Abstract

A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several 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-κΒ pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.

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Gene Expression Omnibus

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The SNP array data have been deposited to the Gene Expression Omnibus (GEO) under accession number GSE19399.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NIH) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P50CA90578, R01CA109038, R01CA109467, P01CA085859, P01CA 098101 and K08CA122833), the Doris Duke Charitable Foundation, the Sarah Thomas Monopoli Lung Cancer Research Fund, the Seaman Corporation Fund for Lung Cancer Research, and the Lucas Foundation. Medulloblastoma samples were obtained in collaboration with the Children’s Oncology Group. N. Vena provided technical assistance with FISH, and I. Mellinghoff, P. S. Mischel, L. Liau and T. F. Cloughesy provided DNA samples. We thank T. Ried, R. Weinberg and B. Vogelstein for critical review of the manuscript and for comments about its context in the field of cancer genetics.

Author Contributions R.B., C.H.M., E.S.L., G.G., W.R.S. and M.M. conceived and designed the study; R.B., J.B., M.U., A.H.L., Y.-J.C., W.W., B.A.W., D.Y.C., A.J.B., J.P., S.S., E.M., F.J.K., H.S., J.E.T., J.A.F., J.T., J.B., M.-S.T., F.D., M.A.R., P.A.J., C.N., R.L.L., B.L.E., S.G., A.K.R., C.R.A., M.L., L.A.G., M.L., D.G.B., L.D.T., A.O., S.L.P., S.S. and M.M. contributed primary samples and/or assisted in the generation of the data; R.B., C.H.M., S.R., J.Dob., M.S.L., B.A.W., M.J.D. and G.G. performed the data analysis; R.B., D.P., G.W., J.Don., J.S.B., K.T.M., L.H., H.G., K.E.T., A.L., C.H., D.Y., A.L., L.A.G., T.R.G. and M.M. designed and performed the functional experiments on BCL2 family member genes; R.B., C.H.M., R.M.P., M.R., T.L. and Q.G. designed and built the cancer copy-number portal; R.B., C.H.M., E.S.L. and M.M. wrote, and all other authors have critically read and commented on, the manuscript.

Author information

Author notes

    • Rameen Beroukhim
    •  & Craig H. Mermel

    These authors contributed equally to this work.

Affiliations

  1. Cancer Program and Medical and Population Genetics Group, The Broad Institute of M.I.T. and Harvard, 7 Cambridge Center,

    • Rameen Beroukhim
    • , Craig H. Mermel
    • , Guo Wei
    • , Soumya Raychaudhuri
    • , Jordi Barretina
    • , Jesse S. Boehm
    • , Jennifer Dobson
    • , Reid M. Pinchback
    • , Leila Haery
    • , Heidi Greulich
    • , Michael Reich
    • , Wendy Winckler
    • , Michael S. Lawrence
    • , Barbara A. Weir
    • , Kumiko E. Tanaka
    • , Derek Y. Chiang
    • , Adam J. Bass
    • , Carter Hoffman
    • , John Prensner
    • , Ted Liefeld
    • , Qing Gao
    • , Mark J. Daly
    • , Benjamin L. Ebert
    • , Stacey Gabriel
    • , Levi A. Garraway
    • , Todd R. Golub
    • , Eric S. Lander
    • , Gad Getz
    •  & Matthew Meyerson
  2. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA

    • Eric S. Lander
  3. Departments of Medical Oncology, Pediatric Oncology, and Cancer Biology, and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 44 Binney Street,

    • Rameen Beroukhim
    • , Craig H. Mermel
    • , Jordi Barretina
    • , Jennifer Dobson
    • , Leila Haery
    • , Heidi Greulich
    • , Barbara A. Weir
    • , Kumiko E. Tanaka
    • , Derek Y. Chiang
    • , Adam J. Bass
    • , Carter Hoffman
    • , John Prensner
    • , Derek Yecies
    • , Sabina Signoretti
    • , Pasi A. Janne
    • , Anthony Letai
    • , Levi A. Garraway
    • , Massimo Loda
    • , Todd R. Golub
    •  & Matthew Meyerson
  4. Departments of Medicine and Pathology, Brigham and Women’s Hospital, 75 Francis Street,

