokine A4 (homologous to (Regulatory factor X, 4 (influences HLA class II expres- mouse Mip-1b)) SCYA5 (Small inducible cytokine A5 sion)); RFX5 (Regulatory factor X, 5 (influences HLA (RANTES)); SCYA7 (Small inducible cytokine A7 (mono- class II expression)); RFXAP (Regulatory factor X-asso- 5 cyte chemotactic protein 3)); SCYA8 (Small inducible cy- ciated protein); RGS2 (Regulator of G-protein signalling tokine subfamily A (Cys-Cys), member 8 (monocyte 2, 24kD); RHCE (Rhesus blood group, CcEe antigens); chemotactic protein 2)); SCYB5 (Small inducible cy- RHD (Rhesus blood group, D antigen); RHO (Rhodopsin tokine subfamily B (Cys-X-Cys), member 5 (epithelial- (retinitis pigmentosa 4, autosomal dominant)); RMSAI derived neutrophil-activating peptide 78)); SCYB6 (Small (Regulator of mitotic spindle assembly 1); RN5S1@ 10 inducible cytokine subfamily B (Cys-X-Cys), member 6 (RNA, 5S cluster 1); RNR1 (RNA, ribosomal 1); RNU1A (granulocyte chemotactic protein 2)); SCYC1 (Small in- (RNA, U1A small nuclear); RNU2 (RNA, U2 small nucle- ducible cytokine subfamily C, member 1 (lymphotactin)); ar); ROM1 (Retinal outer segment membrane protein 1); SCYD1 (Small inducible cytokine subfamily D (Cys-X3- RP2 (Retinitis pigmentosa 2 (X-linked recessive)); Cys), member 1 (fractalkine, neurotactin)); SDF1 (Stro- RPE65 (Retinal pigment epithelium-specific protein 15 mal cell-derived factor 1); SDHC (Succinate dehydroge- (65kD)); RPL7A (Ribosomal protein L7a); RPS4X (Ri- nase complex, subunit C, integral membrane protein, bosomal protein S4, X-linked); RRAD (Ras-related as- 15kD); SELE (Selectin E (endothelial adhesion molecule sociated with diabetes); RRM1 (Ribonucleotide reduct- 1)); SELL (Selectin L (lymphocyte adhesion molecule 1)); ase M1 polypeptide); RSN (Restin (Reed-Steinberg cell- SELP (Selectin P (granule membrane protein 140kD, an- expressed intermediate filament-associated protein)); 20 tigen CD62)); SELPLG (Selectin P ligand); SERK1 RTS (Rothmund-Thomson syndrome); RXRB (Retinoid (SAPK/Erk kinase 1); SF (Stoltzfus blood group); X receptor, beta); RYR1 ( 1 (skele- SFTPA1 (Surfactant, pulmonary-associated protein A1); tal)); S100A4 (S 100 calcium-binding protein A4 (calcium SFTPA2 (Surfactant, pulmonary-associated protein A2); protein, calvasculin, metastasin, murine placental ho- SFTPB (Surfactant, pulmonary-associated protein B); molog)); S100A7 (S100 calcium-binding protein A7 (pso- 25 SFTPD (Surfactant, pulmonary-associated protein D); riasin 1)); S100A8 (S100 calcium-binding protein A8 (cal- SGCB (Sarcoglycan, beta (43kD dystrophin-associated granulin A)); SAA1 (Serum amyloid A1); SAG (S-antigen; glycoprotein)); SGCD (Sarcoglycan, delta (35kD dys- retina and pineal gland ()); SAR1 (RasGAP-like trophin-associated glycoprotein)); SGSH (N-sulfoglu- with IQ motifs); SCLC1); SCN1B ( channel, volt- cosamine sulfohydrolase (sulfamidase)); SH2D1A (SH2 age-gated, type I, beta polypeptide); SCN4A (Sodium 30 domain protein 1A, Duncan’s disease (lymphoprolifera- channel, voltage-gated, type IV, alpha polypeptide); tive syndrome)); SHH (Sonic hedgehog (Drosophila) ho- SCN5A (Sodium channel, voltage-gated, type V, alpha molog); SHMT2 (Serine hydroxymethyltransferase 2 (mi- polypeptide (long (electrocardiographic) QT syndrome tochondrial)); SHOX (Short stature homeobox); SIAH1 3)); SCNN1G (Sodium channel, nonvoltage-gated 1, (Seven in absentia (Drosophila) homolog 1); SIPA1 (Sig- gamma); SCYA1 (Small inducible cytokine A1 (I-309, ho- 35 nal-induced proliferation-associated gene 1); SKIV2L mologous to mouse Tca-3)); SCYA11 (Small inducible (Superkiller viralicidic activity 2 (S. cerevisiae ho- cytokine subfamily A (Cys-Cys), member 11 (eotaxin)); molog)-like); SLC12A1 (Solute carrier family 12 (sodium/ SCYA13 (Small inducible cytokine subfamily A (Cys- potassium/chloride transporters), member 1); SLC14A1 Cys), member 13); SCYA14 (Small inducible cytokine (Solute carrier family 14 (urea transporter), member 1 subfamily A (Cys-Cys), member 14); SCYA15 (Small in- 40 (Kidd blood group)); SLC18A2 (Solute carrier family 18 ducible cytokine subfamily A (Cys-Cys), member 15); (vesicular monoamine), member 2); SLC1A5 (Solute car- SCYA16 (Small inducible cytokine subfamily A (Cys- rier family 1 (neutral amino acid transporter), member 5); Cys), member 16); SCYA17 (Small inducible cytokine SLC20A1 (Solute carrier family 20 (phosphate transport- subfamily A (Cys-Cys), member 17); SCYA18 (Small in- er), member 1); SLC20A2 (Solute carrier family 20 (phos- ducible cytokine subfamily A (Cys-Cys), member 18, pul- 45 phate transporter), member 2); SLC2A1 (Solute carrier monary and activation-regulated); SCYA19 (Small induc- family 2 (facilitated glucose transporter), member 1); ible cytokine subfamily A (Cys-Cys), member 19); SLC2A2 (Solute carrier family 2 (facilitated glucose trans- SCYA2 (Small inducible cytokine A2 (monocyte chemo- porter), member 2); SLC2A4 (Solute carrier family 2 (fa- tactic protein 1, homologous to mouse Sig-je)); SCYA20 cilitated glucose transporter), member 4); SLC3A1 (Sol- (Small inducible cytokine subfamily A (Cys-Cys), mem- 50 ute carrier family 3 (cystine, dibasic and neutral amino ber 20); SCYA21 (Small inducible cytokine subfamily A acid transporters, activator of cystine, dibasic and neutral (Cys-Cys), member 21); SCYA22 (Small inducible cy- amino acid transport), member 1); SLC4A1 (Solute car- tokine subfamily A (Cys-Cys), member 22); SCYA23 rier family 4, anion exchanger, member 1 (erythrocyte (Small inducible cytokine subfamily A (Cys-Cys), mem- membrane protein band 3, Diego blood group) ); SLC5A5 ber 23); SCYA24 (Small inducible cytokine subfamily A 55 (Solute carrier family 5 (sodium iodide symporter), mem- (Cys-Cys), member 24); SCYA25 (Small inducible cy- ber 5); SLC6A2 (Solute carrier family 6 ( tokine subfamily A (Cys-Cys), member 25); SCYA3 transporter, noradrenalin), member 2); SLC6A3 (Solute (Small inducible cytokine A3 (homologous to mouse Mip- carrier family 6 (neurotransmitter transporter, dopamine),

37 73 EP 1 364 069 B1 74 member 3); SLC6A4 (Solute carrier family 6 (neurotrans- TBX2 (T-box 2); TBXA2R (Thromboxane A2 receptor); mitter transporter, serotonin), member 4); SLC7A7 (Sol- TBXAS1 (Thromboxane A synthase 1 (platelet, cyto- ute carrier family 7 (cationic amino acid transporter, y+ chrome P450, subfamily V)); TCF1 (Transcription factor system), member 7); SLC9A1 (Solute carrier family 9 (so- 1, hepatic; LF-B1, hepatic nuclear factor (HNF1), albumin dium/hydrogen exchanger), isoform 1 (antiporter, 5 proximal factor); TCF19 (Transcription factor 19 (SC1)); Na+/H+, amiloride sensitive)); SLEB1 (Systemic TCF3 (Transcription factor 3 (E2A immunoglobulin en- erythematosus susceptibility 1); SLPI (Secretory leuko- hancer binding factors E12/E47)); TCF7 (Transcription cyte protease inhibitor (antileukoproteinase)); SM1 factor 7 (T-cell specific, HMG-box)); TCF8 (Transcription (Schistosoma mansoni, susceptibility/resistance to); factor 8 (represses interleukin 2 expression)); TCL1A (T- SMN1 (Survival of motor neuron 1, telomeric); SNAP23 10 cell leukemia/lymphoma 1A); TCL4 (T-cell leukemia/lym- (Synaptosomal-associated protein, 23kD); SNCG (Sy- phoma 4); TCN1 ( I (vitamin B12 binding nuclein, gamma (breast cancer-specific protein 1)); protein, R binder family)); TCN2 (Transcobalamin II; SNRP70 (Small nuclear ribonucleoprotein 70kD macrocytic anemia); TCP1 (T-complex 1); TCRA (T-cell polypeptide (RNP antigen)); SNRPB (Small nuclear ri- receptor, alpha (V,D,J,C)); TCRB (T-cell receptor, beta bonucleoprotein polypeptides B and B1); SNRPN (Small 15 cluster); TCRB (T-cell receptor, beta cluster); TCRG (T- nuclear ribonucleoprotein polypeptide N); SOAT1 (Sterol cell receptor, gamma cluster); TCTE1 (T-complex-asso- O-acyltransferase (acyl-Coenzyme A: cholesterol acyl- ciated-testis-expressed 1); TDO2 (Tryptophan 2,3-diox- transferase) 1); SOD1 (Superoxide dismutase 1, soluble ygenase); TECTA (Tectorin alpha); TERF2 (Telomeric (amyotrophic lateral sclerosis 1 (adult))); SOD2 (Super- repeat binding factor 2); TF (Transferrin); TFF2 (Trefoil oxide dismutase 2, mitochondrial); SORL1 (Sortilin-re- 20 factor 2 (spasmolytic protein 1)); TFPI (Tissue factor lated receptor, L(DLR class) A repeats-containing); pathway inhibitor (lipoprotein-associated coagulation in- SOX10 (SRY (sex-determining region Y)-box 10); SOX4 hibitor)); TFPI2 (Tissue factor pathway inhibitor-2); TFRC (SRY (sex determining region Y)-box 4); SPG3A (Spastic ( (p90, CD71)); TG (Thyroglobulin); paraplegia 3A (autosomal dominant)); SPN (Sialophorin TGFB1 (Transforming growth factor, beta 1); TGFB2 (gpL115, leukosialin, CD43)); SPN (Sialophorin (gpL115, 25 (Transforming growth factor, beta 2); TGFB3 (Transform- leukosialin, CD43)); SPP1 (Secreted phosphoprotein 1 ing growth factor, beta 3); TGFBI (Transforming growth (osteopontin, bone sialoprotein I, early T-lymphocyte ac- factor, beta-induced, 68kD); TGFBR3 (Transforming tivation 1)); SPTA1 (Spectrin, alpha, erythrocytic 1 (ellip- growth factor, beta receptor III (betaglycan, 300kD)); tocytosis 2)); SRD5A2 (Steroid-5-alpha-reductase, al- TGM1 ( 1 (K polypeptide epidermal pha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehy- 30 type I, protein-glutamine-gamma-glutamyltransferase)); drogenase alpha 2)); SSA2 (Sjogren syndrome antigen TGM2 (Transglutaminase 2 (C polypeptide, protein- A2 (60kD, ribonucleoprotein autoantigen SS-A/Ro)); glutamine-gamma-glutamyltransferase)); TH (Tyrosine SSB (Sjogren syndrome antigen B (autoantigen La)); hydroxylase); THBS1 (Thrombospondin 1); THBS2 SSTR1 (); ST3 (Suppression of (Thrombospondin 2); THPO ( (myelopro- tumorigenicity 3); STAM (Signal transducing adaptor 35 liferative leukemia virus oncogene ligand, megakaryo- molecule (SH3 domain and ITAM motif) 1); STAT1 (Sig- cyte growth and development factor)); THRA (Thyroid nal transducer and activator of transcription 1, 91kD); hormone receptor, alpha (avian erythroblastic leukemia STAT2 (Signal transducer and activator of transcription viral (v-erb-a) oncogene homolog)); THRB (Thyroid hor- 2, 113kD); STAT3 (Signal transducer and activator of mone receptor, beta (avian erythroblastic leukemia viral transcription 3 (acute-phase response factor)); STAT4 40 (v-erb-a) oncogene homolog 2)); THY1 (Thy-1 cell sur- (Signal transducer and activator of transcription 4); face antigen); TIEG (TGFB inducible early growth re- STAT5A (Signal transducer and activator of transcription sponse); TIMP3 (Tissue inhibitor of metalloproteinase 3 5A); STAT6 (Signal transducer and activator of transcrip- (Sorsby fundus dystrophy, pseudoinflammatory)); TK1 tion 6, interleukin-4 induced); STATH (Statherin); (Thymidine kinase 1, soluble); TKT (Transketolase STATI2 (STAT induced STAT inhibitor-2); STX1B (Syn- 45 (Wemicke-Korsakoff syndrome)); TLR1 (Toll-like recep- taxin 1B); SULT1A1 (Sulfotransferase family 1A, phenol- tor 1); TLR2 (Toll-like receptor 2); TLR3 (Toll-like receptor preferring, member 1); SULT1A3 (Sulfotransferase fam- 3); TLR4 (Toll-like receptor 4); TLR5 (Toll-like receptor ily 1A, phenol-preferring, member 3); SULT2A1 (Sul- 5); TM4SF7 (Transmembrane 4 superfamily member 7); fotransferase family 2A, TMEM1 (Transmembrane protein 1); TNF (Tumor necro- (DHEA) -preferring, member 1); SUOX (Sulfite oxidase); 50 sis factor (TNF superfamily, member 2)); TNFAIP2 (Tu- SUR (Sulfonylurea receptor (hyperinsulinemia)); SURF1 mor necrosis factor, alpha-induced protein 2); TNFAIP6 (Surfeit 1); SW (Swann blood group); T (T brachyury (Tumor necrosis factor, alpha-induced protein 6); (mouse) homolog); TAP1 (Transporter 1, ABC (ATP TNFRSF11B (Tumor necrosis factor receptor superfami- binding cassette)); TAP2 (Transporter 2, ABC (ATP bind- ly, member 11b (osteoprotegerin)); TNFRSF12 (Tumor ing cassette)); TAT (Tyrosine aminotransferase); TAZ 55 necrosis factor receptor superfamily, member 12 (trans- ( (, dilated 3A (X-linked), endo- locating chain-association membrane protein)); cardial fibroelastosis 2; Barth syndrome)); TBG (Thyrox- TNFRSF14 (Tumor necrosis factor receptor superfamily, in-binding globulin); TBP (TATA box binding protein); member 14 (herpesvirus entry mediator)); TNFRSF17

