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(12) Patent Application Publication (10) Pub. No.: US 2003/0170678A1 Tanzi Et Al

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US 2003.017O678A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0170678A1 Tanzi et al. (43) Pub. Date: Sep. 11, 2003 (54) GENETIC MARKERS FOR ALZHEIMER'S Related U.S. Application Data DISEASE AND METHODS USING THE SAME (60) Provisional application No. 60/348,065, filed on Oct. (75) Inventors: Rudolph E. Tanzi, Hull, MA (US); 25, 2001. Provisional application No. 60/336,983, Kenneth David Becker, San Diego, CA filed on Nov. 2, 2001. (US); Gonul Velicelebi, San Diego, CA (US); Kathryn J. Elliott, San Diego, Publication Classification CA (US); Xin Wang, San Diego, CA (US); Lars Bertram, Brighton, MA (51) Int. C.7 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - C12O 1/68 (US); Aleister J. Saunders, (52) U.S. Cl. .................................................................. 435/6 Philadelphia, PA (US); Deborah Lynne Blacker, Newton, MA (US) (57) ABSTRACT Correspondence Address: HELLER EHRMAN WHITE & MCAULIFFE LLP Genetic markers associated with Alzheimer's disease are 4350 LA JOLLAVILLAGE DRIVE provided. Also provided are methods of determining the 7TH FLOOR presence or absence in a Subject of one or more polymor SAN DIEGO, CA 92122-1246 (US) phisms associated with Alzheimer's disease and methods of determining the level of risk for Alzheimer's disease in a (73) Assignee: Neurogenetics, Inc. Subject. Further provided are nucleic acid compositions and kits for use in determining the presence or absence in a (21) Appl. No.: 10/281,456 Subject of one or more polymorphisms associated with Alzheimer's disease and kits for determining the level of (22) Filed: Oct. 25, 2002 risk for Alzheimer's disease in a Subject. Patent Application Publication Sep. 11, 2003 Sheet 1 of 34 US 2003/0170678A1 C V O l Patent Application Publication Sep. 11, 2003 Sheet 2 of 34 US 2003/0170678A1 V O L Patent Application Publication Sep. 11, 2003 Sheet 3 of 34 US 2003/0170678A1 H Patent Application Publication Sep. 11, 2003 Sheet 5 of 34 US 2003/0170678A1 Patent Application Publication Sep. 11, 2003 Sheet 6 of 34 US 2003/0170678A1 L V O L Patent Application Publication Sep. 11, 2003 Sheet 7 of 34 US 2003/0170678A1 Patent Application Publication Sep. 11, 2003 Sheet 8 of 34 US 2003/0170678A1 V O Patent Application Publication Sep. 11, 2003 