title: Identification of overexpressed genes in frequently gained/amplified chromosome regions in multiple myeloma.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  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.
authors.affiliation: Cytogenetics Unit, Spanish National Cancer Centre, (CNIO), C/ Melchor Fernandez Almagro 3, Madrid, 28029, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Largo
authors.forename: Sara
authors.initials: S
authors.lastname: Alvarez
authors.forename: Borja
authors.initials: B
authors.lastname: Saez
authors.forename: David
authors.initials: D
authors.lastname: Blesa
authors.forename: Jose I
authors.initials: JI
authors.lastname: Martin-Subero
authors.forename: Ines
authors.initials: I
authors.lastname: González-García
authors.forename: Jose A
authors.initials: JA
authors.lastname: Brieva
authors.forename: Joaquin
authors.initials: J
authors.lastname: Dopazo
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: María J
authors.initials: MJ
authors.lastname: Calasanz
authors.forename: Juan C
authors.initials: JC
authors.lastname: Cigudosa
mesh_terms: D020169:Caspases; D045744:Cell Line, Tumor; D002877:Chromosomes, Human; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D052138:Genes, Neoplasm; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009101:Multiple Myeloma / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics
chemical_list: D007143:Immunoglobulin Heavy Chains; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein