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(12) Patent Application Publication (10) Pub. No.: US 2002/0137086 A1 Olek Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2002/0137086 A1 Olek Et Al US 2002O137086A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0137086 A1 Olek et al. (43) Pub. Date: Sep. 26, 2002 (54) METHOD FOR THE DEVELOPMENT OF Publication Classification GENEPANELS FOR DIAGNOSTIC AND THERAPEUTIC PURPOSES BASED ON THE (51) Int. Cl." ............................ C12O 1/68; G06F 19/00; EXPRESSION AND METHYLATION STATUS G01N 33/48; G01N 33/50 OF THE GENES (52) U.S. Cl. ................................................... 435/6; 702/20 (57) ABSTRACT A method for the development of gene panels for diagnostic (76) Inventors: Alexander Olek, Berlin (DE); Kurt and therapeutic purposes comprising the steps of: (a) iso Berlin, Stahnsdorf (DE) lating at least one biological Sample from each of at least two groups of biological material containing mRNA and/or Correspondence Address: proteins; (b) analyzing the expression level of at least one KRIEGSMAN & KREGSMAN gene in the at least one biological Sample; (c) Selecting the 665 Franklin Street gene(s) exhibiting a different expression level between the at Framingham, MA 01702 (US) least two groups of biological material, whereby a first knowledge base is generated; (d) analyzing the level of (21) Appl. No.: 10/087,466 cytosine methylation in the methylation relevant regions of (22) Filed: Mar. 1, 2002 at least one gene of at least one of the biological Samples of Step (a), wherein the gene is selected on the basis of the first knowledge base; (e) selecting the gene(s) exhibiting a dif Related U.S. Application Data ferent level of cytosine methylation between the at least two groups of biological material, whereby a Second knowledge (60) Provisional application No. 60/272.549, filed on Mar. base is generated; and (f) adding selected genes from the 1, 2001. Second knowledge base to a gene panel. US 2002/0137086 A1 Sep. 26, 2002 METHOD FOR THE DEVELOPMENT OF GENE Because it is often difficult to predict the function of a PANELS FOR DIAGNOSTIC AND THERAPEUTIC protein based on homology to other proteins or even their PURPOSES BASED ON THE EXPRESSION AND three-dimensional Structure, determination of the compo METHYLATION STATUS OF THE GENES nents of a protein complex or of a cellular Structure is central in functional analysis (Pandey A et al. “Proteomics to study FIELD OF THE INVENTION genes and genomes.” Nature Jun. 15, 2000;405(6788):837 46). 0001. The present invention concerns a method for the development of gene panels for diagnostic and therapeutic 0007 Due to the complexity of higher eukaryotic cells, purposes. The invention further concerns gene panels devel Single-step characterization of a proteome is likely to be oped using the method of the present invention and their difficult to achieve. Jung et al. (“Proteomics meets cell SCS. biology: the establishment of Subcellular proteomes” Elec trophoresis October 2000:21(16):3369-77) describe, that BACKGROUND OF THE INVENTION advantage can be taken of the macromolecular architecture of a cell, e.g., Subcellular compartments, organelles, mac 0002 The levels of observation that have been well romolecular structures and multi-protein complexes, to Studied by the methodological developments of recent years establish Subcellular proteomes. in molecular biology include the gene itself, the translation of genes in RNA, and the resulting proteins. When, during 0008. Despite the recent developments in the art, the the course of the development of an individual, a gene is detection of proteins that are of regulatory importance, from Switched on, and how the activation and inhibition of certain small quantities of cells still fails because of the fact that the genes in certain cells and tissues is controlled, can be sensitivity of the methods used is much too low. Indeed, in correlated with a high degree of probability with the extent contrast to nucleic acids, proteins cannot be amplified. In and the character of the methylation of the gene or the addition, the method is very complex, not amenable to genome. In this regard, it is reasonable to assume that automation, and very expensive. In contrast, RNA analysis pathogenic conditions are expressed in a modified methy presents considerable advantages, and due to of the use of lation pattern of individual genes or of the genome. PCR it is more sensitive. Above all, each RNA species recognized to be important can be identified immediately by STATE OF THE ART its Sequence. 