Sheet 9 of 34 US 2003/0170678A1 V O Patent Application Publication Sep. 11, 2003 Sheet 10 of 34 US 2003/0170678A1 Patent Application Publication Sep. 11, 2003 Sheet 11 of 34 US 2003/0170678A1 US 2003/0170678A1 - ve O co o rt wr l Mr. Mr. Patent Application Publication US 2003/0170678A1 Patent Application Publication Sep. 11, 2003 Sheet 14 of 34 US 2003/0170678A1 Genes on Chromosome 1 O Cytogenetic O CMOAT CANALICULAR MULTISPECIFIC ORGANIC ANION TRANSPORTER . " O ATP-BINDING CASSETTE, SUB-FAMILY C ABCC2 (CFTR/MRP), MEMBER 2 GDB:6089489 10q24-10q24 • ABC O MRP2 o CMRP o DJS o ATP-BINDIN SUB-FAMILY D ABCDIP2 o ALD1OP1E.I.S.S." GDB99641383,3'- LIMAB1 ABLIM LIMACT IN BINDING PROTEIN 1 GDB.7173461 10q25-10q25 o IMATIN ACADSB o ACYL-COENZYME A DEHYDROGENASE, GDB-388699 F5. SHORT/BRANCHED CHAIN ACTA2 e ACTSA GDB:1251.97 10q22 ce o ACTIN, ALPHA 2, SMOOTH MUSCLE, AORTA - - - 10q24. ARP1 (ACTIN-RELATED PROTEIN 1, YEASI) 10q24.2- ACTR1A\ HOMOLOG A (CENTRACTIN ALPHA) CDB:9958719 10q24.3UQ4. o ARP1 o A DISINTEGRIN AND METAL LOPROTEINASE DOMAIN 12 (MELTRIN ALPHA) GDB:9958807 10q26.3- ADAM12 O MLTN 10q26.3 o MCMP o MTNA O A DISINTEGRIN AND METAL LOPROTEASE GDB:4573992 10O26.3-q o ADENOSINE DEAMINASE, RNA-SPECIFIC, B2 ADARB2 (HOMOLOG OF RAT BLUE) GDB:5929209 10p15-10p15 o RED2 o HRED2 a ADDL 10q24.2 ADD •. ADDUCINA55 N. 3 (GAMMA) -GDB:6O45066 - 10q24.3(4.4 s HS.81 10 ADK to HS.94.382 GDB:1 18979 3. N 8 ADENOSINE KINASE -- o ADORA2L CDB. 128572 10q25.5- ADOR2- . ADENOSINE A2 RECEPTOR-LIKE 1 10q26.5+. oO ADRARADRA2 GDB:120538:1 10q25qZo ADRA2A o ADRA2R - 1025. ADRENERGIC, ALPHA-2A-, RECEPTOR Patent Application Publication Sep. 11, 2003 Sheet 15 of 34 US 2003/0170678A1 Cytogenetic O HS.999.13 10 25 ADRB1 a ADRB1R GDB: 19654 :55, ADRENERGIC, BETA-1-, RECEPTOR q AF10 ALL1 FUSED GENE FROM CHROMOSOME 10 GDB:9954451 10p12-10p12 o DDH a DIHYDRODIOL DEHYDROGENASE 1 (TRANS 1,2-DIHYDROBENZENE-1,2-DIOL 1 OD14 AKR1C1 ACIDDEHYDROGENASE, BINDING) HIGH AFFINITY BILE GDB.202890 10p14.p14 o HS.78183 o DDH 0 MBAB DDH2 DIHYDRODIOL DEHYDROGENASE 2 (TRANS- GDB:385038 10p15 AKR1C2 1,2-DIHYDROBENZENE-1,2-DIOL - || 10p14. DEHYDROGENASE) O ALDO-KETO REDUCTASE FAMILY 1. MEMBER C3 (3-ALPHA HYDROXYSTEROID GDB:9864779 | 10p15-10p15 AKR1C3 DEHYDROGENASE, TYPE II) a O KAAO 119 O CHDR 10p15 AKR1C4 O CHLORDECONE REDUCTASE GDB:127896 15:3. HS.76790 ALDOAP2 o ALDOLASEPSEUDOGENE A, FRUCTOSE-BISPHOSPHATE2 GDB11895GDB:118995 || 10qter.10pter ALOX5 e ARACHIDONATE 5-LIPOXYGENASE GDB:132455 10q11.2- o HS.894.99 - 10q11.2. o ANKYRIN-LIKE REPEAT PROTEIN o CARP ALRP o C-193 GDB:9993042 o CYTOKINE INDUCIBLE NUCLEAR PROTEIN o CARDIAC ANKYRIN REPEAT PROTEIN O HS.96029 rrd. - ANK3 o ANKRIS3,HS.75893 NODE OF RANVIER (ANKYRING) SPB-29. 