38 75 EP 1 364 069 B1 76

(Tumor necrosis factor receptor superfamily, member (Uroporphyrinogen III synthase (congenital erythropoiet- 17); TNFRSF1A (Tumor necrosis factor receptor super- ic porphyria)); USH2A (Usher syndrome 2A (autosomal family, member 1A); TNFRSF 1 B (Tumor necrosis factor recessive, mild)); USP7 (Ubiquitin specific protease 7 receptor superfamily, member 1B); TNFRSF5 (Tumor (herpes virus-associated)); VASP (Vasodilator-stimulat- necrosis factor receptor superfamily, member 5); 5 ed phosphoprotein); VCAM1 (Vascular cell adhesion TNFRSF6 (Tumor necrosis factor receptor superfamily, molecule 1); VDAC1 (Voltage-dependent anion channel member 6); TNFRSF6B (Tumor necrosis factor receptor 1); VDR (Vitamin D (1,25- dihydroxyvitamin D3) recep- superfamily, member 6b, decoy); TNFRSF7 (Tumor tor); VHL (Von Hippel-Lindau syndrome); VMD2 (Vitelli- necrosis factor receptor superfamily, member 7); form macular dystrophy (Best disease, bestrophin)); TNFRSF9 (Tumor necrosis factor receptor superfamily, 10 VPREB1 (Pre-B lymphocyte gene 1 (non-standard pro- member 9); TNFSF11 (Tumor necrosis factor (ligand) visional symbol)); VPREB2 (Pre-B lymphocyte-specific superfamily, member 11); TNFSF12 (Tumor necrosis protein-2); VSD1 (Ventricular septal defect 1); VTN (Vit- factor (ligand) superfamily, member 12); TNFSF14 (Tu- ronectin (serum spreading factor, somatomedin B, com- mor necrosis factor (ligand) superfamily, member 14); plement S-protein)); VWF (Von Willebrand factor); WAS TNFSF5 (Tumor necrosis factor (ligand) superfamily, 15 (Wiskott-Aldrich syndrome (ecezema-thrombocytope- member 5); TNFSF6 (Tumor necrosis factor (ligand) su- nia)); (Wee1+ (S. pombe) homolog); WFS (Wolf- perfamily, member 6); TNNT2 (Troponin T2, cardiac); ram syndrome); WT1 (Wilms tumor 1); WT3 (Wilms tu- TP53 (Tumor protein p53 (Li-Fraumeni syndrome)); mor-3); WWS (Wieacker-Wolff syndrome); XBP1 (X-box TP73 (Tumor protein ); TPH (Tryptophan hydroxyla- binding protein 1); XG (Xg blood group (pseudoautosom- se (tryptophan 5-monooxygenase)); TPI1 (Triosephos- 20 al boundary-divided on the X chromosome)); XGR (Ex- phate isomerase 1); TPM1 (Tropomyosin 1 (alpha)); TP- pression of XG and MIC2 on erythrocytes); XK (Kell blood MT (Thiopurine S-methyltransferase); TPO (Thyroid per- group precursor (McLeod phenotype)); XPA (Xeroderma oxidase); TPT1 (Tumor protein, translationally-controlled pigmentosum, complementation group A); XPC (Xero- 1); TRAF1 (TNF receptor-associated factor 1); TRAF1 derma pigmentosum, complementation group C); XPN- (TNF receptor-associated factor 1); TRAF2 (TNF recep- 25 PEPL (X-prolyl aminopeptidase (aminopeptidase tor-associated factor 2); TRAF3 (TNF receptor-associat- P)-like); XRCC1 (X-ray repair complementing defective ed factor 3); TRAF4 (TNF receptor-associated factor 4); repair in Chinese hamster cells 1); XRCC2 (X-ray repair TRAF5 (TNF receptor-associated factor 5); TRAF6 (TNF complementing defective repair in Chinese hamster cells receptor-associated factor 6); TRP1 (TRNA proline 1); 2); XRCC3 (X-ray repair complementing defective repair TSHB (Thyroid stimulating hormone, beta); TSHR (Thy- 30 in Chinese hamster cells 3); YB1 (Major histocompatibil- roid stimulating hormone receptor); TSSC3 (Tumor sup- ity complex, class II, Y box-binding protein I; DNA-binding pressing subtransferable candidate 3); TST (Thiosulfate protein B); ZFP161 (Zinc finger protein homologous to sulfurtransferase (rhodanese)); TSTA3 (Tissue specific Zfp161 in mouse); ZFP36 (Zinc finger protein homolo- transplantation antigen P35B); TTIM1 (T-cell tumor inva- gous to Zfp-36 in mouse); ZFY (Zinc finger protein, Y- sion and metastasis 1); TTR ( (prealbumin, 35 linked); ZNF121 (Zinc finger protein 121 (clone ZHC32)); amyloidosis type I)); TUB (Tubby (mouse) homolog); ZRK (Zona pellucida receptor tyrosine kinase, 95kD); TUBA3 (Tubulin, alpha, brain-specific); TUBAL1 (Tubu- lin, alpha-like 1); TUBB (Tubulin, beta polypeptide); Metabolism TWIST (Twist (Drosophila) homolog); TXN (Thioredox- in); U2AF1 (U2(RNU2) small nuclear RNA auxillary factor 40 [0089] ACAT1 (Acetyl-Coenzyme A acetyltransferase 1 (non-standard symbol)); UBC (Ubiquitin C); UBE1 1 (acetoacetyl Coenzyme A thiolase); ACAT2 (Acetyl- (Ubiquitin-activating enzyme E1 (A1S9T and BN75 tem- Coenzyme A acetyltransferase 2 (acetoacetyl Coen- perature sensitivity complementing)); UBE2B (Ubiquitin- zyme A thiolase); ACATN (Acetyl-Coenzyme A trans- conjugating enzyme E2B (RAD6 homolog)); UBE2I porter; BCAT1 (Branched chain aminotransferase 1, cy- (Ubiquitin-conjugating enzyme E2I (homologous to yeast 45 tosolic; CRAT (Carnitine acetyltransferase; DIA4 (Dia- UBC9)); UBE2V2 (Ubiquitin-conjugating enzyme E2 var- phorase (NADH/NADPH) (cytochrome b-5 reductase); iant 2); UBE3A (Ubiquitin protein ligase E3A (human pap- DUSP2 (Dual specificity phosphatase 2; EPHX1 (Epox- illoma virus E6-associated protein, Angelman syn- ide hydrolase 1, microsomal (xenobiotic); EPHX2 (Epox- drome)); UBL1 (Ubiquitin-like 1 (sentrin)); UCP2 (Uncou- ide hydrolase 2, cytoplasmic; GATM (Glycine amidi- pling protein 2 (mitochondrial, proton carrier)); UCP3 50 notransferase (L-arginine:glycine amidinotransferase); (Uncoupling protein 3 (mitochondrial, proton carrier)); GJA4 (Gap junction protein, alpha 4, 37kD (connexin 37); UFS (Urofacial syndrome); UGB (Uteroglobin); UGDH HADHSC (L-3-hydroxyacyl-Coenzyme A dehydroge- (UDP-glucose dehydrogenase); UGT1 (UDP glycosyl- nase, short chain; HK1 (Hexokinase 1; HK3 (Hexokinase transferase 1); UMPK (Uridine monophosphate kinase); 3 (white cell); HMBS (Hydroxymethylbilane synthase; UMPS (Uridine monophosphate synthetase (orotate 55 IARS (Isoleucine-tRNA synthetase; NAT1 (N-acetyl- phosphoribosyl transferase and); orotidine-5’-decarbox- transferase 1 (arylamine N-acetyltransferase); OAT (Or- ylase)); UP (); UPK1B (Uroplakin nithine aminotransferase (gyrate atrophy); OTC (Orni- 1B); UROD (Uroporphyrinogen decarboxylase); UROS thine carbamoyltransferase; PCCA (Propionyl Coen-

39 77 EP 1 364 069 B1 78 zyme A carboxylase, alpha polypeptide; PCCB (Propio- (thromboplastin, tissue factor)); FAP (Fibroblast activa- nyl Coenzyme A carboxylase, beta polypeptide; PDHA1 tion protein, alpha); FAT (FAT tumor suppressor (Dro- ( (lipoamide) alpha 1; QDPR sophila) homolog); FLNA (Filamin A, alpha (actin-binding (Quinoid dihydropteridine reductase; SGSH (N-sulfoglu- protein-280)); FN1 (Fibronectin 1); GJA4 (Gap junction cosamine sulfohydrolase (sulfamidase); SHBG (Sex hor- 5 protein, alpha 4, 37kD (connexin 37)); HMMR (Hyaluro- mone-binding globulin; SHMT2 (Serine hydroxymethyl- nan-mediated motility receptor (RHAMM)); ICAM1 (Inter- transferase 2 (mitochondrial); SLC7A1 (Solute carrier cellular adhesion molecule 1 (CD54), human rhinovirus family 7 (cationic amino acid transporter, y+ system), receptor); ICAM2 (Intercellular adhesion molecule 2); member 1; SLC7A2 (Solute carrier family 7 (cationic ami- ICAM3 (Intercellular adhesion molecule 3); ITGA2 (In- no acid transporter, y+ system), member 2; SLC7A4 (Sol- 10 tegrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 recep- ute carrier family 7 (cationic amino acid transporter, y+ tor)); ITGA3 (Integrin, alpha 3 (antigen CD49C, alpha 3 system), member 4; SOAT1 (Sterol O-acyltransferase subunit of VLA-3 receptor)); ITGA4 (Integrin, alpha 4 (an- (acyl-Coenzyme A: cholesterol acyltransferase) 1; tigen CD49D, alpha 4 subunit of VLA-4 receptor)); ITGA5 SOAT2 (Sterol O-acyltransferase 2; SORD (Sorbitol de- (Integrin, alpha 5 (fibronectin receptor, alpha polypep- hydrogenase; TPI1 (Triosephosphate isomerase 1; 15 tide)); ITGA6 (Integrin, alpha 6); ITGA7 (Integrin, alpha TYMS (Thymidylate synthetase; TYR (Tyrosinase (ocu- 7); ITGA9 (Integrin, alpha 9); ITGAE (Integrin, alpha E locutaneous albinism IA); TYRP1 (Tyrosinase-related (antigen CD103, human mucosal lymphocyte antigen 1; protein 1; UGT2B 17 (UDP 2 family, alpha polypeptide)); ITGAL (Integrin, alpha L (antigen polypeptide B17; UGT2B7 (UDP glycosyltransferase 2 CD11A (p180), lymphocyte function-associated antigen family, polypeptide B7; UGTREL1 (UDP-galactose trans- 20 1; alpha polypeptide)); ITGAM (Integrin, alpha M (com- porter related; plement component receptor 3, alpha; also known as CD11b (p170), macrophage antigen alpha polypeptide)); Metastasis ITGAV (Integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)); ITGAX (Integrin, alpha X [0090] ACTG1 (Actin, gamma 1); ADD3 (Adducin 3 25 (antigen CD11C (p150), alpha polypeptide)); ITGB1 (In- (gamma)); ALCAM (Activated leucocyte cell adhesion tegrin, beta 1 (fibronectin receptor, beta polypeptide, an- molecule); ANK1 (Ankyrin 1, erythrocytic); ANPEP (Ala- tigen CD29 includes MDF2, MSK12)); ITGB2 (Integrin, nyl (membrane) aminopeptidase (aminopeptidase N, beta 2 (antigen CD18 (p95), lymphocyte function-asso- aminopeptidase M, microsomal aminopeptidase, CD13, ciated antigen 1; macrophage antigen 1 (mac-1) beta p150)); BTN (Butyrophilin); CD14 (CD14 antigen); CD 30 subunit)); ITGB3 (Integrin, beta 3 (platelet glycoprotein 19 (CD19 antigen); CD1D (CD1D antigen, d polypep- IIIa, antigen CD61)); ITGB4 (Integrin, beta 4); ITGB5 (In- tide); CD2 (CD2 antigen (p50), sheep red blood cell re- tegrin, beta 5); ITGB7 (Integrin, beta 7); ITGB8 (Integrin, ceptor); CD20 (CD20 antigen); CD22 (CD22 antigen); beta 8); JAG1 (Jagged1 (Alagille syndrome)); JAG2 (Jag- CD33 (CD33 antigen (gp67)); CD34 (CD34 antigen); ged 2); KAI1 (Kangai 1 (suppression of tumorigenicity 6, CD37 (CD37 antigen); CD38 (CD38 antigen (p45)); 35 prostate; CD82 antigen (R2 leukocyte antigen, antigen CD39 (CD39 antigen); CD4 (CD4 antigen (p55)); CD44 detected by monoclonal and antibody IA4))); KPNB1 (CD44 antigen (homing function and Indian blood group (Karyopherin (importin) beta 1); LAG3 (Lymphocyte-ac- system)); CD47 (CD47 antigen (Rh-related antigen, in- tivation gene 3); LY64 (Lymphocyte antigen 64 (mouse) tegrin-associated signal transducer)); CD48 (CD48 anti- homolog, radioprotective, 105kD); LYZ (Lysozyme (renal gen (B-cell membrane protein)); CD53 (CD53 antigen); 40 amyloidosis)); MAP1B (Microtubule-associated protein CD58 (CD58 antigen, (lymphocyte function-associated 1B); MDU1 (Antigen identified by monoclonal antibodies antigen 3)); CD59 (CD59 antigen p18-20 (antigen iden- 4F2, TRA1.10, TROP4, and T43); MIC2 (Antigen identi- tified by monoclonal antibodies 16.3A5, EJ16, EJ30, fied by monoclonal antibodies 12E7, F21 and 013); MICA EL32 and G344)); CD63 (CD63 antigen (melanoma 1 (MHC class I polypeptide-related sequence A); MME antigen)); CD68 (CD68 antigen); CD7 (CD7 antigen 45 (Membrane metallo-endopeptidase (neutral endopepti- (p41)); CD72 (CD72 antigen); CD8A (CD8 antigen, alpha dase, enkephalinase, CALLA, CD10)); MYL2 (Myosin, polypeptide (p32)); CD9 (CD9 antigen (p24)); CD97 light polypeptide 2, regulatory, cardiac, slow); MYL3 (My- (CD97 antigen); CDH13 (Cadherin 13, H-cadherin osin, light polypeptide 3, alkali; ventricular, skeletal, (heart)); CDH17 (Cadherin 17, LI cadherin (liver-intes- slow); NCAM1 (Neural cell adhesion molecule 1); NEO1 tine)); CDH2 (Cadherin 2, N-cadherin (neuronal)); CDH4 50 (Neogenin (chicken) homolog 1); NME3 (Non-metastatic (Cadherin 4, R-cadherin (retinal)); CDH5 (Cadherin 5, cells 3, protein expressed in); PCDH1 (Protocadherin 1 VE-cadherin (vascular epithelium)); CDW52 (CDW52 (cadherin-like 1)); PDNP1 (Phosphodiesterase I/nucle- antigen (CAMPATH-1 antigen)); CLTB (Clathrin, light otide pyrophosphatase 1 (homologous to mouse Ly-41 polypeptide (Lcb)); DAF (Decay accelerating factor for antigen)); PECAM1 (Platelet/endothelial cell adhesion complement (CD55, Cromer blood group system)); 55 molecule (CD31 antigen)); PKD1 (Polycystic kidney dis- DPP4 (Dipeptidylpeptidase IV (CD26, adenosine deam- ease I (autosomal dominant)); PTCH (Patched (Dro- inase complexing protein 2)); ENG (Endoglin (Osler- sophila) homolog); RSN (Restin (Reed-Steinberg cell- Rendu-Weber syndrome 1)); F3 (Coagulation factor III expressed intermediate filament-associated protein));

40 79 EP 1 364 069 B1 80

RTN1 (Reticulon 1); SDC1 (Syndecan 1); SDC2 (Syn- binding protein, acid labile subunit); NGFB (Nerve growth decan 2 (heparan sulfate proteoglycan 1, cell surface- factor, beta polypeptide); PDGFA (Platelet-derived associated, fibroglycan)); SDC4 (Syndecan 4 (amphig- growth factor alpha polypeptide); PDGFRB (Platelet-de- lycan, ryudocan)); SELE (Selectin E (endothelial adhe- rived growth factor receptor, beta polypeptide); PGF (Pla- sion molecule 1)); SELL (Selectin L (lymphocyte adhe- 5 cental growth factor, vascular endothelial growth factor- sion molecule 1)); SELP (Selectin P (granule membrane related protein); PTN (Pleiotrophin (heparin binding protein 140kD, antigen CD62)); SELPLG (Selectin P lig- growth factor 8, neurite growth-promoting factor 1)); and); SIAT1 (Sialyltransferase 1 (beta-galactoside al- QSCN6 (Quiescin Q6); TAK1 (Transforming growth fac- pha-2,6-sialytransferase)); SLAM (Signaling lym- tor beta-activated kinase 1); TIEG (TGFB inducible early phocytic activation molecule); SPTA1 (Spectrin, alpha, 10 growth response); TIEG2 (TGFB inducible early growth erythrocytic 1 (elliptocytosis 2)); SPTB (Spectrin, beta, response 2); VEGF (Vascular endothelial growth factor); erythrocytic (includes sperocytosis, clinical type I)); ST2 VEGFB (Vascular endothelial growth factor B); VGF (Suppression of tumorigenicity 2); TBCC (Tubulin-spe- (VGF nerve growth factor inducible); VTN (Vitronectin cific chaperone c); THBS1 (Thrombospondin 1); (serum spreading factor, somatomedin B, complement TM4SF2 (Transmembrane 4 superfamily member 2); 15 S-protein)); A2M (Alpha-2-macroglobulin); ADAM17 (A TM4SF3 (Transmembrane 4 superfamily member 3); disintegrin and metalloproteinase domain 17 (tumor TNFSF4 (Tumor necrosis factor (ligand) superfamily, necrosis factor, alpha, converting enzyme)); ADSL (Ade- member 4 (tax-transcriptionally activated glycoprotein 1, nylosuccinate lyase); AOAH (Acyloxyacyl hydrolase 34kD)); TNFSF5 (Tumor necrosis factor (ligand) super- (neutrophil)); AOX1 (Aldehyde oxidase 1); ATP5J (ATP family, member 5); TNFSF7 (Tumor necrosis factor (lig- 20 synthase, H+ transporting, mitochondrial F0 complex, and) superfamily, member 7); TTN (Titin); TUBA1 (Tu- subunit F6); BCAT2 (Branched chain aminotransferase bulin, alpha 1 (testis specific)); TUBG (Tubulin, gamma 2, mitochondrial); BCKDHA (Branched chain keto acid polypeptide); VCAM1 (Vascular cell adhesion molecule dehydrogenase E1, alpha polypeptide (maple syrup 1); VCL (Vinculin); VIM (Vimentin); urine disease)); BCL6 (B-cell CLL/lymphoma 6 (zinc fin- 25 ger protein 51)); BCL7 (B-cell CLL/lymphoma 7); BHMT Miscellaneous (Betaine-homocysteine methyltransferase); BSG (Basi- gin); BTG1 (B-cell translocation gene 1, anti-prolifera- [0091] AREG (Amphiregulin (schwannoma-derived tive); C5 (Complement component 5); CAD (Carbamoyl- growth factor)); BCGF1 (B-cell growth factor 1 (12D)); phosphate synthetase 2, aspartate transcarbamylase, CTGF (Connective tissue growth factor); CTGF-L (Con- 30 and dihydroorotase); CATR1 (CATR tumorigenicity con- nective tissue growth factor-like protein); ECGF1 (En- version 1); CDR1 (Cerebellar degeneration-related pro- dothelial cell growth factor 1 (platelet-derived)); EGF (Ep- tein (34kD)); CHGB (Chromogranin B (secretogranin 1)); idermal growth factor); EPS15 (Epidermal growth factor CHIT1 (Chitinase 1); COL9A2 (Collagen, type IX, alpha receptor pathway substrate 15); EPS8 (Epidermal 2); COX10 (Cytochrome c oxidase subunit X (heme A: growth factor receptor pathway substrate 8); FGF1 (Fi- 35 famesyltransferase)); COX11 (Cytochrome c oxidase broblast growth factor 1 (acidic)); FGF10 (Fibroblast subunit 11); COX15 (Cytochrome c oxidase subunit 15); growth factor 10); FGF11 (Fibroblast growth factor 11); COX17 (Human homolog of yeast mitochondrial copper FGF12B (Fibroblast growth factor 12B); FGF13 (Fibrob- recruitment gene); COX5A (Cytochrome c oxidase sub- last growth factor 13); FGF14 (Fibroblast growth factor unit Va); COX5B (Cytochrome c oxidase subunit Vb); 14); FGF16 (Fibroblast growth factor 16); FGF6 (Fibrob- 40 COX6A1 (Cytochrome c oxidase subunit VIa polypeptide last growth factor 6); FGF7 (Fibroblast growth factor 7 1); COX6A2 (Cytochrome c oxidase subunit VIa polypep- (keratinocyte growth factor)); FGF8 (Fibroblast growth tide 2); COX6B (Cytochrome c oxidase subunit VIb); factor 8 (androgen-induced)); FGF9 (Fibroblast growth COX6C (Cytochrome c oxidase subunit VIc); COX7C factor 9 (glia-activating factor)); FGFR1 (Fibroblast (Cytochrome c oxidase subunit VIIc); COX7RP (Cyto- growth factor receptor 1 (fms-related tyrosine kinase 2, 45 chrome c oxidase subunit VII-related protein); COX8 (Cy- Pfeiffer syndrome)); FGFR2 (Fibroblast growth factor re- tochrome c oxidase subunit VIII); CPA1 (Carboxypepti- ceptor 2 (bacteria-expressed kinase, keratinocyte growth dase A1 (pancreatic)); CRHBP (Corticotropin releasing factor receptor, craniofacial dysostosis 1, Crouzon syn- hormone-binding protein); CRIP2 (Cysteine-rich protein drome, Pfeiffer syndrome, Jackson-Weiss syndrome)); 2); CTH (Cystathionase (cystathionine gamma-lyase)); FGFR3 (Fibroblast growth factor receptor 3 (achondro- 50 CTSB (Cathepsin B); CTSL (Cathepsin L); CYP (Clk-as- plasia, thanatophoric dwarfism)); FGFR4 (Fibroblast sociating RS-cyclophilin); DARS (Aspartyl-tRNA syn- growth factor receptor 4); FIBP (Fibroblast growth factor thetase); DEFA1 (Defensin, alpha 1, myeloid-related se- (acidic) intracellular binding protein); FIGF (C-fos in- quence); DSCAM (Down syndrome cell adhesion mole- duced growth factor (vascular endothelial growth factor cule); DUSP2 (Dual specificity phosphatase 2); DYT1 D)); HDGF (Hepatoma-derived, growth factor (high-mo- 55 (Dystonia 1, torsion (autosomal dominant)); EDN1 (En- bility group protein 1-like)); IGF1 (Insulin-like growth fac- dothelin 1); EGFL2 (EGF-like-domain, multiple 2); F5 tor 1 (somatomedin C)); IGF2 (Insulin-like growth factor (Coagulation factor V (proaccelerin, labile factor)); FMO1 2 (somatomedin A)); IGFALS (Insulin-like growth factor (Flavin containing monooxygenase 1); FUS (Fusion, de-