    • Rameen Beroukhim
    • , Soumya Raychaudhuri
    • , Azra H. Ligon
    • , Heidi Greulich
    • , Adam J. Bass
    • , Sabina Signoretti
    • , Jonathan A. Fletcher
    • , Pasi A. Janne
    • , Benjamin L. Ebert
    •  & Massimo Loda
  5. Departments of Medicine, Pathology, Pediatrics, and Systems Biology, Harvard Medical School, 25 Shattuck Street,

    • Rameen Beroukhim
    • , Heidi Greulich
    • , Benjamin L. Ebert
    • , Eric S. Lander
    •  & Matthew Meyerson
  6. Department of Neurology, Children’s Hospital Boston, 300 Longwood Avenue,

    • Yoon-Jae Cho
    •  & Scott L. Pomeroy
  7. Department of Pathology, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, Boston, Massachusetts 02115, USA

    • Carmelo Nucera
  8. Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

    • Dale Porter
    • , Jerry Donovan
    • , Kevin T. Mc Henry
    • , Alice Loo
    •  & William R. Sellers
  9. Division of Molecular Epidemiology, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan

    • Mitsuyoshi Urashima
  10. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75390-9186, USA

    • Elizabeth Maher
  11. Genetics Branch, Center for Cancer Research, National Cancer Institute and National Naval Medical Center, Bethesda, Maryland 20889, USA

    • Frederic J. Kaye
  12. Department of Surgery II, Nagoya City University Medical School, Nagoya 467-8601, Japan

    • Hidefumi Sasaki
  13. Department of Genetics and Radiation Oncology, UNC/Lineberger Comprehensive Cancer Center, University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27599, USA

    • Derek Y. Chiang
    •  & Joel E. Tepper
  14. Medical Oncology Program, Vall d’Hebron University Hospital Research Institute, Vall d’Hebron Institute of Oncology, and Autonomous University of Barcelona, 08035 Barcelona, Spain

    • Josep Tabernero
    •  & José Baselga
  15. Department of Pathology and Division of Applied Molecular Oncology, University Health Network, Princess Margaret Hospital and Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada

    • Ming-Sound Tsao
  16. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA

    • Francesca Demichelis
    •  & Mark A. Rubin
  17. Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Center, Boston, Massachusetts 02114, USA

    • Mark J. Daly
  18. Departments of Medicine and Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA

    • Ross L. Levine
    • , Cristina R. Antonescu
    • , Marc Ladanyi
    •  & Samuel Singer
  19. Departments of Medicine (GI Division) and Genetics, and Abramson Cancer Center, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA

    • Anil K. Rustgi
  20. Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, Ann Arbor, Michigan 48109, USA

    • David G. Beer
  21. Department of Pathology, University of Washington Medical Center, 1959 North East Pacific Street, Seattle, Washington 98195-6100, USA

    • Lawrence D. True
  22. Department of Obstetrics and Gynecology, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan

    • Aikou Okamoto
  23. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA

    • Todd R. Golub

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Corresponding authors

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Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-8 with Legends, Supplementary Methods, Supplementary Notes 1-7 and Supplementary References.

Excel files

  1. 1.

    Supplementary Table 1

    This table presents the breakdown of our sample set according to tissue type, origin, and publication status.

  2. 2.

    Supplementary Table 2

    This table reports the significant peak regions of amplification and deletion identified in the pooled analysis of all samples.

  3. 3.

    Supplementary Table 3

    This table reports the results of the comparison of the significant peak regions of amplification and deletion identified in this study with those reported in 18 prior publications.

  4. 4.

    Supplementary Table 4

    This table reports the literature terms identified by GRAIL as being most significantly reached in the significant peak regions of amplifications and deletion identified in this study.

  5. 5.

    Supplementary Table 5

    This table reports the 199 peak regions of amplification and deletion identified to be significant in analysis of individual tumor types but not in the analysis of the pooled dataset.

  6. 6.

    Supplementary Table 6

    This table reports the significant arm-level SCNAs that distinguish the major developmental clusters displayed in Supplementary Figure 7, as determined by comparative marker selection.

  7. 7.

    Supplementary Table 7

    This table reports a comparison of the peak regions of deletion identified using the marker-based (SNP-GISTIC) rather than the gene-based (GENE-GISTIC) scoring function (described in the Supplementary Methods).

  8. 8.

    Supplementary Table 8

    This table lists the tumor types in which significant levels of gains or losses are observed for each of the 39 chromosome arms probed by the 250K StyI SNP Array.

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DOI

https://doi.org/10.1038/nature08822

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