03074nas a2200325   4500008004100000245011200041210006900153300001100222490000700233520182100240653001102061653002302072653009602095653012202191653006602313653004102379653002302420100001402443700001602457700001302473700001402486700002602500700002402526700001902550700001502569700001602584700002102600700002102621856010602642       2006                        eng d00aIdentification of overexpressed genes in frequently gained/amplified chromosome regions in multiple myeloma0 aIdentification of overexpressed genes in frequently gainedamplif  a184-910 v913 aBACKGROUND AND OBJECTIVES: Multiple myeloma (MM) is a malignancy characterized by clonal expansion of plasma cells. In 50% of the cases, the neoplastic transformation begins with a chromosomal translocation that juxtaposes the IGH gene locus to an oncogene. Gene copy number changes are also frequent in MM but less characterized than in other neoplasias. We aimed to characterize genes that are amplified and overexpressed in human myeloma cell lines (HMCL) to provide putative molecular targets for MM therapy. DESIGN AND METHODS: Nine HMCL were characterized by fluorescent in situ hybridization, comparative genomic hybridization (CGH) and cDNA microarrays for gene expression profiling and copy number changes. RESULTS: After defining the IGH-translocations present in the cell lines, we conducted expression-profiling analysis. Supervised analysis identified 166 genes with significantly different expression among the cell lines harboring MMSET/FGFR3 (4p16), MAF (16q) and CCND1 (11q13) rearrangements. Array-CGH was then performed. Five chromosomes recurrently affected by gains/amplifications in primary samples and cell lines were analyzed in detail. Sixty amplified and overexpressed genes were found and 25 (42%) of them were only overexpressed when amplified; moreover, six showed a significant association between overexpression and gain/amplification. We also found co-amplification and overexpression for genes located within the same amplicons, such as MALT1 and BCL2. INTERPRETATION AND CONCLUSIONS: Parallel analysis of gene copy numbers and expression levels by cDNA microarray in MM allowed efficient identification of genes whose expression levels are elevated because of increased copy number. This is the first time that MALT1 and BCL2 have been shown to be overexpressed and amplified in MM.10aB-Cell10aCaspases Cell Line10aHuman *Gene Amplification Gene Dosage Gene Expression Profiling *Gene Expression Regulation10aMarginal Zone/genetics Multiple Myeloma/*genetics Neoplasm Proteins/genetics Proto-Oncogene Proteins c-bcl-2/genetics10aNeoplasm Humans Immunoglobulin Heavy Chains/genetics Lymphoma10aNeoplastic Gene Rearrangement *Genes10aTumor *Chromosomes1 aLargo, C.1 aAlvarez, S.1 aSaez, B.1 aBlesa, D.1 aMartin-Subero, J., I.1 aGonzalez-Garcia, I.1 aBrieva, J., A.1 aDopazo, J.1 aSiebert, R.1 aCalasanz, M., J.1 aCigudosa, J., C.  uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1646130202881nas a2200397   4500008004100000245016800041210006900209300001200278490000700290520143600297653010101733653002201834653001001856653008301866653003301949653003301982653003302015653003202048653005102080100001602131700002102147700001502168700001602183700001602199700001602215700001602231700001802247700001602265700001402281700001302295700002102308700001502329700001702344700001602361856010602377       2005                        eng d00aA predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non-BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation0 apredictor based on the somatic genomic changes of the BRCA1BRCA2  a1146-530 v113 aThe genetic changes underlying in the development and progression of familial breast cancer are poorly understood. To identify a somatic genetic signature of tumor progression for each familial group, BRCA1, BRCA2, and non-BRCA1/BRCA2 (BRCAX) tumors, by high-resolution comparative genomic hybridization, we have analyzed 77 tumors previously characterized for BRCA1 and BRCA2 germ line mutations. Based on a combination of the somatic genetic changes observed at the six most different chromosomal regions and the status of the estrogen receptor, we developed using random forests a molecular classifier, which assigns to a given tumor a probability to belong either to the BRCA1 or to the BRCA2 class. Because 76.5% (26 of 34) of the BRCAX cases were classified with our predictor to the BRCA1 class with a probability of >50%, we analyzed the BRCA1 promoter region for aberrant methylation in all the BRCAX cases. We found that 15 of the 34 BRCAX analyzed tumors had hypermethylation of the BRCA1 gene. When we considered the predictor, we observed that all the cases with this epigenetic event were assigned to the BRCA1 class with a probability of >50%. Interestingly, 84.6% of the cases (11 of 13) assigned to the BRCA1 class with a probability >80% had an aberrant methylation of the BRCA1 promoter. This fact suggests that somatic BRCA1 inactivation could modify the profile of tumor progression in most of the BRCAX cases.10aBRCA1 Protein/*genetics BRCA2 Protein/*genetics Breast Neoplasms/*genetics/pathology Chromosomes10aGenetic/*genetics10aHuman10aHuman Humans Male Mutation Nucleic Acid Hybridization/methods Promoter Regions10aPair 12/genetics Chromosomes10aPair 15/genetics Chromosomes10aPair 18/genetics Chromosomes10aPair 2/genetics Chromosomes10aPair 8/genetics *DNA Methylation Female Genome1 aAlvarez, S.1 aDiaz-Uriarte, R.1 aOsorio, A.1 aBarroso, A.1 aMelchor, L.1 aPaz, M., F.1 aHonrado, E.1 aRodriguez, R.1 aUrioste, M.1 aValle, L.1 aDiez, O.1 aCigudosa, J., C.1 aDopazo, J.1 aEsteller, M.1 aBenitez, J.  uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15709182