41 81 EP 1 364 069 B1 82 rived from t(12;16) malignant liposarcoma); FVT1 (Fol- ABC (ATP binding cassette)); TAPBP (TAP binding pro- licular lymphoma variant translocation 1); GARS (Glycyl- tein (tapasin)); ARHGDIB (Rho GDP dissociation inhib- tRNA synthetase); GZMB (Granzyme B (granzyme 2, cy- itor (GDI) beta); ATRX (Alpha thalassemia/mental retar- totoxic T-lymphocyte-associated serine esterase 1)); dation syndrome X-linked); BMZF2 (Zinc finger 2, bone GZMK (Granzyme K (, granzyme 3; tryp- 5 marrow); BMZF3 (Bone marrow zinc finger 3); BPI (Bac- tase II)); HGFAC (HGF activator); HRMT1L2 (HMT1 (hn- tericidal/permeability-increasing protein); CD14 (CD14 RNP methyltransferase, S. cerevisiae)-like 2); HSJ1 antigen); EPB41 (Erythrocyte membrane protein band (Heat shock protein, neuronal DNAJ-like 1); HSJ2 (Heat 4.1 (elliptocytosis 1, RH-linked)); EPB42 (Erythrocyte shock protein, DNAJ-like 2); IDUA (Iduronidase, alpha- membrane protein band 4.2); GATA1 (GATA-binding L-); IGFBP10 (Insulin-like growth factor binding protein 10 protein 1 (globin transcription factor 1)); GATA2 (GATA- 10); LDHA (Lactate dehydrogenase A); LDHB (Lactate binding protein 2); GATA3 (GATA-binding protein 3); dehydrogenase B); LGALS1 (Lectin, galactoside-bind- GATA4 (GATA-binding protein 4); GATA6 (GATA-bind- ing, soluble, I (galectin 1)); LMO1 (LIM domain only 1 ing protein 6); GZMA (Granzyme A (granzyme 1, cyto- (rhombotin 1)); LNPEP (Leucyl/cystinyl aminopepti- toxic T-lymphocyte-associated serine esterase 3)); dase); LPP (LIM domain-containing preferred transloca- 15 HBA1 (Hemoglobin, alpha 1); HBB (Hemoglobin, beta); tion partner in lipoma); MANA2 (Mannosidase, alpha type HBG1 (Hemoglobin, gamma A); HBZ (Hemoglobin, ze- II); MAOA (Monoamine oxidase A); MFNG (Manic fringe ta); HCF2 (Heparin cofactor II); HHEX (Hematopoietical- (Drosophila) homolog); MMP-20 (Enamelysin); MMP10 ly expressed homeobox); HK2 (Hexokinase 2); HP (Hap- (Matrix metalloproteinase 10 (stromelysin 2)); MMP19 toglobin); HPS (Hermansky-Pudlak syndrome); HPX (Matrix metalloproteinase 19); MMP8 (Matrix metallopro- 20 (Hemopexin); LAF4 (Lymphoid nuclear protein related to teinase 8 (neutrophil collagenase)); MT7SDNA (7S AF4); LCP1 (Lymphocyte cytosolic protein 1 (L-plastin)); DNA); NB (Neuroblastoma (neuroblastoma suppres- LRMP (Lymphoid-restricted membrane protein); MAL sor)); NB4S (Neuroblastoma stage 4S gene); NPAT (Nu- (Mal, T-cell differentiation protein); MLL (Myeloid/lym- clear protein, ataxia-telangiectasia locus); OAS2 (2’-5’ol- phoid or mixed-lineage leukemia (trithorax (Drosophila) igoadenylate synthetase 2); ORCTL3 (Organic cationic 25 homolog)); MLL2 (Myeloid/lymphoid or mixed-lineage transporter-like 3); PDHA1 (Pyruvate dehydrogenase leukemia 2); MLLT1 (Myeloid/lymphoid or mixed-lineage (lipoamide) alpha 1); PGAM1 (Phosphoglycerate mutase leukemia (trithorax (Drosophila) homolog); translocated 1 (brain)); PITX2 (Paired-like homeodomain transcription to, 1); MLLT2 (Myeloid/lymphoid or mixed-lineage leuke- factor 2); PRNP (Prion protein (p27-30) (Creutzfeld-Ja- mia (trithorax (Drosophila) homolog); translocated to, 2); kob disease, Gerstmann-Strausler-Scheinker syn- 30 MLLT3 (Myeloid/lymphoid or mixed-lineage leukemia drome, fatal familial insomnia)); PRSM1 (Protease, met- (trithorax (Drosophila) homolog); translocated to, 3); allo, 1, 33kD); PTGS2 (Prostaglandin-endoperoxide syn- MLLT4 (Myeloid/lymphoid or mixed-lineage leukemia thase 2 (prostaglandin G/H synthase and cyclooxygen- (trithorax (Drosophila) homolog); translocated to, 4); ase)); RAD50 (RAD50 (S. cerevisiae) homolog); MLLT6 (Myeloid/lymphoid or mixed-lineage leukemia RAD51C (RAD51 (S. cerevisiae) homolog C); RCN2 (Re- 35 (trithorax (Drosophila) homolog); translocated to, 6); ticulocalbin 2, EF-hand calcium binding domain); SET MLLT7 (Myeloid/lymphoid or mixed-lineage leukemia (SET translocation (myeloid leukemia-associated)); (trithorax (Drosophila) homolog); translocated to, 7); SIAT4A (Sialyltransferase 4A (beta-galactosidase al- MPO (Myeloperoxidase); MYD88 (Myeloid differentia- pha-2,3-sialytransferase)); SPARC (Secreted protein, tion primary response gene (88)); POU2F1 (POU do- acidic, cysteine-rich ()); TAL1 (T-cell acute 40 main, class 2, transcription factor 1); POU2F2 (POU do- lymphocytic leukemia 1); TBG (Thyroxin-binding globu- main, class 2, transcription factor 2); POU3F1 (POU do- lin); TFF1 (Trefoil factor 1 (breast cancer, estrogen-in- main, class 3, transcription factor 1); SCYC1 (Small in- ducible sequence expressed in)); TIMP4 (Tissue inhibitor ducible cytokine subfamily C, member 1 (lymphotactin)); of metalloproteinase 4); TSC1 ( 1); TNFRSF17 (Tumor necrosis factor receptor superfamily, TSC2 (Tuberous sclerosis 2); UCP2 (Uncoupling protein 45 member 17); VWF (Von Willebrand factor); 2 (mitochondrial, proton carrier)); UROS (Uroporphyrin- ogen III synthase (congenital erythropoietic porphyria)); Pharmacology VWF (Von Willebrand factor); ANT2 (Adenine nucleotide translocator 2 (fibroblast)); BSEP (Bile salt export pump [0092] ALDH1 (Aldehyde dehydrogenase 1, soluble); (ABC member 16, MDR/TAP subfamily)); GJB1 (Gap 50 ALDH10 (Aldehyde dehydrogenase 10 (fatty aldehyde junction protein, beta 1, 32kD (connexin 32, Charcot- dehydrogenase)); ALDH2 (Aldehyde dehydrogenase 2, Marie-Tooth neuropathy, X-linked)); KCNN3 (Potassium mitochondrial); ALDH3 (Aldehyde dehydrogenase 3); intermediate/small conductance calcium-activated chan- ALDH6 (Aldehyde dehydrogenase 6); ALDH7 (Aldehyde nel, subfamily N, member 3); OCLN (Occludin); PGY3 dehydrogenase 7); ALDH8 (Aldehyde dehydrogenase (P glycoprotein 3/multiple drug resistance 3); SLC2A3 55 8); ANT2 (Adenine nucleotide translocator 2 (fibroblast)); (Solute carrier family 2 (facilitated glucose transporter), APEX (APEX nuclease (multifunctional DNA repair en- member 3); SLC2A5 (Solute carrier family 2 (facilitated zyme)); BCHE (Butyrylcholinesterase); BLMH (Bleomy- glucose transporter), member 5); TAP1 (Transporter 1, cin hydrolase); CAT (Catalase); CDA (Cytidine deami-

42 83 EP 1 364 069 B1 84 nase); CYP11A (Cytochrome P450, subfamily XIA (cho- (Glutathione S-transferase M4); GSTM5 (Glutathione S- lesterol side chain cleavage)); CYP11B1 (Cytochrome transferase M5); GSTP1 (Glutathione S-transferase pi); P450, subfamily XIB (steroid 11-beta-hydroxylase), GSTT1 (Glutathione S-transferase theta 1); GSTT2 (Glu- polypeptide 1); CYP11B2 (Cytochrome P450, subfamily tathione S-transferase theta 2); GSTTLp28 (Glutathione- XIB (steroid 11-beta-hydroxylase), polypeptide 2); 5 S-transferase like); GSTZ1 (Glutathione S-transferase CYP17 (Cytochrome P450, subfamily XVII (steroid 17- Zeta 1 (maleylacetoacetate isomerase)); HPRT1 (Hy- alpha-hydroxylase), adrenal hyperplasia); CYP19 (Cyto- poxanthine phosphoribosyltransferase 1 (Lesch-Nyhan chrome P450, subfamily XIX (aromatization of andro- syndrome)); IMPDH1 (IMP (inosine monophosphate) de- gens)); CYP1A1 (Cytochrome P450, subfamily I (aromat- hydrogenase 1); IMPDH2 (IMP (inosine monophos- ic compound-inducible), polypeptide 1); CYP1A2 (Cyto- 10 phate) dehydrogenase 2); KCNN3 (Potassium interme- chrome P450, subfamily I (aromatic compound-induci- diate/small conductance calcium-activated channel, ble), polypeptide 2); CYP1B1 (Cytochrome P450, sub- subfamily N, member 3); MGST1 (Microsomal glutath- family I (dioxin-inducible), polypeptide 1 (glaucoma 3, pri- ione S-transferase 1); MGST2 (Microsomal glutathione mary infantile)); CYP21 (Cytochrome P450, subfamily S-transferase 2); MGST3 (Microsomal glutathione S- XXI (steroid 21-hydroxylase, congenital adrenal hyper- 15 transferase 3); MRP1 (Multiple drug resistance protein plasia)); CYP27A1 (Cytochrome P450, subfamily XXVIIA 1); NAT1 (N-acetyltransferase 1 (arylamine N-acetyl- (steroid 27-hydroxylase, cerebrotendinous xanthomato- transferase)); NMOR2 (NAD(P)H menadione oxidore- sis), polypeptide 1); CYP2A6 (Cytochrome P450, sub- ductase 2, dioxin-inducible); OCLN (Occludin); PGY1 (P family IIA (phenobarbital-inducible), polypeptide 6); glycoprotein 1/multiple drug resistance 1); PGY3 (P glyc- CYP2B (Cytochrome P450, subfamily IIB (phenobarbi- 20 oprotein 3/multiple drug resistance 3); RRM1 (Ribonu- tal-inducible)); CYP2B6 (Cytochrome P450, subfamily cleotide reductase M1 polypeptide); RRM2 (Ribonucle- IIB (phenobarbital-inducible), polypeptide 6); CYP2C18 otide reductase M2 polypeptide); SLC2A3 (Solute carrier (Cytochrome P450, subfamily IIC (mephenytoin 4-hy- family 2 (facilitated glucose transporter), member 3); droxylase), polypeptide 18); CYP2C19 (Cytochrome SLC2A5 (Solute carrier family 2 (facilitated glucose trans- P450, subfamily IIC (mephenytoin 4-hydroxylase)); 25 porter), member 5); SOD1 (Superoxide dismutase 1, sol- CYP2C9 (Cytochrome P450, subfamily IIC (mepheny- uble (amyotrophic lateral sclerosis 1 (adult))); SOD2 (Su- toin 4-hydroxylase), polypeptide 9); CYP2D6 (Cyto- peroxide dismutase 2, mitochondrial); SOD3 (Superox- chrome P450, subfamily IID (debrisoquine, sparteine, ide dismutase 3, extracellular); TAP1 (Transporter 1, etc., - metabolizing), polypeptide 6); CYP2E (Cyto- ABC (ATP binding cassette)); TAPBP (TAP binding pro- chrome P450, subfamily IIE (ethanol-inducible)); 30 tein (tapasin)); TK1 (Thymidine kinase 1, soluble); TPMT CYP2F1 (Cytochrome P450, subfamily IIF, polypeptide (Thiopurine S-methyltransferase); TXNRD1 (Thioredox- 1); CYP2J2 (Cytochrome P450, subfamily IIJ (arachidon- in reductase 1); TYMS (Thymidylate synthetase); ic acid epoxygenase) polypeptide 2); CYP3A3 (Cyto- UGALT (UDP-galactose translocator); UGT2B10 (UDP chrome P450, subfamily IIIA (niphedipine oxidase), glycosyltransferase 2 family, polypeptide B10); polypeptide 3); CYP3A5 (Cytochrome P450, subfamily 35 UGT2B15 (UDP glycosyltransferase 2 family, polypep- IIIA (niphedipine oxidase), polypeptide 5); CYP3A7 (Cy- tide B15); UGT2B4 (UDP glycosyltransferase 2 family, tochrome P450, subfamily IIIA, polypeptide 7); CYP4A11 polypeptide B4); UGT2B7 (UDP glycosyltransferase 2 (Cytochrome P450, subfamily IVA, polypeptide 11); family, polypeptide B7); UGT8 (UDP glycosyltransferase CYP4F3 (Cytochrome P450, subfamily IVF, polypeptide 8 (UDP-galactose ceramide galactosyltransferase)); 3 (leukotriene B4 omega hydroxylase)); CYP51 (Cyto- 40 UMPS (Uridine monophosphate synthetase (orotate chrome P450, 51 (lanosterol 14-alpha-demethylase)); phosphoribosyl transferase and orotidine-5’-decarboxy- DCK (Deoxycytidine kinase); DGUOK (Deoxyguanosine lase)); XDH (Xanthene dehydrogenase); kinase); DHFR (Dihydrofolate reductase); DIA4 (Diapho- rase (NADH/NADPH) (cytochrome b-5 reductase)); DPYD (Dihydropyrimidine dehydrogenase); EPHX1 45 (Epoxide hydrolase 1, microsomal (xenobiotic)); EPHX2 [0093] ABL1 (V-abl Abelson murine leukemia viral on- (Epoxide hydrolase 2, cytoplasmic); GJB1 (Gap junction cogene homolog 1); ABL2 (V-abl Abelson murine leuke- protein, beta 1, 32kD (connexin 32, Charcot-Marie-Tooth mia viral oncogene homolog 2 (arg, Abelson-related neuropathy, X-linked)); GLRX (Glutaredoxin (thioltrans- gene)); ABR (Active BCR-related gene); ACVR1B (Ac- ferase)); GPX1 (Glutathione peroxidase 1); GPX2 (Glu- 50 tivin A receptor, type IB); ADK (Adenosine kinase); tathione peroxidase 2 (gastrointestinal)); GPX3 (Glutath- ADRBK1 (Adrenergic, beta, receptor kinase 1); AK1 ione peroxidase 3 (plasma)); GPX4 (Glutathione perox- (Adenylate kinase 1); AK2 (Adenylate kinase 2); AK3 idase 4 (phospholipid hydro-peroxidase)); GSR (Glutath- (Adenylate kinase 3); AKT1 (V-akt murine thymoma viral ione reductase); GSS (Glutathione synthetase); GSTA2 oncogene homolog 1); AKT2 (V-akt murine thymoma vi- (Glutathione S-transferase A2); GSTA3 (Glutathione S- 55 ral oncogene homolog 2); ALOX12 (Arachidonate 12- transferase A3); GSTM1 (Glutathione S-transferase M1); lipoxygenase); ALOX5 (Arachidonate 5-lipoxygenase); GSTM2 (Glutathione S-transferase M2 (muscle)); ARAF1 (V-raf murine sarcoma 3611 viral oncogene ho- GSTM3 (Glutathione S-transferase M3 (brain)); GSTM4 molog 1); ARHA (Ras homolog gene family, member A);