3. ANKRD2 O ANKYRIN REPEAT DOMAIN 2 (STRETCH GDB:10795364 10q23.1 RESPONSIVE MUSCLE) - 10q25.1 O ANX11 ANXA11 o ANNEXIN XI (56KD AUTOANTIGEN) GDB:313076 10q22-10q25 HS.75510 Ya O ANX2P3 ANXA2P3 : Fic GDB:120553 10q21 o ANX2L3 - 10q22. ... ANNEXIN II (LIPOCORTIN II) PSEUDOGENE 3 ass, GDB:369042 3. 3. ANNEXIN VII (SYNEXIN qZ.Z. FIG. 2B Patent Application Publication Sep. 11, 2003 Sheet 16 of 34 US 2003/0170678A1 Cytogenetic O ANX8 10q11.2- ANXA8 O ANNEXIN VIII GDB. 128069 5:3. o HS.87268 AP3M1 ADAPTOR-RELATED PROTEIN COMPLEX 3, GDB: 0013490 10q22.1- MU 1 SUBUNIT --- 100.22.5 o ADIPOSE SPECIFIC 2 GOB:9958.670 10-10 - 10q25.1- | ARPP o ANKYRIN REPEAT PROTEIN GDB:11499581 10q25.1 o ATP5C1 o ATP SYNTHASE, H+TRANSPORTING, MITOCHONDRIAL F1 COMPLEX, GAMMA 10q22-10q23 ATP5C1 POLYPEPIDE 1 CD8:137187 14q22.2- o ATP SYNTHASE, H+TRANSPORTING, 14q22.3 MITOCHONDRIAL F1 COMPLEX, GAMMA POLYPEPTIOE-LIKE 1 ATP5 e ATP SYNTHASE, H+ TRANSPORTING, MITOCHONDRIAL FO COMPLEX, SUBUNIT F6 • ATP SYNTHASE, H+ TRANSPORTING, 10pter-1 Oqter MITOCHONORIAL ATPM e ATP5A HS,73851 HS.451 - 10p15 o MURINE LEUKEMIA VIRAL (BMI-1) GDB:249556 10p13. ONCOGENE HOMOLOG ACVRLK3 BONE MORPHOGENETIC PROTEIN BMPR1A REPOR, TYPE 1A GDB:23.0245 o ACTIVIN A RECEPTOR, TYPE II-LIKE KINASE 3. o HBRAG BRAC 0 KIAAO598 GDB: 10013998 10q26-10q26 o B-CELL RAG ASSOCIATED PROTEIN - m BS69 o ADENOVIRUS 5 E1A BINDING PROTEIN GDB9958263 10-10 BTRC o BETA-TRANSDUCIN REPEAT CONTAINING GDB:995,5268 10q24-10q25 e BUB3 (BUDDING UNINHIBITED BY N BENZIMIDAZOLES 5, YEAST) HOMOLOG ur-ma o CACNLB2 o MYSB m - CACNB2 o CALCIUM CHANNEL VOLTAGE-DEPENDENT, GDB. 132014 10p12-10p12 BETA 2 SUBUNIT • MYASTHENIC (LAMBERT-EATON) SYNDROME ANTIGEN B FIG. 2C Patent Application Publication Sep. 11, 2003 Sheet 17 of 34 US 2003/0170678A1 Symbol Alioses Cytogenetic Location callsCALML5 ao CALMODULIN-IKECLP 3 GDB.p 138290 10pter103. CAMKG CAMK2G o CALCIUM/CALMODULIN-DEPENDENT GDB: 138469 10q22 PROTEIN KINASE (CAM KINASE) II GAMMA - 10q22. o CASPASE 7, APOPTOSIS-RELATED CYSTEINE PRO EASE CASP7 o MCH3 GDB:5750011 10q25-10q25 o CMH-1 o ICE-AP3 CORNEAL DYSTROPHY OF BOWMAN'S LAYER TYPE II (THIEL-BEHNKE) CDTB GDB:69 19860 10q23-10q24 CDC2 O Fl DMISION CYCLE 2, G1 TO S AND G2 TO GDB:119052 10q21.1 - O. HS.58,393 10q21.1 CADHERIN RELATED 23 - o DEAFNESS, AUTOSOMAL RECESSIVE 12 GDB. 1591799 10q21-10q22 • USHER SYNDROME 1 D (AUTOSOMAL : FSTEROL 25-HYDROXASE GDB9954776. 