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    Initial genome sequencing and analysis of multiple myeloma

    Authors: 1 , 1 , 2 , 3 , 1 , 1 , 4 , 1 , 1 , 2 , 3 , 1 , 5 , 3 , 4 , 1 , 3 , 6 , 7 , 2 , 3 , 1 , 5 , 8 , 9 , 1 , 10 , 2 , 3 , 1 , 3 , 11 , 3 , 12 , 3 , 13 , 3 , 14 , 3 , 6 , 1 , 3 , 15 , 1 , 3 , 6 , 1 , 3 , 6 , 1 , 1 , 3 , 16 , 1 , 3 , 17 , 1 , 3 , 18 , 3 , 19 , 1 , 1 , 3 , 20 , 7 , 7 , 1 , 4 , 8 , 1 , 4 , 1 , 4 , 8 , 1 , 8 , 21 , 1 , 1 , 4 , 8 , 9

    Publication date PMC-release

    Journal: Nature

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        Abstract

        Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the dataset. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signaling was suggested by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.

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        Most cited references 48

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        Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.

         Vamsi K Mootha,  Todd R. Golub,  Jill Mesirov … (2005)
        Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.
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          PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.

           Elias N Houstis,  Roger Daly,  Vamsi K Mootha … (2003)
          DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1alpha and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.
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            Mutations of the BRAF gene in human cancer.

             Catherine Mould,  Sarah Hall,  Jon Teague … (2002)
            Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.
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              Author and article information

              Affiliations
              [1 ]The Eli and Edythe L. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02412, USA
              [2 ]Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA
              [3 ]On behalf of the Multiple Myeloma Research Consortium, 383 Main Avenue, 5 th Floor, Norwalk, Connecticut 06581, USA
              [4 ]Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
              [5 ]Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA
              [6 ]Multiple Myeloma Research Foundation, 383 Main Avenue, 5 th Floor, Norwalk, Connecticut 06581, USA
              [7 ]The Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, Arizona 85004, USA
              [8 ]Harvard Medical School, Boston, Massachusetts 02115, USA
              [9 ]Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
              [10 ]Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel
              [11 ]The Ohio State University Medical Center, 320 West 10 th Avenue, Columbus, Ohio 43210, USA
              [12 ]St. Vincent's Comprehensive Cancer Center, 325 West 15 th Street, New York, New York 11001, USA
              [13 ]University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA
              [14 ]City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, California 91010, USA
              [15 ]Winship Cancer Institute, Emory University, 1365-C Clifton Road, NE Atlanta, Georgia 30322, USA
              [16 ]Mayo Clinic Rochester, 200 1 st Street S.W. Rochester, Minnesota, 55905, USA
              [17 ]Hackensack University Medical Center, 30 Prospect Avenue, Hackensack, New Jersey 07601, USA
              [18 ]Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada
              [19 ]Washington University School of Medicine, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA
              [20 ]University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, Illinois 60637, USA
              [21 ]Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA
              Author notes
              [* ]To whom correspondence should be addressed: Correspondence and requests for materials should be addressed to T.R.G. ( golub@ 123456broadinstitute.org ) or G.G. ( gadgetz@ 123456broadinstitute.org )
              Journal
              Journal ID (nlm-journal-id): 0410462
              Journal ID (pubmed-jr-id): 6011
              Journal ID (nlm-ta): Nature
              Journal ID (iso-abbrev): Nature
              Title: Nature
              ISSN (Print): 0028-0836
              ISSN (Electronic): 1476-4687
              Publication date Nihms-submitted 20 January 2013
              Publication date (Print): 24 March 2011
              Publication date PMC-release 30 January 2013
              Volume: 471
              Issue: 7339
              Pages: 467-472
              PubMed ID: 21430775
              PMC ID: 3560292
              DOI: 10.1038/nature09837
              Manuscript ID: NIHMS385546

              License:

              Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

              Funding
              Funded by: National Cancer Institute : NCI
              Award ID: R01 CA133966-03 || CA
              Funded by: National Cancer Institute : NCI
              Award ID: R01 CA133115-04 || CA
              Funded by: National Institute on Aging : NIA
              Award ID: R01 AG020686-07 || AG
              Funded by: National Cancer Institute : NCI
              Award ID: K12 CA133250 || CA
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