43 85 EP 1 364 069 B1 86

ARHC (Ras homolog gene family, member C); ARHGDIB gene homolog)); ERBB3 (V-erb-b2 avian erythroblastic (Rho GDP dissociation inhibitor (GDI) beta); BLK (B lym- leukemia viral oncogene homolog 3); ERBB4 (V-erb-a phoid tyrosine kinase); BMPR2 (Bone morphogenetic avian erythroblastic leukemia viral oncogene homolog- protein receptor, type II (serine/threonine kinase)); BMX like 4); FBL (Fibrillarin); FER (Fer (fps/fes related) tyro- (BMX non-receptor tyrosine kinase); BRAF (V-raf murine 5 sine kinase (phosphoprotein NCP94)); FES (Feline sar- sarcoma viral oncogene homolog B1); BTK (Bruton ag- coma (Snyder-Theilen) viral (v-fes)/Fujinami avian sar- ammaglobulinemia tyrosine kinase); CAK (Cell adhesion coma (PRCII) viral (v-fps) oncogene homolog); FGFR1 kinase); CALM1 (Calmodulin 1 (phosphorylase kinase, (Fibroblast growth factor receptor 1 (fms-related tyrosine delta)); CAMK4 (Calcium/calmodulin-dependent protein kinase 2, Pfeiffer syndrome)); FGFR2 (Fibroblast growth kinase IV); CBLB (Cas-Br-M (murine) ectropic retroviral 10 factor receptor 2 (bacteria-expressed kinase, keratinoc- transforming sequence b); CCNH (Cyclin H); CDC2L1 yte growth factor receptor, craniofacial dysostosis 1, (Cell division cycle 2-like 1 (PITSLRE proteins)); CDC42 Crouzon syndrome, Pfeiffer syndrome, Jackson-Weiss (Cell division cycle 42 (GTP-binding protein, 25kD)); syndrome)); FGR (Gardner-Rasheed feline sarcoma vi- CDC42 (Cell division cycle 42 (GTP-binding protein, ral (v-fgr) oncogene homolog); FLT1 (Fms-related tyro- 25kD)); CDC7L1 (CDC7 (cell division cycle 7, S. cerevi- 15 sine kinase 1 (vascular endothelial growth factor/vascu- siae, homolog)-like 1); CDK2 (Cyclin-dependent kinase lar permeability factor receptor)); FLT3LG (Fms-related 2); CDK5 (Cyclin-dependent kinase 5); CDK6 (Cyclin- tyrosine kinase 3 ligand); FLT4 (Fms-related tyrosine ki- dependent kinase 6); CDK7 (Cyclin-dependent kinase 7 nase 4); FRK (Fyn-related kinase); FYB (FYN-binding (homolog of Xenopus MO15 cdk-activating kinase)); protein (FYB-120/130)); FYN (FYN oncogene related to CDK8 (Cyclin-dependent kinase 8); CDKN2B (Cyclin-de- 20 SRC, FGR, YES); GLA (Galactosidase, alpha); GNAI1 pendent kinase inhibitor 2B (p15, inhibits CDK4)); (Guanine nucleotide binding protein (G protein), alpha CHEK1 (CHK1 (checkpoint, S.pombe) homolog); CHN1 inhibiting activity polypeptide 1); GNG10 (Guanine nu- ( (chimaerin) 1); CHN2 (Chimerin (chimaerin) cleotide binding protein 10); GPRK6 (G protein-coupled 2); CHUK (Conserved helix-loop-helix ubiquitous ki- receptor kinase 6); GRB2 (Growth factor receptor-bound nase); CIS4 (STAT induced STAT inhibitor-4); CKS1 25 protein 2); GUCY1B3 ( 1, soluble, beta (CDC28 protein kinase 1); CKS2 (CDC28 protein kinase 3); HCK (Hemopoietic cell kinase); HIPK3 (Homeodo- 2); CLGN (Calmegin); CLK2 (CDC-like kinase 2); CLK3 main-interacting protein kinase 3); HRK (Harakiri, BCL2- (CDC-like kinase 3); CNK (Cytokine-inducible kinase); interacting protein (contains only BH3 domain)); ILK (In- COT (Cot (cancer Osaka thyroid) oncogene); CSK (C- tegrin-linked kinase); IRAK1 (Interleukin-1 receptor-as- src tyrosine kinase); CSNK1A1 (Casein kinase 1, alpha 30 sociated kinase 1); IRAK2 (Interleukin-1 receptor-asso- 1); CSNK1D (Casein kinase 1, delta); CSNK1E (Casein ciated kinase 2); ITPKB (Inositol 1,4,5-trisphosphate 3- kinase 1, epsilon); CSNK2A2 (Casein kinase 2, alpha kinase B); JAK1 (Janus kinase 1 (a protein tyrosine ki- prime polypeptide); CSNK2B (Casein kinase 2, beta nase)); JAK2 (Janus kinase 2 (a protein tyrosine kinase)); polypeptide); CTNNA1 (Catenin (cadherin-associated JAK3 (Janus kinase 3 (a protein tyrosine kinase, leuko- protein), alpha 1 (102kD)); CTNNB1 (Catenin (cadherin- 35 cyte)); KDR (Kinase insert domain receptor (a type III associated protein), beta 1 (88kD)); CTNND2 (Catenin receptor tyrosine kinase)); KIAA0641 (Apoptosis-asso- (cadherin-associated protein), delta 2 (neural plakophi- ciated tyrosine kinase); LCAT (Lecithin-cholesterol acyl- lin-related arm-repeat protein)); DGKA (Diacylglycerol ki- transferase); LCK (Lymphocyte-specific protein tyrosine nase, alpha (80kD)); DGKG (Diacylglycerol kinase, gam- kinase); LIMK1 (LIM domain kinase 1); LIMK2 (LIM do- ma (90kD)); DGKQ (Diacylglycerol kinase, theta 40 main kinase 2); LTK (Leukocyte tyrosine kinase); LYN (110kD)); DMPK (Dystrophia myotonica-protein kinase); (V-yes-1 Yamaguchi sarcoma viral related oncogene ho- DRG2 (Developmentally regulated GTP-binding protein molog); MACS (Myristoylated alanine-rich protein kinase 2); DVL3 (Dishevelled 3 (homologous to Drosophila C substrate (MARCKS, 80K-L)); MADH1 (MAD (mothers dsh)); DYRK1 (Dual-specificity tyrosine-(Y)-phosphor- against decapentaplegic, Drosophila) homolog 1); ylation regulated kinase 1); DYRK1B (Dual-specificity ty- 45 MADH2 (MAD (mothers against decapentaplegic, Dro- rosine-(Y)-phosphorylation regulated kinase 1B); sophila) homolog 2); MADH3 (MAD (mothers against de- DYRK2 (Dual-specificity tyrosine-(Y)-phosphorylation capentaplegic, Drosophila) homolog 3); MAPKAPK2 (Mi- regulated kinase 2); DYRK3 (Dual-specificity tyro- togen-activated protein kinase-activated protein kinase sine-(Y)-phosphorylation regulated kinase 3); DYRK4 2); MAPKAPK5 (Mitogen-activated protein kinase-acti- (Dual-specificity tyrosine-(Y)-phosphorylation regulated 50 vated protein kinase 5); MATK (Megakaryocyte-associ- kinase 4); EFNA1 (Ephrin-A1); EFNA5 (Ephrin-A5); ated tyrosine kinase); MEKK3 (MAP/ERK kinase kinase EFNB1 (Ephrin-B1); EFNB2 (Ephrin-B2); EGFR (Epider- 3); MEKK4 (MAP/ERK kinase kinase 4); MEKK5 mal growth factor receptor (avian erythroblastic leukemia (MAP/ERK kinase kinase 5); MST1R (Macrophage stim- viral (v-erb-b) oncogene homolog)); EPHA2 (EphA2); ulating 1 receptor (c-met-related tyrosine kinase)); NCK1 EPHA4 (EphA4); EPHA5 (EphA5); EPHA7 (EphA7); 55 (NCK adaptor protein 1); NEK3 (NIMA (never in mitosis EPHB3 (EphB3); EPHB4 (EphB4); EPHB6 (EphB6); gene a)-related kinase); NME1 (Non-metastatic cells 1, ERBB2 (V-erb-b2 avian erythroblastic leukemia viral on- protein (NM23A) expressed in); NME2 (Non-metastatic cogene homolog 2 (neuro/glioblastoma derived onco- cells 2, protein (NM23B) expressed in); NMI (N-myc (and

44 87 EP 1 364 069 B1 88

STAT) interactor); NPM1 (Nucleophosmin (nucleolar togen-activated 1 (MAP kinase 1; p40, p41)); PRKM10 phosphoprotein B23, numatrin)); NTRK1 (Neurotrophic (Protein kinase mitogen-activated 10 (MAP kinase)); tyrosine kinase, receptor, type 1); NTRK2 (Neurotrophic PRKM11 (Protein kinase mitogen- activated 11); tyrosine kinase, receptor, type 2); NTRK3 (Neurotrophic PRKM13 (Protein kinase mitogen- activated 13); PRKM3 tyrosine kinase, receptor, type 3); NTRKR1 (Neurotroph- 5 (Protein kinase, mitogen-activated 3 (MAP kinase 3; ic tyrosine kinase, receptor-related 1); NTRKR2 (Neuro- p44)); PRKM4 (Protein kinase, mitogen-activated 4 trophic tyrosine kinase, receptor-related 2); NTRKR3 (MAP kinase 4; p63)); PRKM6 (Protein kinase, mitogen- (Neurotrophic tyrosine kinase, receptor-related 3); activated 6 (extracellular signal-regulated kinase, p97)); PCTK3 (PCTAIRE protein kinase 3); PDE4B (Phos- PRKM7 (Protein kinase mitogen-activated 7 (MAP ki- phodiesterase 4B, cAMP-specific (dunce (Drosophi- 10 nase)); PRKM8 (Protein kinase mitogen-activated 8 la)-homolog phosphodiesterase E4)); PDGFA (Platelet- (MAP kinase)); PRKM9 (Protein kinase mitogen-activat- derived growth factor alpha polypeptide); PDGFB (Plate- ed 9 (MAP kinase)); PRKMK1 (Protein kinase, mitogen- let-derived growth factor beta polypeptide (simian sarco- activated, kinase 1 (MAP kinase kinase 1)); PRKMK1 ma viral (v-sis) oncogene homolog)); PDGFRA (Platelet- (Protein kinase, mitogen-activated, kinase 1 (MAP ki- derived growth factor receptor, alpha polypeptide); PDG- 15 nase kinase 1)); PRKMK2 (Protein kinase, mitogen-ac- FRB (Platelet-derived growth factor receptor, beta tivated, kinase 2, p45 (MAP kinase kinase 2)); PRKMK3 polypeptide); PDGFRL (Platelet-derived growth factor (Protein kinase, mitogen-activated, kinase 3 (MAP ki- receptor-like); PDK2 (Pyruvate dehydrogenase kinase, nase kinase 3)); PRKMK5 (Protein kinase, mitogen-ac- isoenzyme 2); PDK4 (Pyruvate dehydrogenase kinase, tivated, kinase 5 (MAP kinase kinase 5)); PRKMK7 (Pro- isoenzyme 4); PDPK1 (3-phosphoinositide dependent 20 tein kinase, mitogen-activated, kinase 7 (MAP kinase ki- protein kinase-1); PHKA2 (Phosphorylase kinase, alpha nase 7)); PRKR (Protein kinase, interferon-inducible 2 (liver), glycogen storage disease IX); PHKG2 (Phos- double stranded RNA dependent); PTK2 (PTK2 protein phorylase kinase, gamma 2 (testis)); PIASX-BETA (Pro- tyrosine kinase 2); PTK2B (Protein tyrosine kinase 2 be- tein inhibitor of activated STAT X); PIK3C3 (Phosphoi- ta); PTK7 (PTK7 protein tyrosine kinase 7); PTK9 (Pro- nositide-3-kinase, class 3); PIK3CA (Phosphoinositide- 25 tein tyrosine kinase 9); RAB8IP (Rab8 interacting protein 3-kinase, catalytic, alpha polypeptide); PIK3CA (Phos- (GC kinase)); RASA1 (RAS p21 protein activator (GT- phoinositide-3-kinase, catalytic, alpha polypeptide); Pase activating protein) 1); RET (Ret proto-oncogene PIK3CG (Phosphoinositide-3-kinase, catalytic, gamma (multiple endocrine neoplasia MEN2A, MEN2B and med- polypeptide); PIM1 (Pim-1 oncogene); PLA2G2A (Phos- ullary thyroid carcinoma 1, Hirschsprung disease)); pholipase A2, group IIA (platelets, synovial fluid)); PLCB4 30 RGS1 (Regulator of G-protein signalling 1); RGS16 (Phospholipase C, beta 4); PLCE (Phospholipase C, ep- (Regulator of G-protein signalling 16); RGS7 (Regulator silon); PLCG2 (Phospholipase C, gamma 2 (phosphati- of G-protein signalling 7); RHO7 (GTP-binding protein dylinositol-specific)); PPP2R5A (Protein phosphatase 2, Rho7); RHOK (Rhodopsin kinase); ROCK1 (Rho-asso- regulatory subunit B (B56), alpha isoform); PPP2R5B ciated, coiled-coil containing protein kinase 1); RPS6KA2 (Protein phosphatase 2, regulatory subunit B (B56), beta 35 (Ribosomal protein S6 kinase, 90kD, polypeptide 2); isoform); PPP2R5C (Protein phosphatase 2, regulatory RPS6KB 1 (Ribosomal protein S6 kinase, 70kD, polypep- subunit B (B56), gamma isoform); PPP2R5D (Protein tide 1); RYK (RYK receptor-like tyrosine kinase); SAPK3 phosphatase 2, regulatory subunit B (B56), delta iso- (Stress-activated protein kinase 3); SERK1 (SAPK/Erk form); PPP2R5E (Protein phosphatase 2, regulatory sub- kinase 1); SFN (Stratifin); SH2D1A (SH2 domain protein unit B (B56), epsilon isoform); PRKAA2 (Protein kinase, 40 1A, Duncan’s disease (lymphoproliferative syndrome)); AMP-activated, alpha 2 catalytic subunit); PRKACA (Pro- SH3D1B (SH3 domain protein 1B); SRC (V-src avian sar- tein kinase, cAMP-dependent, catalytic, alpha); coma (Schmidt-Ruppin A-2) viral oncogene homolog); PRKACB (Protein kinase, cAMP-dependent, catalytic, SRPK2 (SFRS protein kinase 2); SSI-1 (JAK binding pro- beta); PRKACG (Protein kinase, cAMP-dependent, cat- tein); SSI-3 (STAT induced STAT inhibitor 3); STAT1 alytic, gamma); PRKAG1 (Protein kinase, AMP-activat- 45 (Signal transducer and activator of transcription 1, 91kD); ed, gamma 1 non-catalytic subunit); PRKAR1A (Protein STAT2 (Signal transducer and activator of transcription kinase, cAMP-dependent, regulatory, type I, alpha (tis- 2, 113kD); STAT3 (Signal transducer and activator of sue specific extinguisher 1)); PRKAR1B (Protein kinase, transcription 3 (acute-phase response factor)); STAT4 cAMP-dependent, regulatory, type I, beta); PRKAR2B (Signal transducer and activator of transcription 4); (Protein kinase, cAMP-dependent, regulatory, type II, be- 50 STAT5A (Signal transducer and activator of transcription ta); PRKCA (Protein kinase C, alpha); PRKCB1 (Protein 5A); STAT6 (Signal transducer and activator of transcrip- kinase C, beta 1); PRKCG (Protein kinase C, gamma); tion 6, interleukin-4 induced); STATI2 (STAT induced PRKCI (Protein kinase C, iota); PRKCL1 (Protein kinase STAT inhibitor-2); STK11 (Serine/threonine kinase 11 C-like 1); PRKCL2 (Protein kinase C-like 2); PRKCM (Peutz-Jeghers syndrome)); STK15 (Serine/threonine (Protein kinase C, mu); PRKCQ (Protein kinase C, theta); 55 kinase 15); STK17A (Serine/threonine kinase 17a (ap- PRKCZ (Protein kinase C, zeta); PRKG1 (Protein kinase, optosis-inducing)); STK17B (Serine/threonine kinase cGMP-dependent, type I); PRKG2 (Protein kinase, 17b (apoptosis-inducing)); STK2 (Serine/threonine ki- cGMP-dependent, type II); PRKM1 (Protein kinase, mi- nase 2); STK3 (Serine/threonine kinase 3 (Ste20, yeast