0003) 1. State of the Art of Molecular Analysis of Cell 0009. Overexpression or underexpression of individual Phenotypes RNAS with a known sequence can usually be easily detected; however, in connection with the applications dis 0004. The study of gene expression can be at the RNA cussed here, they are only valid in exceptional cases. level or at the protein level. Both levels in principle reflect important phenotypic parameters. Protein assays using two 0010) The method of “differential displays” at best allows dimensional gels (McFarrel method) have been known for a Semiquantitative Study of expression. Expression products approximately 15 years. Using these assays, it is possible to amplified by PCR are separated by gel electrophoresis. The elaborate the analysis of the chromatographic positions of validity is limited as a result of the resolution of the gel Several thousand proteins. Very early on, Such electrophero electrophoresis. In addition, the method is insufficiently grams were already processed or evaluated with data pro Sensitive and robust for use in routine diagnosis (Liang, P. cessing means. In principle, the validity of the method is and Pardee, A. B., Science 257,967-971). high, however, it is inferior to the modern methods of gene 0011 Genes with high overexpression or underexpres expression based on RNA analysis in two regards. Sion are frequently identified by Subtractive techniques. 0005 The global analysis of cellular proteins has recently Here, cDNA clones of a cell or tissue species to be examined been termed proteomics and is a key area of research that is are plated. Against the clones, cDNA is hybridized as developing in the post-genome era. Proteomics uses a com comparison material. Expression patterns cannot be reliably bination of Sophisticated techniques including two-dimen prepared using this technique. Sional (2D) gel electrophoresis, image analysis, mass spec 0012 Sturtevant et al. (“Applications of differential-dis trometry, amino acid Sequencing, and bio-informatics to play reverse transcription-PCR to molecular pathogenesis resolve comprehensively, to quantify, and to characterize and medical mycology. Clin Microbiol Rev July proteins (for reviews, see Chambers Get al. “Proteomics: a 2000;13(3):408-27) describe the characterisation of host new approach to the study of disease” J. Pathol November fungus interactions by changes in gene expression in both 2000; 192(3):280-8; Banks R E et al. “Proteomics: new host and pathogen. Differential-display reverse transcription perspectives, new biomedical opportunities' Lancet Nov. PCR (DDRT-PCR) is a PCR-based method that allows 18, 2000:356(9243):1749-56). extensive analysis of gene expression among Several cell 0006 Proteomics is further said to contribute greatly to populations. DDRT-PCR has been used to address biological the understanding of gene function in the post-genomic era. questions in mammalian Systems, including cell differentia Proteomics can be divided into three main areas: (1) protein tion, cell activation, cell StreSS, and identification of drug micro-characterization for large-scale identification of pro targets. In microbial pathogenesis and plant pathogenesis, teins and their post-translational modifications; (2) “differ DDRT-PCR has allowed the identification of virulence fac ential display proteomics for comparison of protein levels tors, genes involved in cell death, and Signaling genes. with potential application in a wide range of diseases, and Further, To (“Identification of differential gene expression (3) Studies of protein-protein interactions using techniques by high throughput analysis' Comb Chem High Throughput Such as maSS Spectrometry or the yeast two-hybrid System. Screen June 2000;3(3):235-41) describes the high through US 2002/0137086 A1 Sep. 26, 2002 put analysis of differential gene expression as a powerful defined tumor groups, there are Such differences in the tool that can be applied to many areas in molecular cell behavior that the conclusion must be drawn that additional biology, including differentiation, development, physiology, unknown genetic parameters (Such as, for example, the and pharmacology. In recent years, a variety of techniques genetic background of the individual) play an important have been developed to analyze differential gene expression, role. Immunological tumor markers are helpful auxiliary including comparative expressed Sequence tag Sequencing, parameters, but they continue to make only a modest con differential display, representational difference analysis, tribution, in addition to the other conventional diagnostic cDNA or oligonucleotide arrays, and Serial analysis of gene parameters. However, they can be used for the purpose of expression. Similar Strategies are described by Oetting preSelecting Suspect cells. (“Gene expression analysis. Pigment Cell Res February 2000;13(1):21-7) and Watson (“Differential cDNA screen 0017. Histology plays an important and indispensable ing Strategies to identify novel Stage-specific proteins in the role in the identification of degenerated tissues, but not developing mammalian brain. Dev
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