10q25-10q25 CHAT CHOLINE ACETYLTRANSFERASE GDB.119775 ER3. o UBIQUTOUSCONSERVED HELIX-LOOP-HELIXKINASE s o IKK1 10q24 o NFKBIKA GDB:46241 O KBKA 10q25. o IKK-ALPHA • TCF16 CMD1 C SEGi to 1C GDB:9140455 10q21-10q25 • COLLAGEN, TYPE XIII, ALPHA 1 GDB:1 19789 3. a BPAG2 COL17A COLLAGEN, TYPE XVII, ALPHA 1 o BULLOUS PEMPHIGOID ANTIGEN 2 (18OKD) e BP18O n 9 BCD1 e CORE PROMOTER ELEMENT BENDING COPEB PROTEIN GDB:9120625 10p15-10p15 9 B-CELL, DERVED 1 - . e CPBP e CYTOCHORME C OXIDASE SUBUNIT 5 COX15 COX115 (YEAST) HOMOLOG, CYTOCHROME C GDB9862902 10q24-10q24 OXIDASE ASSEMBLY PROTEIN FIG. 2D Patent Application Publication Sep. 11, 2003 Sheet 18 of 34 US 2003/0170678A1 Cytogenetic CARBOXYPEPTIDASE N, POLYPEPTIDE 1, CPN1 5OKD GDB,9835951 10pter-10qter 0 CPNE1 . o CAMP RESPONSIVE ELEMENT MODULATOR GOB:269801 o HS.79 106 O CHONOROTIN SULFATE PROTEOCLYCAN 6 (BAMACAN) BAM GDB:9958904 10q25-10q25- CSPG6 o HCAP CHONDROITIN SULFATE PROTEOGLYCAN 6 (BAMACAN) o CTSL 10q11.2- CSLL1 o CATHEPSIN L-LIKE 1 saan-n-GDB-250757. 1021, 10q22 CSLL2 O CATHEPSIN L-LIKE 2 GDB250758 1022, d d. 10q22.5- CTSLL3 CATHEPSIN L-LIKE 3 GDB,250760 6,231. O MGA1 CUBN o CUBILINRECEPTOR) (INTRINSIC FACTOR-COBALAMIN GDB,6360496049 O MEGALOBLASTIC ANEMA 1 • CUG TRIPLET REPEAT, RNA-BINDING PROTEIN 2 CUGBP2 O ELAV-TYPE RNA-BINDING PROTEIN GDB:9958105 | 10p15-10p13 O ETR-3 o NAPOR-2 CUL4B O CULLIN 4B GDB:9955.179 10pter-10qter o HS. 1363 o CYTOCHROME P450, SUBFAMILY XVII GDB: 119829 CYP17 (STEROID 17-ALPHA-HYDROXYLASE), ADRENAL HYPERPLASIA ge:Episo, SUB FAMILY WA • P450RAI - o CYP2C17 CYTOCHROME P450, SUBFAMILY IIC N (MEPHENYTOIN 4-HYDROXYLASE), pOLYPEPTIDE 17 CYP2C8 o HS.702 y GDB:128983 10q24-10q24 o P450IIC17 o CYTOCHROME P450, SUBFAMILY IIC (MEPHENYTOIN 4-HYDROXYLASE), POLYPEPTIDE 17 FIG. 2E Patent Application Publication Sep. 11, 2003 Sheet 19 of 34 US 2003/0170678A1 - r Cytogenetic o CYP2C a CYTOCHROME P450, SUBFAMILY IIC (MEPHENYTOIN 4-HYDROXYLASE), CYP2C19 EPIDE 19 GDB:1198.31 o CYTOCHROME P450, SUBFAMILY IIC (MEPHENYTOIN 4-HYDROXYLASE) o P450IIC 19 o CYTOCHROME P450, SUBFAMILY IIC 10q24.1- CYP2C8 (MEPHENYTOIN 4-HYDROXYLASE), GDB:127450 10241, W POLYPEPTIDE 8 CYP2C10 o CYTOCHROME P450, SUBFAMILY IIC CYP2C (MEPHENYTOIN 4-HYDROXYLASE), GDB.