45 89 EP 1 364 069 B1 90 homolog)); STK4 (Serine/threonine kinase 4); SUB1.5 (Down-regulator of transcription 1, TBP-binding (nega- (Guanine nucleotide exchange factor; 115-kD; mouse tive cofactor 2)); DUT (DUTP pyrophosphatase); E2F1 Lsc homolog); SYK (Spleen tyrosine kinase); TESK1 (E2F transcription factor 1); E2F2 (E2F transcription fac- (Testis-specific kinase 1); TIAM1 (T-cell lymphoma inva- tor 2); E2F5 (E2F transcription factor 5, p130-binding); sion and metastasis 1); TK2 (Thymidine kinase 2, mito- 5 EGR1 (Early growth response 1); EIF3S6 (Eukaryotic chondrial); TNFAIP1 (Tumor necrosis factor, alpha-in- translation initiation factor 3, subunit 6 (48kD)); ELF1 duced protein 1 (endothelial)); TRK (Oncogene TRK); (E74-like factor 1 (ets domain transcription factor)); ELF3 TRK1 (TRNA lysine 1); TTK (TTK protein kinase); TXK (E74-like factor 3 (ets domain transcription factor)); ELK4 (TXK tyrosine kinase); TYK2 (Tyrosine kinase 2); TYRO3 (ELK4, ETS-domain protein (SRF accessory protein 1) (TYRO3 protein tyrosine kinase); TYROBP (TYRO pro- 10 NOTE: Symbol and name provisional); EP300 (E1A bind- tein tyrosine kinase binding protein); UBE1L (Ubiquitin- ing protein p300); ERV3 (Endogenous retroviral se- activating enzyme E1, like); UBE2A (Ubiquitin-conjugat- quence 3 (includes zinc finger protein H-plk/HPF9)); ing enzyme E2A (RAD6 homolog)); UBE2B (Ubiquitin- ESR1 (Estrogen receptor 1); ETS2 (V-ets avian eryth- conjugating enzyme E2B (RAD6 homolog)); VASP (Va- roblastosis virus E26 oncogene homolog 2); ETV1 (Ets sodilator-stimulated phosphoprotein); VAV2 (Vav 2 on- 15 variant gene 1); ETV3 (Ets variant gene 3); ETV4 (Ets cogene); VRK2 (Vaccinia related kinase 2); WAS (Wisko- variant gene 4 (E1A enhancer-binding protein, E1AF)); tt-Aldrich syndrome (ecezema-thrombocytopenia)); ETV5 (Ets variant gene 5 (ets-related molecule)); EZF YES1 (V-yes-1 Yamaguchi sarcoma viral oncogene ho- (Endothelial Kruppel-like zinc finger protein); FKHR molog 1); YESP (V-yes-1 Yamaguchi sarcoma viral on- (Forkhead (Drosophila) homolog 1 (rhabdomyosarco- cogene homolog pseudogene); ZAP70 (Zeta-chain 20 ma)); FLI1 (Friend leukemia virus integration 1); FSRG1 (TCR) associated protein kinase (70 kD)); ZPK (Zipper (Female sterile homeotic-related gene 1 (mouse ho- (leucine) protein kinase); molog)); GART (Phosphoribosylglycinamide formyl- transferase, phosphoribosylglycinamide synthetase, Transcription phosphoribosylaminoimidazole synthetase); GATA1 25 (GATA-binding protein 1 (globin transcription factor 1)); [0094] ADA (Adenosine deaminase); ADPRT (ADP- GATA2 (GATA-binding protein 2); GATA3 (GATA-bind- ribosyltransferase (NAD+; poly (ADP-ribose) polymer- ing protein 3); GATA4 (GATA-binding protein 4); GLI (Gli- ase)); ADSS (Adenylosuccinate synthase); AHR (Aryl oma-associated oncogene homolog (zinc finger pro- hydrocarbon receptor); ATBF1 (AT-binding transcription tein)); GRSF1 (G-rich RNA sequence binding factor 1); factor 1); ATF1 (Activating transcription factor 1); ATF3 30 GTF2H2 (General transcription factor IIH, polypeptide 2 (Activating transcription factor 3); ATF4 (Activating tran- (44kD subunit)); H4FI (H4 histone family, member I); scription factor 4 (tax-responsive enhancer element HHEX (Hematopoietically expressed homeobox); HIF1A B67)); BARD1 (BRCA1 associated RING domain 1); (Hypoxia-inducible factor 1, alpha subunit (basic helix- BCL6 (B-cell CLL/lymphoma 6 (zinc finger protein 51)); loop-helix transcription factor)); HIVEP1 (Human immu- BMZF2 (Zinc finger 2, bone marrow); BMZF3 (Bone mar- 35 nodeficiency virus type I enhancer-binding protein 1); row zinc finger 3); CBF2 (CCAAT-box-binding transcrip- HLF (Hepatic leukemia factor); HMG17 (High-mobility tion factor); CBFA2 (Core-binding factor, runt domain, group (nonhistone chromosomal) protein 17); HMG2 alpha subunit 2 (acute myeloid leukemia 1; aml1 onco- (High-mobility group (nonhistone chromosomal) protein gene)); CBFA3 (Core-binding factor, runt domain, alpha 2); HNRPK (Heterogeneous nuclear ribonucleoprotein subunit 3); CBFB (Core-binding factor, beta subunit); 40 K); HZF2 (Zinc finger (C2H2)); ICSBP1 (Interferon con- CEBPA (CCAAT/enhancer binding protein (C/EBP), al- sensus sequence binding protein 1); ID1 (Inhibitor of pha); CEBPB (CCAAT/enhancer binding protein DNA binding 1, dominant negative helix-loop-helix pro- (C/EBP), beta); CEBPD (CCAAT/enhancer binding pro- tein); ID2 (Inhibitor of DNA binding 2, dominant negative tein (C/EBP), delta); CEBPE (CCAAT/enhancer binding helix-loop-helix protein); ID3 (Inhibitor of DNA binding 3, protein (C/EBP), epsilon); CEBPG (CCAAT/enhancer 45 dominant negative helix-loop-helix protein); ID4 (Inhibitor binding protein (C/EBP), gamma); CENPE (Centromere of DNA binding 4, dominant negative helix-loop-helix pro- protein E (312kD)); CHD1 (Chromodomain helicase DNA tein); IRF1 (Interferon regulatory factor 1); IRF2 (Inter- binding protein 1); CHD2 (Chromodomain helicase DNA feron regulatory factor 2); IRF4 (Interferon regulatory fac- binding protein 2); CHD3 (Chromodomain helicase DNA tor 4); IRF5 (Interferon regulatory factor 5); IRF7 (Inter- binding protein 3); CHD4 (Chromodomain helicase DNA 50 feron regulatory factor 7); JUN (V-jun avian sarcoma vi- binding protein 4); CREB2 (CAMP responsive element rus 17 oncogene homolog); JUND (Jun D proto-onco- binding protein 2); CREBBP (CREB binding protein gene); KIAA0646 (C3HC4-type zinc finger protein); LAF4 (Rubinstein-Taybi syndrome)); CSE1L (Chromosome (Lymphoid nuclear protein related to AF4); LKLF (Lung segregation 1 (yeast homolog)-like); CSTF3 (Cleavage Kruppel-like zinc finger transcription factor); LYF1 (Zinc stimulation factor, 3’ pre-RNA, subunit 3, 77kD); CTPS 55 finger protein, subfamily 1A, 1 (Ikaros)); LYL1 (Lymphob- (CTP synthase); DCK (Deoxycytidine kinase); DCTD lastic leukemia derived sequence 1); MAFG (V-maf mus- (DCMP deaminase); DDIT3 (DNA-damage-inducible culoaponeurotic fibrosarcoma (avian) oncogene family, transcript 3); DGUOK (Deoxyguanosine kinase); DR1 protein G); MAX (MAX protein); MAZ (MYC-associated

46 91 EP 1 364 069 B1 92 zinc finger protein (purine-binding transcription factor)); protein); SOX4 (SRY (sex determining region Y)-box 4); MBLL (C3H-type zinc finger protein; similar to D. mela- SP100 (Nuclear antigen Sp100); SPIB (Spi-B transcrip- nogaster muscleblind B protein); MDM2 (Mouse double tion factor (Spi-1/PU.1 related)); SRF (Serum response minute 2, human homolog of; p53-binding protein); factor (c-fos serum response element-binding transcrip- MHC2TA (MHC class II transactivator); MKI67 (Antigen 5 tion factor)); STAT3 (Signal transducer and activator of identified by monoclonal antibody Ki-67); MNDA (Mye- transcription 3 (acute-phase response factor)); STAT4 loid cell nuclear differentiation antigen); MSX1 (Msh (Dro- (Signal transducer and activator of transcription 4); sophila) homeo box homolog 1 (formerly homeo box 7)); STAT5A (Signal transducer and activator of transcription MTHFD (5,10-methylenetetrahydrofolate dehydroge- 5A); TAF2C2 (TATA box binding protein (TBP)-associ- nase, 5,10-methylenetetrahydrofolate cyclohydrolase, 10 ated factor, RNA polymerase II, C2, 105kD); TAL2 (T- 10-formyltetrahydrofolate synthetase); MYC (V-myc avi- cell acute lymphocytic leukemia 2); TCEB1L (Transcrip- an myelocytomatosis viral oncogene homolog); NCBP tion elongation factor B (SIII), polypeptide 1-like); TCF1 (Nuclear cap binding protein, 80kD); NCBP (Nuclear cap (Transcription factor 1, hepatic; LF-B1, hepatic nuclear binding protein, 80kD); NDP52 (Nuclear domain 10 pro- factor (HNF1), albumin proximal factor); TCF12 (Tran- tein); NFE2 (Nuclear factor (erythroid-derived 2), 45kD); 15 scription factor 12 (HTF4, helix-loop-helix transcription NFKB 1 (Nuclear factor of kappa light polypeptide gene factors 4)); TCF3 (Transcription factor 3 (E2A immu- enhancer in B-cells 1 (p 105)); NFKB2 (Nuclear factor of noglobulin enhancer binding factors E12/E47)); TCF7 kappa light polypeptide gene enhancer in B-cells 2 (Transcription factor 7 (T-cell specific, HMG-box)); TCF8 (p49/p100)); NFYA (Nuclear transcription factor Y, al- (Transcription factor 8 (represses interleukin 2 expres- pha); NP (Nucleoside phosphorylase); NURR1 (Nuclear 20 sion)); TCF9 (Transcription factor 9 (binds GC-rich se- receptor related 1 (transcriptionally inducible)); ODC1 quences)); TEGT (Testis enhanced gene transcript); (Ornithine decarboxylase 1); PAX3 (Paired box gene 3 TFAP2B (Transcription factor AP-2 beta (activating en- (Waardenburg syndrome 1)); PBX1 (Pre-B-cell leukemia hancer-binding protein 2 beta)); TFAP4 (Transcription transcription factor 1); PBX3 (Pre-B-cell leukemia tran- factor AP-4 (activating enhancer-binding protein 4)); scription factor 3); PCNA (Proliferating cell nuclear anti- 25 TFDP2 (Transcription factor Dp-2 (E2F dimerization part- gen); PEX6 (Peroxisomal biogenesis factor 6); PITX2 ner 2)); THRA (Thyroid hormone receptor, alpha (avian (Paired-like homeodomain transcription factor 2); PML erythroblastic leukemia viral (v-erb-a) oncogene ho- (Promyelocytic leukemia); POU1F1 (POU domain, class molog)); TIAL1 (TIA1 cytotoxic granule-associated RNA- 1, transcription factor 1 (Pit1, growth hormone factor 1)); binding protein-like 1); TK1 (Thymidine kinase 1, solu- POU2AF1 (POU domain, class 2, associating factor 1); 30 ble); TOP1 (Topoisomerase (DNA) I); TOP2B (Topoi- POU2F1 (POU domain, class 2, transcription factor 1); somerase (DNA) II beta (180kD)); TP53 (Tumor protein POU2F2 (POU domain, class 2, transcription factor 2); p53 (Li-Fraumeni syndrome)); UBL1 (Ubiquitin-like 1 POU3F1 (POU domain, class 3, transcription factor 1); (sentrin)); WT1 (Wilms tumor 1); WT1 (Wilms tumor 1); POU3F2 (POU domain, class 3, transcription factor 2); XPO1 (Exportin 1 (CRM1, yeast, homolog)); ZFP103 POU5F1 (POU domain, class 5, transcription factor 1); 35 (Zinc finger protein homologous to Zfp103 in mouse); PPAT (Phosphoribosyl pyrophosphate amidotrans- ZFP36 (Zinc finger protein homologous to Zfp-36 in ferase); PROP1 (Prophet of Pit1, paired-like homeodo- mouse); ZFP37 (Zinc finger protein homologous to Zfp37 main transcription factor); PRPS1 (Phosphoribosyl pyro- in mouse); ZFP93 (Zinc finger protein); ZFX (Zinc finger phosphate synthetase 1); PTB (Polypyrimidine tract protein, X-linked); ZFY (Zinc finger protein, Y-linked); binding protein (heterogeneous nuclear ribonucleopro- 40 ZK1 (Kruppel-type zinc finger (C2H2)); ZNF10 (Zinc fin- tein I)); RANBP2 (RAN binding protein 2); RARB (Retin- ger protein 10 (KOX 1)); ZNF121 (Zinc finger protein 121 oic acid receptor, beta); RARG (Retinoic acid receptor, (clone ZHC32)); ZNF124 (Zinc finger protein 124 (HZF- gamma); RECQL (RecQ protein-like (DNA helicase Q1- 16)); ZNF127 (Zinc finger protein 127); ZNF 131 (Zinc like)); RENBP (Renin-binding protein); RFX1 (Regulato- finger protein 131 (clone pHZ-10)); ZNF132 (Zinc finger ry factor X, 1 (influences HLA class II expression)); RFX2 45 protein 132 (clone pHZ-12)); ZNF133 (Zinc finger protein (Regulatory factor X, 2 (influences HLA class II expres- 133 (clone pHZ-13)); ZNF134 (Zinc finger protein 134 sion)); RFX3 (Regulatory factor X, 3 (influences HLA (clone pHZ-15)); ZNF135 (Zinc finger protein 135 (clone class II expression)); RFX4 (Regulatory factor X, 4 (in- pHZ-17)); ZNF136 (Zinc finger protein 136 (clone pHZ- fluences HLA class II expression)); RFX5 (Regulatory 20)); ZNF137 (Zinc finger protein 137 (clone pHZ-30)); factor X, 5 (influences HLA class II expression)); RFXAP 50 ZNF139 (Zinc finger protein 139 (clone pHZ-37)); (Regulatory factor X-associated protein); RXRA (Retin- ZNF140 (Zinc finger protein 140 (clone pHZ-39)); oid X receptor, alpha); SATB1 (Special AT-rich sequence ZNF141 (Zinc finger protein 141 (clone pHZ-44)); binding protein 1 (binds to nuclear matrix/scaffold-asso- ZNF142 (Zinc finger protein 142 (clone pHZ-49)); ciating DNA’s)); SFRS7 (Splicing factor, arginine/serine- ZNF143 (Zinc finger protein 143 (clone pHZ-1)); ZNF144 rich 7 (35kD)); SKIL (SKI-like); SLUG (Slug (chicken ho- 55 (Zinc finger protein 144 (Mel-18)); ZNF145 (Zinc finger molog), zinc finger protein); SMARCA2 (SWI/SNF relat- protein 145 (Kruppel-like, expressed in promyelocytic ed, matrix associated, actin dependent regulator of chro- leukemia)); ZNF147 (Zinc finger protein 147 (estrogen- matin, subfamily a, member 2); SON (SON DNA binding responsive finger protein)); ZNF148 (Zinc finger protein

