1,606
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      The landscape of somatic copy-number alteration across human cancers

      research-article
      1 , 2 , 3 , 4 , 1 , 2 , 5 , 1 , 1 , 3 , 5 , 1 , 2 , 1 , 1 , 2 , 6 , 5 , 1 , 3 , 7 , 1 , 2 , 1 , 2 , 3 , 4 , 1 , 1 , 1 , 1 , 2 , 1 , 2 , 1 , 2 , 11 , 1 , 2 , 3 , 5 , 1 , 2 , 1 , 2 , 1 , 1 , 2 , 2 , 3 , 8 , 9 , 10 , 11 , 3 , 12 , 12 , 13 , 14 , 14 , 2 , 3 , 1 , 15 , 16 , 17 , 1 , 3 , 4 , 1 , 18 , 17 , 17 , 2 , 1 , 2 , 2 , 3 , 19 , 20 , 21 , 7 , 17 , 1 , 2 , 22 , 1 , 4 , 23 , , 1 , , 5 , , 1 , 2 , 4 ,
      Nature

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          A powerful way to discover key genes playing causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here, we report high-resolution analyses of somatic copy-number alterations (SCNAs) from 3131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across multiple cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κB pathway. We show that cancer cells harboring amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend upon expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in multiple cancer types.

          Related collections

          Most cited references40

          • Record: found
          • Abstract: found
          • Article: not found

          Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.

          Systematic analyses of cancer genomes promise to unveil patterns of genetic alterations linked to the genesis and spread of human cancers. High-density single-nucleotide polymorphism (SNP) arrays enable detailed and genome-wide identification of both loss-of-heterozygosity events and copy-number alterations in cancer. Here, by integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, we identified the melanocyte master regulator MITF (microphthalmia-associated transcription factor) as the target of a novel melanoma amplification. We found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF mutation and p16 inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF(V600E) mutant transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Together, these data suggest that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumour progression.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma.

            Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximately 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Characterizing the cancer genome in lung adenocarcinoma.

              Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in approximately 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.
                Bookmark

                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                22 January 2010
                18 February 2010
                18 August 2010
                : 463
                : 7283
                : 899-905
                Affiliations
                [1 ] Cancer Program, Medical and Population Genetics Group, The Broad Institute of M.I.T. and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
                [2 ] Departments of Medical Oncology, Pediatric Oncology, and Cancer Biology, and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
                [3 ] Departments of Medicine and Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA
                [4 ] Departments of Medicine, Pathology, and Pediatrics, and Systems Biology, Harvard Medical School, Boston, MA 02115, USA
                [5 ] Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
                [6 ] Division of Molecular Epidemiology, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461 Japan
                [7 ] Department of Neurology, Children’s Hospital Boston, Boston, MA 02115, USA
                [8 ] Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75390-9186
                [9 ] Genetics Branch, Center for Cancer Research, National Cancer Institute and National Naval Medical Center, Bethesda, Maryland 20889, USA
                [10 ] Department of Surgery II, Nagoya City University Medical School, Nagoya 467-8601, Japan
                [11 ] Department of Genetics and Radiation Oncology, UNC/Lineberger Comprehensive Cancer Center, University of North Carolina, School of Medicine, Chapel Hill, NC 27599, USA
                [12 ] Medical Oncology Program, Vall d’Hebron University Hospital Research Institute, Vall d’Hebron Institute of Oncology, and Autonomous University of Barcelona, 08035 Barcelona, Spain
                [13 ] Department of Pathology and Division of Applied Molecular Oncology, University Health Network, Princess Margaret Hospital and Ontario Cancer Institute, Toronto, ON, Canada
                [14 ] Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York
                [15 ] Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Center, Boston, Massachusetts 02114, USA
                [16 ] Department of Pathology, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, Boston MA 02115, USAA
                [17 ] Departments of Medicine and Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065
                [18 ] Departments of Medicine (GI Division) and Genetics, and Abramson Cancer Center, University of Pennsylvania, 415 Curie Blvd. Philadelphia, PA 19104
                [19 ] Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, Ann Arbor, MI, 48109
                [20 ] Department of Pathology, University of Washington Medical Center, 1959 NE Pacific St, Seattle, WA, 98195-6100
                [21 ] Department of Obstetrics and Gynecology. Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461 Japan
                [22 ] Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
                [23 ] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                nihpa167245
                10.1038/nature08822
                2826709
                20164920
                02246a72-9304-4f1f-9906-b0cbe0474fe5

                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

                History
                Funding
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: U24 CA126546 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: R01 CA109038 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: K08 CA122833-03 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: K08 CA122833-02 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: K08 CA122833-01A1 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: K08 AR055688-04 ||AR
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: K08 AR055688-03 ||AR
                Categories
                Article

                Uncategorized
                Uncategorized

                Comments

                Comment on this article