%0 Journal Article %T The shaping and functional consequences of the dosage effect landscape in multiple myeloma. %+ Department of Biostatistics and Computational Biology %+ Department of Biostatistics and Medical Informatics %+ Department of Bioinformatics %+ Centre de Recherche en Cancérologie Nantes-Angers (CRCNA) %+ Department of Medical Oncology %A Samur, Mehmet %A Shah, Parantu %A Wang, Xujun %A Minvielle, Stéphane %A Magrangeas, Florence %A Avet-Loiseau, Hervé %A Munshi, Nikhil %A Li, Cheng %Z NIH R01 GM077122 (C Li), National Basic Research Program of China (973 Program; No. 2010CB944904) (X Wang), and Claudia Adams Barr Program in Innovative Basic Cancer Research and the Multiple Myeloma Career Development award (PK Shah). This work is also supported in part by grants from the National Institutes of Health Grants RO1-124929, PO1-155258, P50-100007 and PO1-78378 to NC Munshi and C Li and from the Dept. of Veterans Affairs Merit Review Awards to NC Munshi. S Minvielle and F Magrangeas were supported by French National Research Agency, Grant R08079NS. %< avec comité de lecture %J BMC Genomics %I BioMed Central %V 14 %N 1 %P 672 %8 2013-10-02 %D 2013 %R 10.1186/1471-2164-14-672 %M 24088394 %K Copy number alteration %K Dosage effect %K Multiple myeloma %K Hyperdiploid %K Integrative genomics %Z Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]Journal articles %X BACKGROUND: Multiple myeloma (MM) is a malignant proliferation of plasma B cells. Based on recurrent aneuploidy such as copy number alterations (CNAs), myeloma is divided into two subtypes with different CNA patterns and patient survival outcomes. How aneuploidy events arise, and whether they contribute to cancer cell evolution are actively studied. The large amount of transcriptomic changes resultant of CNAs (dosage effect) pose big challenges for identifying functional consequences of CNAs in myeloma in terms of specific driver genes and pathways. In this study, we hypothesize that gene-wise dosage effect varies as a result from complex regulatory networks that translate the impact of CNAs to gene expression, and studying this variation can provide insights into functional effects of CNAs. RESULTS: We propose gene-wise dosage effect score and genome-wide karyotype plot as tools to measure and visualize concordant copy number and expression changes across cancer samples. We find that dosage effect in myeloma is widespread yet variable, and it is correlated with gene expression level and CNA frequencies in different chromosomes. Our analysis suggests that despite the enrichment of differentially expressed genes between hyperdiploid MM and non-hyperdiploid MM in the trisomy chromosomes, the chromosomal proportion of dosage sensitive genes is higher in the non-trisomy chromosomes. Dosage-sensitive genes are enriched by genes with protein translation and localization functions, and dosage resistant genes are enriched by apoptosis genes. These results point to future studies on differential dosage sensitivity and resistance of pro- and anti-proliferation pathways and their variation across patients as therapeutic targets and prognosis markers. CONCLUSIONS: Our findings support the hypothesis that recurrent CNAs in myeloma are selected by their functional consequences. The novel dosage effect score defined in this work will facilitate integration of copy number and expression data for identifying driver genes in cancer genomics studies. The accompanying R code is available at http://www.canevolve.org/dosageEffect/. %G English %2 https://inserm.hal.science/inserm-00903866/document %2 https://inserm.hal.science/inserm-00903866/file/1471-2164-14-672.pdf %L inserm-00903866 %U https://inserm.hal.science/inserm-00903866 %~ INSERM %~ CNRS %~ UNAM %~ CRCNA