47 93 EP 1 364 069 B1 94

148 (pHZ-52)); ZNF151 (Zinc finger protein 151 (pHZ- ent kinase inhibitor 1A (p21, Cip1)); CDKN1C (Cyclin- 67)); ZNF154 (Zinc finger protein 154 (pHZ-92)); ZNF155 dependent kinase inhibitor 1C (p57, Kip2)); CDKN2A (Zinc finger protein 155 (pHZ-96)); ZNF157 (Zinc finger (Cyclin-dependent kinase inhibitor 2A (melanoma, p16, protein 157 (HZF22)); ZNF162 (Zinc finger protein 162); inhibits CDK4)); CHES1 (Checkpoint suppressor 1); ZNF165 (); ZNF169 (Zinc finger 5 COT (Cot (cancer Osaka thyroid) oncogene); CRK (V- protein 169); ZNF 173 (Zinc finger protein 173); ZNF 177 crk avian sarcoma virus CT10 oncogene homolog); (Zinc finger protein 177); ZNF 189 (Zinc finger protein CRKL (V-crk avian sarcoma virus CT10 oncogene ho- 189); ZNF198 (Zinc finger protein 198); ZNF2 (Zinc finger molog-like); CSF1R (Colony stimulating factor 1 recep- protein 2); ZNF20 (Zinc finger protein, C2H2, rapidly tor, formerly McDonough feline sarcoma viral (v-fms) on- turned over); ZNF200 (Zinc finger protein 200); ZNF202 10 cogene homolog); D10S170 (DNA segment, single copy, (Zinc finger protein 202); ZNF204 (Zinc finger protein probe pH4 (transforming sequence, thyroid-1,); DCC 204); ZNF205 (Zinc finger protein 205); ZNF206 (Zinc (Deleted in colorectal carcinoma); DDX6 (DEAD/H (Asp- finger protein 206); ZNF207 (Zinc finger protein 207); Glu-Ala-Asp/His) box polypeptide 6 (RNA helicase, ZNF239 (Zinc finger protein 239); ZNF259 (Zinc finger 54kD)); E2F1 (E2F transcription factor 1); ECT2 (Epithe- protein 259); ZNF261 (Zinc finger protein 261); ZNF262 15 lial cell transforming sequence 2 oncogene); EGFR (Ep- (Zinc finger protein 262); ZNF263 (Zinc finger protein idermal growth factor receptor (avian erythroblastic 263); ZNF264 (Zinc finger protein 264); ZNF3 (Zinc finger leukemia viral (v-erb-b) oncogene homolog)); EIF3S6 protein 3 (A8-51)); ZNF35 (Zinc finger protein 35 (clone (Eukaryotic translation initiation factor 3, subunit 6 HF.10)); ZNF37A (Zinc finger protein 37a (KOX 21)); (48kD)); ELE1 (RET-activating gene ELE1); ELK1 ZNF42 (Zinc finger protein 42 (myeloid-specific retinoic 20 (ELK1, member of ETS oncogene family); ELK2P1 acid- responsive)); ZNF44 (Zinc finger protein 44 (KOX (ELK2, member of ETS oncogene family, pseudogene 7)); ZNF45 (Zinc finger protein 45 (a Kruppel-associated 1); ELK3 (ELK3, ETS-domain protein (SRF accessory box (KRAB) domain polypeptide)); ZNF6 (Zinc finger pro- protein 2) NOTE: Symbol and name provisional.); EMP1 tein 6 (CMPX1)); ZNF7 (Zinc finger protein 7 (KOX 4, (Epithelial membrane protein 1); EMS1 (Ems1 sequence clone HF.16)); ZNF74 (Zinc finger protein 74 (Cos52)); 25 (mammary tumor and squamous cell carcinoma-associ- ZNF76 (Zinc finger protein 76 (expressed in testis)); ated (p80/85 src substrate)); EPHA1 (EphA1); EPHA3 ZNF8 (Zinc finger protein 8 (clone HF.18)); ZNF84 (Zinc (EphA3); ERBA2L (V-erb-a avian erythroblastic leuke- finger protein 84 (HPF2)); ZNF85 (Zinc finger protein 85); mia viral oncogene homolog 2-like); ERBAL2 (V-erb-a ZNF9 (Zinc finger protein 9 (a cellular retroviral nucleic avian erythroblastic leukemia viral oncogene homolog- acid binding protein)); ZNF91 (Zinc finger protein 91 30 like 2); ERBB2 (V-erb-b2 avian erythroblastic leukemia (HPF7, HTF10)); viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)); ERBB3 (V-erb-b2 avian erythrob- Tumor Suppressor/Oncogenes lastic leukemia viral oncogene homolog 3); ERBB4 (V- erb-a avian erythroblastic leukemia viral oncogene ho- [0095] ABL1 (V-abl Abelson murine leukemia viral on- 35 molog-like 4); ERG (V-ets avian erythroblastosis virus cogene homolog 1); ABL2 (V-abl Abelson murine leuke- E26 oncogene related); ETS1 (V-ets avian erythroblas- mia viral oncogene homolog 2 (arg, Abelson-related tosis virus E26 oncogene homolog 1); ETS2 (V-ets avian gene)); AKT1 (V-akt murine thymoma viral oncogene ho- erythroblastosis virus E26 oncogene homolog 2); ETV 1 molog 1); AKT2 (V-akt murine thymoma viral oncogene (Ets variant gene 1); ETV3 (Ets variant gene 3); ETV6 homolog 2); APC (Adenomatosis polyposis coli); ARAF1 40 (Ets variant gene 6 (TEL oncogene)); EVI1 (Ecotropic (V-raf murine sarcoma 3611 viral oncogene homolog 1); viral integration site 1); EWSR1 (Ewing sarcoma break- ARAF2 (V-raf murine sarcoma 3611 viral oncogene ho- point region 1); FAT (FAT tumor suppressor (Drosophila) molog 2); ARHA (Ras homolog gene family, member A); homolog); FER (Fer (fps/fes related) tyrosine kinase ARHB (Ras homolog gene family, member B); ARHC (phosphoprotein NCP94)); FES (Feline sarcoma (Sny- (Ras homolog gene family, member C); AXL (AXL recep- 45 der-Theilen) viral (v-fes)/Fujinami avian sarcoma (PRCII) tor tyrosine kinase); BCL2 (B-cell CLL/lymphoma 2); viral (v-fps) oncogene homolog); FGF3 (Fibroblast BCL3 (B-cell CLL/lymphoma 3); BCR (Breakpoint cluster growth factor 3 (murine mammary tumor virus integration region); BLYM (Avian lymphoma virus-derived trans- site (v-int-2) oncogene homolog)); FGF4 (Fibroblast forming sequence); BMI1 (Murine leukemia viral (bmi-1) growth factor 4 (heparin secretory transforming protein oncogene homolog); BRAF (V-raf murine sarcoma viral 50 1, Kaposi sarcoma oncogene)); FGF6 (Fibroblast growth oncogene homolog B1); BRAFP (V-raf murine sarcoma factor 6); FGR (Gardner-Rasheed feline sarcoma viral viral oncogene homolog B1 pseudogene); CBFA2 (Core- (v-fgr) oncogene homolog); FKHL1 (Forkhead (Dro- binding factor, runt domain, alpha subunit 2 (acute my- sophila)-like 1); FLI1 (Friend leukemia virus integration eloid leukemia 1; aml1 oncogene)); CBL (Cas-Br-M 1); FLT1 (Fms-related tyrosine kinase 1 (vascular en- (murine) ecotropic retroviral transforming sequence); 55 dothelial growth factor/vascular permeability factor re- CCND1 (Cyclin D1 (PRAD1: parathyroid adenomatosis ceptor)); FOS (V-fos FBJ murine osteosarcoma viral on- 1)); CDH1 (Cadherin 1, E-cadherin (epithelial)); CDK4 cogene homolog); FOSB (FBJ murine osteosarcoma vi- (Cyclin-dependent kinase 4); CDKN1A (Cyclin-depend- ral oncogene homolog B); FOSL1 (FOS-like antigen-1);

48 95 EP 1 364 069 B1 96

FOSL2 (FOS-like antigen 2); FYN (FYN oncogene relat- homolog-like 2); MYC (V-myc avian myelocytomatosis ed to SRC, FGR, YES); GLI (Glioma-associated onco- viral oncogene homolog); MYCL1 (V-myc avian myelo- gene homolog (zinc finger protein)); GLI2 (GLI-Kruppel cytomatosis viral oncogene homolog 1, lung carcinoma family member GLI2); GLI3 (GLI-Kruppel family member derived); MYCL2 (V-myc avian myelocytomatosis viral GLI3 (Greig cephalopolysyndactyly syndrome)); GRF2 5 oncogene homolog 2); MYCLK1 (V-myc avian myelocy- (Guanine nucleotide-releasing factor 2 (specific for crk tomatosis viral oncogene homolog-like 1); MYCN (V-myc proto-oncogene)); GRO1 (GRO1 oncogene (melanoma avian myelocytomatosis viral related oncogene, neurob- growth stimulating activity, alpha)); GRO2 (GRO2 onco- lastoma derived); MYCP (V-myc avian myelocytomato- gene); GRO3 (GRO3 oncogene); HCK (Hemopoietic cell sis viral oncogene homolog pseudogene); NBL1 (Neu- kinase); HKR3 (GLI-Kruppel family member HKR3); 10 roblastoma candidate region, suppression of tumori- HRAS (V-Ha-ras Harvey rat sarcoma viral oncogene ho- genicity 1); NF1 (Neurofibromin 1 (neurofibromatosis, molog); HRASP (V-Ha-ras Harvey rat sarcoma viral on- von Recklinghausen disease, Watson disease)); NF2 cogene homolog pseudogene); INT6P1 (Murine mam- (Neurofibromin 2 (bilateral acoustic neuroma)); NFKB2 mary tumor integration site 6 (oncogene homolog) pseu- (Nuclear factor of kappa light polypeptide gene enhancer dogene 1); IRF4 (Interferon regulatory factor 4); JUN (V- 15 in B-cells 2 (p49/p100)); NKTR (Natural killer-tumor rec- jun avian sarcoma virus 17 oncogene homolog); JUNB ognition sequence); NOTCH4 (Notch (Drosophila) ho- (Jun B proto-oncogene); JUND (Jun D proto-oncogene); molog 4); NOV (Nephroblastoma overexpressed gene); KAI1 (Kangai 1 (suppression of tumorigenicity 6, pros- NRAS (Neuroblastoma RAS viral (v-ras) oncogene ho- tate; CD82 antigen (R2 leukocyte antigen, antigen de- molog); NRASL1 (Neuroblastoma RAS viral (v-ras) on- tected by monoclonal and antibody IA4))); KIT (V-kit Har- 20 cogene homolog-like 1); NRASL2 (Neuroblastoma RAS dy-Zuckerman 4 feline sarcoma viral oncogene ho- viral (v-ras) oncogene homolog-like 2); NRASL3 (Neu- molog); KRAS1P (V-Ki-rasl Kirsten rat sarcoma 1 viral roblastoma RAS viral (v-ras) oncogene homolog-like 3); oncogene homolog, processed pseudogene); KRAS2 NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1); (V-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene ho- OVC (Oncogene OVC (ovarian adenocarcinoma onco- molog); LBC (Lymphoid blast crisis oncogene); LCK 25 gene)); PACE (Paired basic amino acid cleaving enzyme (Lymphocyte-specific protein tyrosine kinase); LCN2 (furin, membrane associated receptor protein)); PDGFB (Lipocalin 2 (oncogene 24p3)); LCO (Liver cancer onco- (Platelet-derived growth factor beta polypeptide (simian gene); LPSA (Oncogene liposarcoma (DNA segment, sarcoma viral (v-sis) oncogene homolog)); PIM1 (Pim-1 single copy, expressed, probes); LTA (Lymphotoxin al- oncogene); PVTI (Pvt-1 (murine) oncogene homolog, pha (TNF superfamily, member 1)); LTB (Lymphotoxin 30 MYC activator); RAB1 (RAB1, member RAS oncogene beta (TNF superfamily, member 3)); LYN (V-yes-1 family); RAB11A (RAB 11A, member oncogene family); Yamaguchi sarcoma viral related oncogene homolog); RAB11A (RAB11A, member RAS oncogene family); M1S1 (Membrane component, , surface RAB 13 (RAB 13, member RAS oncogene family); RAB2 marker 1 (40kD glycoprotein, identified by monoclonal (RAB2, member RAS oncogene family); RAB27A antibody GA733)); M4S1 (Membrane component, chro- 35 (RAB27A, member RAS oncogene family); RAB27B mosomal 4, surface marker (35kD glycoprotein)); (RAB27B, member RAS oncogene family); RAB2L MADH4 (MAD (mothers against decapentaplegic, Dro- (RAB2, member RAS oncogene family-like); RAB3A sophila) homolog 4); MAF (V-maf musculoaponeurotic (RAB3A, member RAS oncogene family); RAB3B fibrosarcoma (avian) oncogene homolog); MAFG (V-maf (RAB3B, member RAS oncogene family); RAB4 (RAB4, musculoaponeurotic fibrosarcoma (avian) oncogene 40 member RAS oncogene family); RAB5A (RAB5A, mem- family, protein G); MAFK (V-maf avian musculoaponeu- ber RAS oncogene family); RAB5B (RAB5B, member rotic fibrosarcoma oncogene family, protein K); MAS1 RAS oncogene family); RAB6 (RAB6, member RAS on- (MAS1 oncogene); MAX (MAX protein); MCC (Mutated cogene family); RAB7L1 (RAB7, member RAS oncogene in colorectal cancers); MCF2 (MCF.2 cell line derived family-like 1); RABL (RAB, member of RAS oncogene transforming sequence); MDM2 (Mouse double minute 45 family-like); RAF1 (V-raf-1 murine leukemia viral onco- 2, human homolog of; p53-binding protein); MEL (Mel gene homolog 1); RAF1P1 (V-raf-1 murine leukemia viral transforming oncogene (derived from cell line NK14)- oncogene homolog 1 pseudogene 1); RALA (V-ral simian RAB8 homolog); MELL1 (Mel transforming oncogene- leukemia viral oncogene homolog A (ras related)); RALB like 1); MET (Met proto-oncogene (hepatocyte growth (V-ral simian leukemia viral oncogene homolog B (ras factor receptor)); MLH1 (MutL (E. coli) homolog 1 (colon 50 related; GTP binding protein)); RAN (RAN, member RAS cancer, nonpolyposis type 2)); MOS (V-mos Moloney oncogene family); RAP1A (RAP1A, member of RAS on- murine sarcoma viral oncogene homolog); MPL (Myelo- cogene family); RAP1AP (RAP1A, member of RAS on- proliferative leukemia virus oncogene); MSH2 (MutS (E. cogene family pseudogene); RAP1B (RAP1B, member coli) homolog 2 (colon cancer, nonpolyposis type 1)); of RAS oncogene family); RAP2A (RAP2A, member of MUM1 (Multiple myeloma oncogene 1); MYB (V-myb avi- 55 RAS oncogene family); RAP2B (RAP2B, member of RAS an myeloblastosis viral oncogene homolog); MYBL1 (V- oncogene family); RB1 (Retinoblastoma I (including os- myb avian myeloblastosis viral oncogene homolog-like teosarcoma)); REL (V-rel avian reticuloendotheliosis vi- 1); MYBL2 (V-myb avian myeloblastosis viral oncogene ral oncogene homolog); RELA (V-rel avian reticuloen-

49 97 EP 1 364 069 B1 98 dotheliosis viral oncogene homolog A (nuclear factor of clin-dependent kinase 4); CDKN1A (Cyclin-dependent kappa light polypeptide gene enhancer in B-cells 3 kinase inhibitor 1A (p21, Cip1)); CDKN1C (Cyclin-de- (p65))); RELB (V-rel avian reticuloendotheliosis viral on- pendent kinase inhibitor 1C (p57, Kip2)); CDKN2A (Cy- cogene homolog B (nuclear factor of kappa light polypep- clin-dependent kinase inhibitor 2A (melanoma, p16, in- tide gene enhancer in B-cells 3)); RET (Ret proto-onco- 5 hibits CDK4)); CDKN2B (Cyclin-dependent kinase inhib- gene (multiple endocrine neoplasia MEN2A, MEN2B and itor 2B (p15, inhibits CDK4)); CHES1 (Checkpoint sup- medullary thyroid carcinoma 1, Hirschsprung disease)); pressor 1); D10S170 (DNA segment, single copy, probe ROS1 (V-ros avian UR2 sarcoma virus oncogene ho- pH4 (transforming sequence, thyroid-1,); DCC (Deleted molog 1); RRAS (Related RAS viral (r-ras) oncogene ho- in colorectal carcinoma); DDX6 (DEAD/H (Asp-Glu-Ala- molog); SEA (S13 avian erythroblastosis oncogene ho- 10 Asp/His) box polypeptide 6 (RNA helicase, 54kD)); E2F1 molog); SKI (V-ski avian sarcoma viral oncogene ho- (E2F transcription factor 1); EIF3S6 (Eukaryotic transla- molog); SMARCB1 (SWI/SNF related, matrix associat- tion initiation factor 3, subunit 6 (48kD)); ELE1 (RET- ed, actin dependent regulator of chromatin, subfamily b, activating gene ELE1); ELK3 (ELK3, ETS-domain pro- member 1); SPI1 (Spleen focus forming virus (SFFV) pro- tein (SRF accessory protein 2) NOTE: Symbol and name viral integration oncogene ); SPINK1 (Serine pro- 15 provisional.); EMP1 (Epithelial membrane protein 1); tease inhibitor, Kazal type 1); SRC (V-src avian sarcoma EMS1 (Ems1 sequence (mammary tumor and squamous (Schmidt-Ruppin A-2) viral oncogene homolog); ST5 cell carcinoma-associated (p80/85 src substrate)); (Suppression of tumorigenicity 5); SUPT3H (Suppressor EPHA1 (EphA1); EPHA3 (EphA3); ETV3 (Ets variant of Ty (S.cerevisiae) 3 homolog); SUPT5H (Suppressor gene 3); EVI1 (Ecotropic viral integration site 1); EWSR1 of Ty (S.cerevisiae) 5 homolog); SUPT6H (Suppressor 20 (Ewing sarcoma breakpoint region 1); FAT (FAT tumor of Ty (S.cerevisiae) 6 homolog); TAL1 (T-cell acute lym- suppressor (Drosophila) homolog); FER (Fer (fps/fes re- phocytic leukemia 1); TGFBR2 (Transforming growth lated) tyrosine kinase (phosphoprotein NCP94)); FHIT factor, beta receptor II (70-80kD)); THPO (Thrombopoi- (Fragile histidine triad gene); FKHL1 (Forkhead (Dro- etin (myeloproliferative leukemia virus oncogene ligand, sophila)-like 1); FLT1 (Fms-related tyrosine kinase 1 megakaryocyte growth and development factor)); THRA 25 (vascular endothelial growth factor/vascular permeability (Thyroid hormone receptor, alpha (avian erythroblastic factor receptor)); FOSL1 (FOS-like antigen-1); FOSL2 leukemia viral (v-erb-a) oncogene homolog)); THRB (FOS-like antigen 2); GLI2 (GLI-Kruppel family member (Thyroid hormone receptor, beta (avian erythroblastic GLI2); GLI3 (GLI-Kruppel family member GLI3 (Greig ce- leukemia viral (v-erb-a) oncogene homolog 2)); TIAM1 phalopolysyndactyly syndrome)); HCK (Hemopoietic cell (T-cell lymphoma invasion and metastasis 1); TIM (On- 30 kinase); HKR3 (GLI-Kruppel family member HKR3); cogene TIM); TM4SF1 (Transmembrane 4 superfamily ING1 (Inhibitor of growth 1); IRF4 (Interferon regulatory member 1); TNF (Tumor necrosis factor (TNF superfami- factor 4); KAI1 (Kangai 1 (suppression of tumorigenicity ly, member 2)); TP53BP2 (Tumor protein p53-binding 6, prostate; CD82 antigen (R2 leukocyte antigen, antigen protein, 2); TP73 (Tumor protein p73); TPR (Translocat- detected by monoclonal and antibody IA4))); LCK (Lym- ed promoter region (to activated MET oncogene)); 35 phocyte-specific protein tyrosine kinase); LTA (Lympho- TRE17 (Tre-2 oncogene); USP4 (Ubiquitin specific pro- toxin alpha (TNF superfamily, member 1)); LTB (Lym- tease 4 (proto-oncogene)); USP6 (Ubiquitin specific pro- photoxin beta (TNF superfamily, member 3)); M1S1 tease 6 (Tre-2 oncogene)); VAV1 (Vav 1 oncogene); (Membrane component, chromosome 1, surface marker VAV2 (Vav 2 oncogene); VHL (Von Hippel-Lindau syn- 1 (40kD glycoprotein, identified by monoclonal antibody drome); WNT1 (Wingless-type MMTV integration site 40 GA733)); M4S1 (Membrane component, chromosomal family, member 1); WNT2 (Wingless-type MMTV inte- 4, surface marker (35kD glycoprotein)); MADH4 (MAD gration site family member 2); WNT5A (Wingless-type (mothers against decapentaplegic, Drosophila) homolog MMTV integration site family, member 5A); WT1 (Wilms 4); MAX (MAX protein); MCC (Mutated in colorectal can- tumor 1); YES1 (V-yes-1 Yamaguchi sarcoma viral on- cers); MEN1 (Multiple endocrine neoplasia I); MLH1 cogene homolog 1); YESP (V-yes-1 Yamaguchi sarcoma 45 (MutL (E. coli) homolog 1 (colon cancer, nonpolyposis viral oncogene homolog pseudogene); AMPHL (Am- type 2)); MSH2 (MutS (E. coli) homolog 2 (colon cancer, phiphysin-like); APC (Adenomatosis polyposis coli); nonpolyposis type 1)); NBL1 (Neuroblastoma candidate ARHA (Ras homolog gene family, member A); ARHB region, suppression of tumorigenicity 1); NF1 (Neurofi- (Ras homolog gene family, member B); ARHC (Ras ho- bromin 1 (neurofibromatosis, von Recklinghausen dis- molog gene family, member C); AXL (AXL receptor tyro- 50 ease, Watson disease)); NF2 (Neurofibromin 2 (bilateral sine kinase); BCL2 (B-cell CLL/lymphoma 2); BCL3 (B- acoustic neuroma)); NFKB2 (Nuclear factor of kappa light cell CLL/lymphoma 3); BCR (Breakpoint cluster region); polypeptide gene enhancer in B-cells 2 (p49/p100)); NK- BLYM (Avian lymphoma virus-derived transforming se- TR (Natural killer-tumor recognition sequence); NME1 quence); BRCA1 (Breast cancer 1, early onset); BRCA2 (Non-metastatic cells 1, protein (NM23A) expressed in); (Breast cancer 2, early onset); CBL (Cas-Br-M (murine) 55 NOV (Nephroblastoma overexpressed gene); NTRK1 ecotropic retroviral transforming sequence); CCND1 (Neurotrophic tyrosine kinase, receptor, type 1); PDG- (Cyclin D1 (PRAD1: parathyroid adenomatosis 1)); FRL (Platelet-derived growth factor receptor-like); CDH1 (Cadherin 1, E-cadherin (epithelial)); CDK4 (Cy- PLA2G2A (Phospholipase A2, group IIA (platelets, syn-