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    Supplemental Table 1. Complete gene lists and GO terms from Figure 3C. Path 1 Genes: RP11-34P13.15, RP4-758J18.10, VWA1, CHD5, AZIN2, FOXO6, RP11-403I13.8, ARHGAP30, RGS4, LRRN2, RASSF5, SERTAD4, GJC2, RHOU, REEP1, FOXI3, SH3RF3, COL4A4, ZDHHC23, FGFR3, PPP2R2C, CTD-2031P19.4, RNF182, GRM4, PRR15, DGKI, CHMP4C, CALB1, SPAG1, KLF4, ENG, RET, GDF10, ADAMTS14, SPOCK2, MBL1P, ADAM8, LRP4-AS1, CARNS1, DGAT2, CRYAB, AP000783.1, OPCML, PLEKHG6, GDF3, EMP1, RASSF9, FAM101A, STON2, GREM1, ACTC1, CORO2B, FURIN, WFIKKN1, BAIAP3, TMC5, HS3ST4, ZFHX3, NLRP1, RASD1, CACNG4, EMILIN2, L3MBTL4, KLHL14, HMSD, RP11-849I19.1, SALL3, GADD45B, KANK3, CTC- 526N19.1, ZNF888, MMP9, BMP7, PIK3IP1, MCHR1, SYTL5, CAMK2N1, PINK1, ID3, PTPRU, MANEAL, MCOLN3, LRRC8C, NTNG1, KCNC4, RP11, 430C7.5, C1orf95, ID2-AS1, ID2, GDF7, KCNG3, RGPD8, PSD4, CCDC74B, BMPR2, KAT2B, LINC00693, ZNF654, FILIP1L, SH3TC1, CPEB2, NPFFR2, TRPC3, RP11-752L20.3, FAM198B, TLL1, CDH9, PDZD2, CHSY3, GALNT10, FOXQ1, ATXN1, ID4, COL11A2, CNR1, GTF2IP4, FZD1, PAX5, RP11-35N6.1, UNC5B, NKX1-2, FAM196A, EBF3, PRRG4, LRP4, SYT7, PLBD1, GRASP, ALX1, HIP1R, LPAR6, SLITRK6, C16orf89, RP11-491F9.1, MMP2, B3GNT9, NXPH3, TNRC6C-AS1, LDLRAD4, NOL4, SMAD7, HCN2, PDE4A, KANK2, SAMD1, EXOC3L2, IL11, EMILIN3, KCNB1, DOK5, EEF1A2, A4GALT, ADGRG2, ELF4, ABCD1 Term Count % PValue Genes regulation of pathway-restricted GDF3, SMAD7, GDF7, BMPR2, GDF10, GREM1, BMP7, LDLRAD4, SMAD protein phosphorylation 9 6.34 1.31E-08 ENG pathway-restricted SMAD protein GDF3, SMAD7, GDF7, BMPR2, GDF10, GREM1, BMP7, LDLRAD4, phosphorylation
  • Noelia Díaz Blanco

    Noelia Díaz Blanco

    Effects of environmental factors on the gonadal transcriptome of European sea bass (Dicentrarchus labrax), juvenile growth and sex ratios Noelia Díaz Blanco Ph.D. thesis 2014 Submitted in partial fulfillment of the requirements for the Ph.D. degree from the Universitat Pompeu Fabra (UPF). This work has been carried out at the Group of Biology of Reproduction (GBR), at the Department of Renewable Marine Resources of the Institute of Marine Sciences (ICM-CSIC). Thesis supervisor: Dr. Francesc Piferrer Professor d’Investigació Institut de Ciències del Mar (ICM-CSIC) i ii A mis padres A Xavi iii iv Acknowledgements This thesis has been made possible by the support of many people who in one way or another, many times unknowingly, gave me the strength to overcome this "long and winding road". First of all, I would like to thank my supervisor, Dr. Francesc Piferrer, for his patience, guidance and wise advice throughout all this Ph.D. experience. But above all, for the trust he placed on me almost seven years ago when he offered me the opportunity to be part of his team. Thanks also for teaching me how to question always everything, for sharing with me your enthusiasm for science and for giving me the opportunity of learning from you by participating in many projects, collaborations and scientific meetings. I am also thankful to my colleagues (former and present Group of Biology of Reproduction members) for your support and encouragement throughout this journey. To the “exGBRs”, thanks for helping me with my first steps into this world. Working as an undergrad with you Dr.
  • Genetic and Pharmacological Approaches to Preventing Neurodegeneration

    Genetic and Pharmacological Approaches to Preventing Neurodegeneration

    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2012 Genetic and Pharmacological Approaches to Preventing Neurodegeneration Marco Boccitto University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Neuroscience and Neurobiology Commons Recommended Citation Boccitto, Marco, "Genetic and Pharmacological Approaches to Preventing Neurodegeneration" (2012). Publicly Accessible Penn Dissertations. 494. https://repository.upenn.edu/edissertations/494 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/494 For more information, please contact [email protected]. Genetic and Pharmacological Approaches to Preventing Neurodegeneration Abstract The Insulin/Insulin-like Growth Factor 1 Signaling (IIS) pathway was first identified as a major modifier of aging in C.elegans. It has since become clear that the ability of this pathway to modify aging is phylogenetically conserved. Aging is a major risk factor for a variety of neurodegenerative diseases including the motor neuron disease, Amyotrophic Lateral Sclerosis (ALS). This raises the possibility that the IIS pathway might have therapeutic potential to modify the disease progression of ALS. In a C. elegans model of ALS we found that decreased IIS had a beneficial effect on ALS pathology in this model. This beneficial effect was dependent on activation of the transcription factor daf-16. To further validate IIS as a potential therapeutic target for treatment of ALS, manipulations of IIS in mammalian cells were investigated for neuroprotective activity. Genetic manipulations that increase the activity of the mammalian ortholog of daf-16, FOXO3, were found to be neuroprotective in a series of in vitro models of ALS toxicity.