50 99 EP 1 364 069 B1 100 ovial fluid)); PTCH (Patched (Drosophila) homolog); ment. PTEN (Phosphatase and tensin homolog (mutated in multiple advanced cancers 1)); RB1 (Retinoblastoma 1 3. Method according to claim 1 or 2, characterised in (including osteosarcoma)); SMARCB1 (SWI/SNF relat- that the biological material comprises a eucaryotic ed, matrix associated, actin dependent regulator of chro- 5 and/or procaryotic cell line, a biopsy sample, blood, matin, subfamily b, member 1); SPINK1 (Serine protease sputum, faeces, urine, cerebral liquid, tissue embed- inhibitor, Kazal type 1); ST5 (Suppression of tumorigenic- ded in paraffin, tissue derived from eyes, intestine, ity 5); SUPT3H (Suppressor of Ty (S.cerevisiae) 3 ho- brain, heart, prostata, kidney, lung, breast or liver, molog); SUPT5H (Suppressor of Ty (S.cerevisiae) 5 ho- histological samples or a combination thereof. molog); SUPT6H (Suppressor of Ty (S.cerevisiae) 6 ho- 10 molog); TAL1 (T-cell acute lymphocytic leukemia 1); 4. Method according to any of claims 1 to 3, charac- TGFBR2 (Transforming growth factor, beta receptor II terised in that at least one of the biological samples (70-80kD)); TIAMI (T-cell lymphoma invasion and me- is derived from biological material of healthy and/or tastasis 1); TIM (Oncogene TIM); TM4SF1 (Transmem- diseased individuals. brane 4 superfamily member 1); TNF (Tumor necrosis 15 factor (TNF superfamily, member 2)); TP53 (Tumor pro- 5. Method according to any of claims 1 to 4, charac- tein p53 (Li-Fraumeni syndrome)); TP53BP2 (Tumor pro- terised in that the isolation of said biological sample tein p53-binding protein, 2); TP73 (Tumor protein p73); comprises isolating subcellular compartments, or- VHL (Von Hippel-Lindau syndrome); WNT1 (Wingless- ganelles, macromolecular structures and multipro- type MMTV integration site family, member 1); WNT2 20 tein complexes, partial or complete preparation of (Wingless-type MMTV integration site family member 2); the mRNA, reverse transcription or partial digestion WNT5A (Wingless-type MMTV integration site family, of the material with an enzyme selected from pro- member 5A); WT1 (Wilms tumor 1) teases, RNAses and/or DNAses or combinations thereof. 25 Claims 6. Method according to any of claims 1 to 5, charac- terised in that the analysis of the expression level 1. An in vitro method for the development of gene pan- of the at least two genes in the biological sample els for diagnostic and therapeutic purposes, com- comprises determining the relative amount of mRNA prising the steps of: 30 or protein derived from said at least two genes.

a) providing at least one biological sample from 7. Method according to claim 6, characterised in that each of at least two groups of biological material the analysis comprises one- or two-dimensional gel containing mRNA and/or proteins; electrophoresis, differential display, analysis of se- b) analysing the expression level of at least two 35 lected sets of tumour markers, subtractive hybridi- genes in at least one of the biological samples; sation, mass spectrometry, comparative expressed c) selecting the gene(s) exhibiting a different ex- sequence tag sequencing, representational differ- pression level between said at least two groups ence analysis, cDNA or oligonucleotide arrays, serial of biological material, analysis of gene expression, enzymatic, fluorescent, whereby a first knowledge base is generated; 40 radioactive, dye and/or antibody labelling. d) analysing the level of cytosine methylation in the methylation relevant regions of at least two 8. Method according to claim 7, characterised in that genes of at least one of the biological samples the analysis further comprises measuring intensities of step a), wherein the gene is selected on the of expression during one- or two-dimensional gel basis of the first knowledge base; 45 electrophoresis, differential display, subtractive hy- e) selecting the gene(s) exhibiting a different lev- bridisation, DNA, RNA or protein sequencing, mass el of cytosine methylation between said at least spectrometry, and enzymatic, radioactive, dye two groups of biological material, and/or antibody labelling. whereby a second knowledge base is generat- ed; and 50 9. Method according to any of claims 6 to 8, charac- f) adding selected genes from the second knowl- terised in that the analysis is at least partially per- edge base to a gene panel. formed by means of a suited automate, for example a robot. 2. Method according to claim 1, comprising that the bi- ological material that is provided from a biopsy, an 55 10. Method according claim 9, characterised in that operation on an individual, a dissection, derived from the expression levels of at least 100 genes are an- a preserved biological sample, collected from body alysed. fluid(s) and/or collected directly from the environ-

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11. Method according to any of claims 1 to 10, charac- terised in that the selection is performed in such a terised in that the selection is based on a combi- way as to give a second knowledge base comprising nation of the analysis of both mRNA level and protein only one set of selected genes. expression. 5 24. Method according to any of claims 1 to 23, charac- 12. Method according to any of claims 1 to 11, charac- terised in that the selection is performed in such a terised in that the selection is based on the result way as to give a second knowledge base comprising of at least two individual rows of analyses. different subsets of selected genes.

13. Method according to any of claims 1 to 12, charac- 10 25. Method according to any of claims 1 to 24, charac- terised in that the selection is performed in such a terised in that the selection is at least partially per- way as to give a first knowledge base comprising formed automatically by means of a suited automate, only one set of selected genes. such as a computer device.

14. Method according to any of claims 1 to 12, charac- 15 26. Method according to any of claims 1 to 25, charac- terised in that the selection is performed in such a terised in that at least two genes are selected in way as to give a first knowledge base comprising parallel. different subsets of selected genes. 27. Method according to claim 26, characterised in that 15. Method according to any of claims 1 to 12, charac- 20 at least 100 genes are selected in parallel. terised in that the selection is at least partially per- formed automatically by means of a suited automate, 28. Method according to any of claims 1 to 27, charac- such as a computer device. terised in that all or a part of the genes of the second knowledge base are added to the gene panel. 16. Method according to any of claims 1 to 15, charac- 25 terised in that at least two genes are selected. 29. Method according to any of claims 1 to 28, charac- terised in that additional information about methyl- 17. Method according to claim 16, characterised in that ation relevant regions of the selected genes is added at least 100 genes are selected. to the gene panel. 30 18. Method according to any of claims 1 to 17, charac- 30. Method according to any of claims 1 to 29, charac- terised in that the methylation relevant regions terised in that steps a) to f) are repeated. comprise the complete genes and/or promoters, in- trons, first exons and/or enhancers of the genes to 31. Method according to claim 30, characterised in that be analysed. 35 it is repeated for at least 100 times.

19. Method according to any of claims 1 to 18, charac- 32. Method according to any of claims 30 or 31,charac- terised in that the analysis of the level of cytosine terised in that the identical biological material, dif- methylation comprises chemical treatment with bi- ferent biological material or a combination thereof is sulphite, hydrogen sulphite or disulphite, polymer- 40 used in step a). ase chain reaction (PCR), hybridisation analyses, sequencing, mass spectrometry and fluorescent, en- 33. Method according to any of claims 1 to 32, charac- zymatic, radioactive, dye and/or antibody labelling. terised in that the steps are performed in the fol- lowing order: step a), step d), step e), step b), step 20. Method according to any of claims 1 to 19, charac- 45 c), and step f). terised in that the analysis is at least partially per- formed by means of a suited automate, for example 34. Method according to any of claims 1 to 33, charac- a robot. terised in that it is at least partially performed by means of a suited automate, for example a robot. 21. Method according claim 20, characterised in that 50 the level of cytosine methylation of at least 100 genes 35. An in vitro method for diagnosing a disease, com- are analysed. prising the following steps:

22. Method according to any of claims 1 to 21, charac- a) providing a gene panel according to any of terised in that the selection is based on the result 55 claims 1 to 34; of at least two individual rows of analyses. b) analysing the level of cytosine methylation at selected sites of the DNA based on said gene 23. Method according to any of claims 1 to 22, charac- panel in biological material of at least one dis-

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eased individual with a known disease or med- unterschiedlichen Expressionsspiegel zwi- ical condition and at least one healthy individual, schen den mindestens zwei Gruppen an biolo- thereby generating a first knowledge base; gischem Material zeigt/zeigen, c) analysing the level of cytosine methylation at wodurch eine erste Wissensdatenbank erzeugt selected sites of the DNA based on said gene 5 wird; panel in biological material of at least one dis- d) Analysieren des Spiegels an Cytosinmethy- eased individual with an unknown disease or lierung in den Methylierungs-relevanten Regio- medical condition, thereby generating a second nen von mindestens zwei Genen von minde- knowledge base; and stens einer der biologischen Proben aus Schritt d) providing a third knowledge base comprising 10 a), wobei das Gen auf der Basis der ersten Wis- a plurality of expert rules for comparing the first sensdatenbank ausgewählt wird; and second knowledge base; e) Auswählen der/des Gens/Gene, das/die ei- e) selecting a type of disease or medical condi- nen unterschiedlichen Spiegel an Cytosinme- tion for the at least one diseased individual with thylierung zwischen den mindestens zwei Grup- an unknown disease or medical condition based 15 pen an biologischem Material aufweisen/auf- on said first to third knowledge bases. weist, wodurch eine zweite Wissensdatenbank er- 36. Method according to claim 35, wherein the disease zeugt wird; und is selected from unwanted side effects of medica- f) Hinzufügen von ausgewählten Genen aus der ments, cancers, dysfunctions, damages or diseases 20 zweiten Wissensdatenbank zu einem Genpa- of the central nerval system (CNS), aggressive nel. symptoms or behavioural disorders, clinical, and psychological consequences of brain injuries, psy- 2. Verfahren nach Anspruch 1, umfassend, dass das chotic disorders, dementia and/or associates syn- biologische Material, das zur Verfügung gestellt dromes, cardiovascular diseases, diseases, mal- 25 wird, aus einer Biopsie, einer Operation an einem functions or damages of the gastrointestine, diseas- Individuum, einer Präparation, aus einer konservier- es, malfunctions or damages of the respiratory sys- ten biologischen Probe abgeleitet ist, aus Körper- tem, injury, inflammation, infection, immunity and/or flüssigkeit(en) entnommen und/oder direkt aus der reconvalescence, diseases, malfunctions or damag- Umgebung entnommen ist. es as consequences of modifications in the devel- 30 opmental process, diseases, malfunctions or dam- 3. Verfahren nach Anspruch 1 oder 2, dadurch ge- ages of the skin, muscles, connective tissue or kennzeichnet, dass das biologische Material eine bones, endocrine or metabolic diseases, malfunc- eukaryontische und/oder prokaryontische Zelllinie, tions or damages, headache, and sexual malfunc- eine Biopsieprobe, Blut, Sputum, Faeces, Urin, Ce- tions or combinations thereof, leukemia, head and 35 rebralflüssigkeit, tissue embedded in Paraffin einge- neck cancer, Hodgkin’s disease, gastric cancer, bettetes Gewebe, von Augen, Darm, Hirn, Herz, Pro- prostate cancer, renal cancer, bladder cancer, stata, Niere, Lunge, Brust oder Leber abgeleitetes breast cancer, Burkitt’s lymphoma, Wilms tumor, Gewebe, histologische Proben oder eine Kombina- Prader-Willi/Angelman syndrome, ICF syndrome, tion davon umfasst. dermatofibroma, hypertension, pediatric neurobio- 40 logical diseases, autism, ulcerative colitis, fragile X 4. Verfahren nach einem der Ansprüche 1 bis 3, da- syndrome, and Huntington’s disease. durch gekennzeichnet, dass mindestens eine der biologischen Proben von biologischen Material von gesunden und/oder erkrankten Individuen abgeleitet Patentansprüche 45 ist.

1. In vitro Verfahren zur Entwicklung von Genpanels 5. Verfahren nach einem der Ansprüche 1 bis 4, da- für diagnostische und therapeutische Zwecke, um- durch gekennzeichnet, dass die Isolierung der fassend die Schritte von: biologischen Probe ein Isolieren subzellulärer Kom- 50 partimente, Organellen, makromolekularer Struktu- a) Zur Verfügung stellen von mindestens einer ren und Multiproteinkomplexe, partielle oder voll- biologischen Probe von jeder von mindestens ständige Präparation der mRNA, reverse Transkrip- zwei Gruppen an biologischem Material enthal- tion oder partiellen Verdau des Materials mit einem tend mRNA und/oder Proteine; Enzym ausgewählt aus Proteasen, RNAsen und/ b) Analysieren des Expressionsspiegels von 55 oder DNAsen oder Kombinationen davon umfasst. mindestens zwei Genen in mindestens einer der biologischen Proben; 6. Verfahren nach einem der Ansprüche 1 bis 5, da- c) Auswählen des/der Gens/Gene, der/die einen durch gekennzeichnet, dass die Analyse des Ex-

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pressionsspiegel der mindestens zwei Gene in der durch gekennzeichnet, dass die Auswahl zumin- biologischen Probe ein Bestimmen der relativen dest teilweise automatisiert mittels eines geeigneten Menge an mRNA oder Protein abgeleitet von den Automaten durchgeführt wird, zum Beispiel einer mindestens zwei Genen umfasst. Computervorrichtung. 5 7. Verfahren nach Anspruch 6, dadurch gekenn- 16. Verfahren nach einem der Ansprüche 1 bis 15, da- zeichnet, dass die Analyse ein- oder zweidimen- durch gekennzeichnet, dass mindestens zwei Ge- sionale Gelelektrophorese, Differential Display, ne ausgewählt werden. Analyse von ausgewählten Sets an Tumormarkern, subtraktive Hybridisierung, Massenspektrometrie, 10 17. Verfahren nach Anspruch 16, dadurch gekenn- vergleichende exprimierte Sequenzmarker-Se- zeichnet, dass mindestens 100 Gene ausgewählt quenzierung, repräsentative Differenzanalyse, cD- werden. NA- oder Oligonukleotidarrays, serielle Analyse der Genexpression, enzymatische, fluoreszente, radio- 18. Verfahren nach einem der Ansprüche 1 bis 17, da- aktive, Farbstoff- und/oder Antikörper-Markierung 15 durch gekennzeichnet, dass die Methylierungs- umfasst. relevanten Regionen die vollständigen Gene und/ oder Promotoren, Introns, erste Exons und/oder En- 8. Verfahren nach Anspruch 7, dadurch gekenn- hancer der zu analysierenden Gene umfassen. zeichnet, dass die Analyse weiter ein Messen von Intensitäten der Expression während ein- oder zwei- 20 19. Verfahren nach einem der Ansprüche 1 bis 18, da- dimensionaler Gelelektrophorese, Differential Dis- durch gekennzeichnet, dass die Analyse des play, subtraktiver Hybridisierung, DNA, RNA oder Spiegels an Cytosinmethylierung die chemische Be- Protein-Sequenzierung, Massenspektrometrie und handlung mit Bisulfit, Hydrogensulfit oder Disulfit, enzymatischer, radioaktiver, Farbstoff- und/oder An- Polymerase-Kettenreaktion (PCR), Hybridisie- tikörper-Markierung umfasst. 25 rungsanalysen, Sequenzierung, Massenspektro- metrie und enzymatische, fluoreszente, radioaktive, 9. Verfahren nach einem der Ansprüche 6 bis 8, da- Farbstoff- und/oder Antikörper-Markierung umfasst. durch gekennzeichnet, dass die Analyse zumin- dest teilweise mittels eines geeigneten Automaten 20. Verfahren nach einem der Ansprüche 1 bis 19, da- durchgeführt wird, zum Beispiel einem Roboter. 30 durch gekennzeichnet, dass die Analyse zumin- dest teilweise mittels eines geeigneten Automaten 10. Verfahren nach Anspruch 9, dadurch gekenn- durchgeführt wird, zum Beispiel einem Roboter. zeichnet, dass die Expressionsspiegel von minde- stens 100 Genen analysiert werden. 21. Verfahren nach Anspruch 20, dadurch gekenn- 35 zeichnet, dass der Spiegel an Cytosinmethylierung 11. Verfahren nach einem der Ansprüche 1 bis 10, da- von mindestens 100 Genen analysiert wird. durch gekennzeichnet, dass die Auswahl auf einer Kombination der Analyse von sowohl mRNA Spiegel 22. Verfahren nach einem der Ansprüche 1 bis 21, da- als auch Proteinexpression basiert wird. durch gekennzeichnet, dass die Auswahl auf dem 40 Ergebnis von mindestens zwei individuellen Reihen 12. Verfahren nach einem der Ansprüche 1 bis 11, da- an Analysen basiert wird. durch gekennzeichnet, dass die Auswahl auf dem Ergebnis von mindestens zwei individuellen Reihen 23. Verfahren nach einem der Ansprüche 1 bis 22, da- an Analysen basiert wird. durch gekennzeichnet, dass die Auswahl auf sol- 45 che Weise durchgeführt wird, dass sie eine zweite 13. Verfahren nach einem der Ansprüche 1 bis 12, da- Wissensdatenbank ergibt, umfassend nur ein Set durch gekennzeichnet, dass die Auswahl auf sol- von ausgewählten Genen. che Weise durchgeführt wird, dass sie eine erste Wissensdatenbank ergibt, umfassend nur ein Set 24. Verfahren nach einem der Ansprüche 1 bis 23, da- von ausgewählten Genen. 50 durch gekennzeichnet, dass die Auswahl auf sol- che Weise durchgeführt wird, dass sie eine zweite 14. Verfahren nach einem der Ansprüche 1 bis 12, da- Wissensdatenbank ergibt, umfassend verschiedene durch gekennzeichnet, dass die Auswahl auf sol- Subsets von ausgewählten Genen. che Weise durchgeführt wird, dass sie eine erste Wissensdatenbank ergibt, umfassend verschiedene 55 25. Verfahren nach einem der Ansprüche 1 bis 24, da- Subsets von ausgewählten Genen. durch gekennzeichnet, dass die Auswahl zumin- dest teilweise automatisiert mittels eines geeigneten 15. Verfahren nach einem der Ansprüche 1 bis 12, da- Automaten durchgeführt wird, zum Beispiel einer

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Computervorrichtung. c) Analysieren der Spiegel an Cytosinmethylie- rung an ausgewählten Stellen der DNA basie- 26. Verfahren nach einem der Ansprüche 1 bis 25, da- rend auf dem Genpanel in biologischem Mate- durch gekennzeichnet, dass mindestens zwei Ge- rial von mindestens einem erkrankten Individu- ne parallel ausgewählt werden. 5 um mit einer unbekannten Erkrankung oder me- dizinischem Zustand, wodurch eine zweite Wis- 27. Verfahren nach Anspruch 26, dadurch gekenn- sensdatenbank erzeugt wird; und zeichnet, dass mindestens 100 Gene parallel aus- d) Zur Verfügung stellen einer dritten Wissens- gewählt werden. datenbank umfassend eine Vielzahl von Exper- 10 tenregeln zum Vergleichen der ersten und zwei- 28. Verfahren nach einem der Ansprüche 1 bis 27, da- ten Wissensdatenbank; durch gekennzeichnet, dass alle oder ein Teil der e) Auswählen eines Typs an Erkrankung oder Gene der zweiten Wissensdatenbank zu dem Gen- medizinischem Zustand für das mindestens ei- panel hinzugefügt werden. ne erkrankte Individuum mit einer unbekannten 15 Erkrankung oder medizinischem Zustand basie- 29. Verfahren nach einem der Ansprüche 1 bis 28, da- rend auf den ersten bis dritten Wissensdaten- durch gekennzeichnet, dass zusätzliche Informa- banken. tion über die Methylierungs-relevanten Regionen der ausgewählten Gene zu dem Genpanel hinzuge- 36. Verfahren nach Anspruch 35, wobei die Erkrankung fügt wird. 20 ausgewählt ist aus unerwünschten Nebenwirkungen von Medikamenten, Krebserkrankungen, Dysfunk- 30. Verfahren nach einem der Ansprüche 1 bis 29, da- tionen, Beschädigungen oder Erkrankungen des durch gekennzeichnet, dass die Schritte a) bis f) zentralen Nervensystems (CNS), aggressiven Sym- wiederholt werden. ptomen oder Verhaltensstörungen, klinischen und 25 psychologischen Konsequenzen von Hirnverletzun- 31. Verfahren nach Anspruch 30, dadurch gekenn- gen, psychotischen Störungen, Demenz und/oder zeichnet, dass es mindestens 100 mal wiederholt assoziierten Syndromen, kardiovaskulären Erkran- wird. kungen, Erkrankungen, Fehlfunktionen oder Be- schädigungen des gastrointestinalen Systems, Er- 32. Verfahren nach einem der Ansprüche 30 oder 31, 30 krankungen, Fehlfunktionen oder Beschädigungen dadurch gekennzeichnet, dass das identische des respiratorischen Systems, Verletzung, Entzün- biologische Material, unterschiedliches biologisches dung, Infektion, Immunität und/oder Rekonvales- Material oder eine Kombination davon in Schritt a) zenz, Erkrankungen, Fehlfunktionen oder Beschä- verwendet wird. digungen als Konsequenzen von Modifikationen im 35 Entwicklungsprozess, Erkrankungen, Fehlfunktio- 33. Verfahren nach einem der Ansprüche 1 bis 32, da- nen oder Beschädigungen der Haut, Muskeln, Bin- durch gekennzeichnet, dass die Schritte in der fol- degewebe oder Knochen, endokrine oder metaboli- genden Reihenfolge durchgeführt werden: Schritt a), schen Erkrankungen, Fehlfunktionen oder Beschä- Schritt d), Schritt e), Schritt b), Schritt c) und Schritt f). digungen, Kopfschmerzen, und sexuelle Fehlfunk- 40 tionen oder Kombinationen davon, Leukämie, Kopf 34. Verfahren nach einem der Ansprüche 1 bis 33, da- und Nackenkrebs, Morbus Hodgkin, Magenkrebs, durch gekennzeichnet, dass es zumindest teilwei- Prostatakrebs, Nierenkrebs, Blasenkrebs, Brust- se mittels eines geeigneten Automaten durchgeführt krebs, Burkitt’s Lymphom, Wilms Tumor, Prader- wird, zum Beispiel einem Roboter. Willi/Angelman Syndrom, ICF Syndrom, Dermatofi- 45 broma, Hochdruck, pädiatrischen neurobiologi- 35. In vitro Verfahren zur Diagnose einer Erkrankung, schen Erkrankungen, Autismus, ulzerative Colitis, umfassend die folgenden Schritte: fragiles X Syndrom und Morbus Huntington.

a) Zur Verfügung stellen eines Genpanel nach einem der Ansprüche 1 bis 34; 50 Revendications b) Analysieren der Spiegel an Cytosinmethylie- rung an ausgewählten Stellen der DNA basie- 1. Procédé in vitro de développement de panels de gè- rend auf dem Genpanel in biologischem Mate- nes pour des objectifs diagnostiques et thérapeuti- rial von mindestens einem erkrankten Individu- ques, comprenant les étapes consistant à : um mit einer bekannten Erkrankung oder medi- 55 zinischem Zustand und mindestens einem ge- a) fournir au moins un échantillon biologique à sunden Individuum, wodurch eine erste Wis- partir de chacun d’au moins deux groupes de sensdatenbank erzeugt wird; matériau biologique contenant de l’ARNm et /

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ou des protéines ; 6. Procédé selon l’une quelconque des revendications b) analyser le taux d’expression d’au moins deux 1 à 5, caractérisé en ce que l’analyse du taux d’ex- gènes dans au moins l’un des échantillons pression des au moins deux gènes dans l’échantillon biologiques ; biologique comprend la détermination de la quantité c) sélectionner le(s) gène(s) présentant un taux 5 relative d’ARNm ou de protéine dérivé(e) desdits au d’expression différent entre lesdits au moins moins deux gènes. deux groupes de matériau biologique, moyennant quoi une première base de connais- 7. Procédé selon la revendication 6, caractérisé en sance est générée ; ce que l’analyse comprend une électrophorèse sur d) analyser le taux de méthylation des cytosines 10 gel mono- ou bi-dimensionnelle, une présentation dans les régions pertinentes de la méthylation différentielle, une analyse d’ensembles choisis de d’au moins deux gènes d’au moins l’un des marqueurs tumoraux, une hybridation soustractive, échantillons biologiques de l’étape a), où le gène une spectrométrie de masse, un séquençage com- est sélectionné sur la base de la première base paratif d’étiquette de séquence exprimée, une ana- de connaissance ; 15 lyse de différence représentationnelle, des puces e) sélectionner le(s) gène(s) présentant un taux d’ADNc ou d’oligonucléotides, une analyse en série différent de méthylation des cytosines entre les- de l’expression génique, un marquage enzymatique, dits au moins deux groupes de matériau biolo- fluorescent, radioactif, avec un colorant et / ou un gique, anticorps. moyennant quoi une seconde base de connais- 20 sance est générée ; et 8. Procédé selon la revendication 7, caractérisé en f) ajouter les gènes sélectionnés à partir de la ce que l’analyse comprend en outre la mesure des seconde base de connaissance à un panel de intensités d’expression au cours de l’électrophorèse gènes. sur gel mono- ou bi-dimensionnelle, de la présenta- 25 tion différentielle, de l’hybridation soustractive, du 2. Procédé selon la revendication 1, comprenant que séquençage d’ADN, d’ARN ou de protéine, de la le matériau biologique est fourni à partir d’une biop- spectrométrie de masse, et du marquage enzyma- sie, d’une opération sur un individu, d’une dissection, tique, radioactif, avec un colorant et / ou un anticorps. dérivé d’un échantillon biologique préservé, recueilli à partir de liquide(s) corporel(s) et / ou recueilli di- 30 9. Procédé selon l’une quelconque des revendications rectement à partir de l’environnement. 6 à 8, caractérisé en ce que l’analyse est réalisée au moins partiellement au moyen d’un automate 3. Procédé selon la revendication 1 ou 2, caractérisé adapté, par exemple un robot. en ce que le matériau biologique comprend une li- gnée cellulaire eucaryote et / ou procaryote, un 35 10. Procédé selon la revendication 9, caractérisé en échantillon de biopsie, du sang, des crachats, des ce que les taux d’expression d’au moins 100 gènes selles, des urines, du liquide cérébral, un tissu noyé sont analysés. dans de la paraffine, du tissu dérivé des yeux, de l’intestin, du cerveau, du coeur, de la prostate, du 11. Procédé selon l’une quelconque des revendications rein, du poumon, du sein ou du foie, des échantillons 40 1 à 10, caractérisé en ce que la sélection est basée histologiques ou une combinaison de ceux-ci. sur une combinaison de l’analyse à la fois du taux d’ARNm et de l’expression de la protéine. 4. Procédé selon l’une quelconque des revendications 1 à 3, caractérisé en ce qu’au moins l’un des échan- 12. Procédé selon l’une quelconque des revendications tillons biologiques est dérivé de matériau biologique 45 1 à 11, caractérisé en ce que la sélection est basée d’individus en bonne santé et / ou malades. sur le résultat d’au moins deux rangées individuelles d’analyses. 5. Procédé selon l’une quelconque des revendications 1 à 4, caractérisé en ce que l’isolement dudit 13. Procédé selon l’une quelconque des revendications échantillon biologique comprend l’isolement de com- 50 1 à 12, caractérisé en ce que la sélection est réa- partiments subcellulaires, d’organites, de structures lisée de telle manière à donner une première base macromoléculaires et de complexes de protéines de connaissance comprenant seulement un ensem- multiples, la préparation partielle ou complète de ble de gènes sélectionnés. l’ARNm, la transcription inverse ou la digestion par- tielle du matériau avec une enzyme choisie parmi 55 14. Procédé selon l’une quelconque des revendications des protéases, des ARNases et / ou des ADNases 1 à 12, caractérisé en ce que la sélection est réa- ou des combinaisons de celles-ci. lisée de telle manière à donner une première base de connaissance comprenant différents sous-en-

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sembles de gènes sélectionnés. 1 à 24, caractérisé en ce que la sélection est réa- lisée au moins partiellement de manière automati- 15. Procédé selon l’une quelconque des revendications que au moyen d’un automate adapté, tel qu’un dis- 1 à 12, caractérisé en ce que la sélection est réa- positif informatique. lisée au moins partiellement de manière automati- 5 que au moyen d’un automate adapté, tel qu’un dis- 26. Procédé selon l’une quelconque des revendications positif informatique. 1 à 25, caractérisé en ce qu’au moins deux gènes sont sélectionnés en parallèle. 16. Procédé selon l’une quelconque des revendications 1 à 15, caractérisé en ce qu’au moins deux gènes 10 27. Procédé selon la revendication 26, caractérisé en sont sélectionnés. ce qu’au moins 100 gènes sont sélectionnés en pa- rallèle. 17. Procédé selon la revendication 16, caractérisé en ce qu’au moins 100 gènes sont sélectionnés. 28. Procédé selon l’une quelconque des revendications 15 1 à 27, caractérisé en ce que la totalité ou une 18. Procédé selon l’une quelconque des revendications partie des gènes de la seconde base de connais- 1 à 17, caractérisé en ce que les régions pertinen- sance sont ajoutés au panel des gènes. tes de méthylation comprennent les gènes complets et / ou les promoteurs, les introns, les premiers exons 29. Procédé selon l’une quelconque des revendications et / ou des amplificateurs des gènes à analyser. 20 1 à 28, caractérisé en ce que les informations sup- plémentaires au sujet des régions pertinentes de 19. Procédé selon l’une quelconque des revendications méthylation des gènes sélectionnés sont ajoutées 1 à 18, caractérisé en ce que l’analyse du taux de au panel des gènes. méthylation des cytosines comprend un traitement chimique avec du bisulfite, du sulfite ou du disulfite 25 30. Procédé selon l’une quelconque des revendications d’hydrogène, une réaction en chaîne de la polymé- 1 à 29, caractérisé en ce que les étapes a) à f) sont rase (PCR), des analyses d’hybridation, un séquen- répétées. çage, une spectrométrie de masse et un marquage fluorescent, enzymatique, radioactif, avec un colo- 31. Procédé selon la revendication 30, caractérisé en rant et / ou un anticorps. 30 ce qu’il est répété pour au moins 100 fois.

20. Procédé selon l’une quelconque des revendications 32. Procédé selon l’une quelconque des revendications 1 à 19, caractérisé en ce que l’analyse est réalisée 30 ou 31, caractérisé en ce que le matériau biolo- au moins partiellement au moyen d’un automate gique identique, le matériau biologique différent ou adapté, par exemple un robot. 35 une combinaison de ceux-ci est utilisé dans l’étape a). 21. Procédé selon la revendication 20, caractérisé en ce que le taux de méthylation des cytosines d’au 33. Procédé selon l’une quelconque des revendications moins 100 gènes est analysé. 1 à 32, caractérisé en ce que les étapes sont réa- 40 lisées dans l’ordre suivant : étape a), étape d), étape 22. Procédé selon l’une quelconque des revendications e), étape b), étape c) et étape f). 1 à 21, caractérisé en ce que la sélection est basée sur le résultat d’au moins deux rangées individuelles 34. Procédé selon l’une quelconque des revendications d’analyses. 1 à 33, caractérisé en ce qu’il est réalisé au moins 45 partiellement au moyen d’un automate adapté, par 23. Procédé selon l’une quelconque des revendications exemple un robot. 1 à 22, caractérisé en ce que la sélection est réa- lisée de telle manière à donner une seconde base 35. Procédé in vitro de diagnostic d’une maladie, com- de connaissance comprenant seulement un ensem- prenant les étapes suivantes : ble de gènes sélectionnés. 50 a) la fourniture d’un panel de gènes selon l’une 24. Procédé selon l’une quelconque des revendications quelconque des revendications 1 à 34 ; 1 à 23, caractérisé en ce que la sélection est réa- b) l’analyse du taux de méthylation des cytosi- lisée de telle manière à donner une seconde base nes au niveau de sites sélectionnés sur l’ADN de connaissance comprenant différents sous-en- 55 en se basant sur ledit panel de gènes dans le sembles de gènes sélectionnés. matériau biologique d’au moins un individu ma- lade avec une maladie ou une affection médi- 25. Procédé selon l’une quelconque des revendications cale connue et d’au moins un sujet en bonne

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santé, générant de cette manière une première base de connaissance ; c) l’analyse du taux de méthylation des cytosi- nes au niveau de sites sélectionnés sur l’ADN en se basant sur ledit panel de gènes dans le 5 matériau biologique d’au moins un individu ma- lade avec une maladie ou une affection médi- cale inconnue, générant de cette manière une deuxième base de connaissance; et d) la fourniture d’une troisième base de connais- 10 sance comprenant une pluralité de règles ex- pertes pour comparer la première et la deuxième bases de connaissance ; e) la sélection d’un type de maladie ou d’affec- tion médicale pour le au moins un individu ma- 15 lade avec une maladie ou une affection médi- cale inconnue en se basant sur la première à la troisième bases de connaissance.

36. Procédé selon la revendication 35, dans lequel la 20 maladie est sélectionnée à partir d’effets secondai- res indésirables de médicaments, de cancers, de dysfonctionnements, de lésions ou de maladies du système nerveux central (SNC), de symptômes d’agressivité ou de troubles comportementaux, de 25 conséquences cliniques et psychologiques de lé- sions cérébrales, de troubles psychotiques, d’une démence et / ou de troubles associés, de maladies cardiovasculaires, de maladies, de mauvais fonc- tionnements ou de lésions du tube digestif, de ma- 30 ladies, de mauvais fonctionnements ou de lésions du système respiratoire, d’une lésion, d’une inflam- mation, d’une infection, d’une immunité et / ou d’une reconvalescence, de maladies, de mauvais fonction- nements ou de lésions comme conséquences de 35 modifications dans le processus développemental, de maladies, de mauvais fonctionnements ou de lé- sions de la peau, des muscles, du tissu conjonctif ou des os, de maladies, de mauvais fonctionne- ments ou de lésions endocrines ou métaboliques, 40 de céphalée, et de mauvais fonctionnements sexuels ou de combinaisons de ceux-ci, d’une leu- cémie, d’un cancer de la tête et du cou, de la maladie de Hodgkin, d’un cancer gastrique, d’un cancer de la prostate, d’un cancer rénal, d’un cancer de la ves- 45 sie, d’un cancer du sein, d’un lymphome de Burkitt, d’une tumeur de Wilms, d’un syndrome de Prader- Willi / Angelman, d’un syndrome ICF, d’un dermato- fibrome, d’une hypertension, de maladies neurobio- logiques pédiatriques, d’un autisme, d’une rectoco- 50 lite hémorragique, d’un syndrome du X fragile et d’une maladie de Huntington.

55

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

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