  • Nuclear Envelope Laminopathies: Evidence for Developmentally Inappropriate Nuclear Envelope-Chromatin Associations

    Nuclear Envelope Laminopathies: Evidence for Developmentally Inappropriate Nuclear Envelope-Chromatin Associations

    Nuclear Envelope Laminopathies: Evidence for Developmentally Inappropriate Nuclear Envelope-Chromatin Associations by Jelena Perovanovic M.S. in Molecular Biology and Physiology, September 2009, University of Belgrade M.Phil. in Molecular Medicine, August 2013, The George Washington University A Dissertation submitted to The Faculty of The Columbian College of Arts and Sciences of The George Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 31, 2015 Dissertation directed by Eric P. Hoffman Professor of Integrative Systems Biology The Columbian College of Arts and Sciences of The George Washington University certifies that Jelena Perovanovic has passed the Final Examination for the degree of Doctor of Philosophy as of May 5, 2015. This is the final and approved form of the dissertation. Nuclear Envelope Laminopathies: Evidence for Developmentally Inappropriate Nuclear Envelope-Chromatin Associations Jelena Perovanovic Dissertation Research Committee: Eric P. Hoffman, Professor of Integrative Systems Biology, Dissertation Director Anamaris Colberg-Poley, Professor of Integrative Systems Biology, Committee Member Robert J. Freishtat, Associate Professor of Pediatrics, Committee Member Vittorio Sartorelli, Senior Investigator, National Institutes of Health, Committee Member ii © Copyright 2015 by Jelena Perovanovic All rights reserved iii Acknowledgments I am deeply indebted to countless individuals for their support and encouragement during the past five years of graduate studies. First and foremost, I would like to express my gratitude to my mentor, Dr. Eric P. Hoffman, for his unwavering support and guidance, and keen attention to my professional development. This Dissertation would not have been possible without the critical input he provided and the engaging environment he created.
  • Apoptotic Genes As Potential Markers of Metastatic Phenotype in Human Osteosarcoma Cell Lines

    Apoptotic Genes As Potential Markers of Metastatic Phenotype in Human Osteosarcoma Cell Lines

    17-31 10/12/07 14:53 Page 17 INTERNATIONAL JOURNAL OF ONCOLOGY 32: 17-31, 2008 17 Apoptotic genes as potential markers of metastatic phenotype in human osteosarcoma cell lines CINZIA ZUCCHINI1, ANNA ROCCHI2, MARIA CRISTINA MANARA2, PAOLA DE SANCTIS1, CRISTINA CAPANNI3, MICHELE BIANCHINI1, PAOLO CARINCI1, KATIA SCOTLANDI2 and LUISA VALVASSORI1 1Dipartimento di Istologia, Embriologia e Biologia Applicata, Università di Bologna, Via Belmeloro 8, 40126 Bologna; 2Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli; 3IGM-CNR, Unit of Bologna, c/o Istituti Ortopedici Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy Received May 29, 2007; Accepted July 19, 2007 Abstract. Metastasis is the most frequent cause of death among malignant primitive bone tumor, usually developing in children patients with osteosarcoma. We have previously demonstrated and adolescents, with a high tendency to metastasize (2). in independent experiments that the forced expression of Metastases in osteosarcoma patients spread through peripheral L/B/K ALP and CD99 in U-2 OS osteosarcoma cell lines blood very early and colonize primarily the lung, and later markedly reduces the metastatic ability of these cancer cells. other skeleton districts (3). Since disseminated hidden micro- This behavior makes these cell lines a useful model to assess metastases are present in 80-90% of OS patients at the time the intersection of multiple and independent gene expression of diagnosis, the identification of markers of invasiveness signatures concerning the biological problem of dissemination. and metastasis forms a target of paramount importance in With the aim to characterize a common transcriptional profile planning the treatment of osteosarcoma lesions and enhancing reflecting the essential features of metastatic behavior, we the prognosis.