Abstract

Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma1 and have surveyed exons of protein-coding genes for mutations in 11 affected individuals2,3. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin4 in colorectal carcinogenesis5,6, the fusion lacks the TCF4 β-catenin–binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events.

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Acknowledgements

We thank all members of the Biological Samples Platform and DNA Sequencing Platforms of the Broad Institute, without whose work this sequencing project could not have occurred, and R. Shivdasani and M. Freedman for helpful discussion. This work was supported by US National Institutes of Health grant K08CA134931 (A.J.B.), a GI SPORE Developmental Project Award (P50CA127003; M.M.) and the National Human Genome Research Institute (E.S.L.).

Author information

Author notes

    • Adam J Bass
    •  & Michael S Lawrence

    These authors contributed equally to this work.

Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Adam J Bass
    • , Lear E Brace
    • , Alex H Ramos
    • , Trevor Pugh
    • , Roel G Verhaak
    • , Adam T Boutin
    • , William G Kaelin
    • , Nicole Spardy
    • , William C Hahn
    • , Shuji Ogino
    • , Ronald A DePinho
    • , Lynda Chin
    • , Levi A Garraway
    • , Charles S Fuchs
    •  & Matthew Meyerson
  2. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Adam J Bass
    • , William G Kaelin
    • , William C Hahn
    • , Ronald A DePinho
    • , Levi A Garraway
    •  & Charles S Fuchs
  3. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Adam J Bass
    • , William C Hahn
    • , Levi A Garraway
    •  & Matthew Meyerson
  4. Broad Institute, Cambridge, Massachusetts, USA.

    • Adam J Bass
    • , Michael S Lawrence
    • , Alex H Ramos
    • , Kristian Cibulskis
    • , Carrie Sougnez
    • , Douglas Voet
    • , Gordon Saksena
    • , Andrey Sivachenko
    • , Rui Jing
    • , Melissa Parkin
    • , Trevor Pugh
    • , Roel G Verhaak
    • , Nicolas Stransky
    • , Jordi Barretina
    • , William C Hahn
    • , Yujin Hoshida
    • , Lynda Chin
    • , Levi A Garraway
    • , Stacey Gabriel
    • , Eric S Lander
    • , Gad Getz
    •  & Matthew Meyerson
  5. Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.

    • Yotam Drier
  6. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • David B Solit
  7. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Evi Vakiani
  8. Novartis Institute of Biomedical Research, Cambridge, Massachusetts, USA.

    • Wenlin Shao
    • , Yuji Mishina
    •  & Markus Warmuth
  9. Department of Medical Oncology, Hospital Vall d'Hebron, Passeig Vall d'Hebron, Barcelona, Spain.

    • Jose Jimenez
    • , Jose Baselga
    •  & Josep Tabernero
  10. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Derek Y Chiang
  11. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.

    • Sabina Signoretti
    • , Shuji Ogino
    •  & Matthew Meyerson
  12. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Sabina Signoretti
    •  & Shuji Ogino
  13. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Shuji Ogino
    •  & Charles S Fuchs
  14. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Ronald A DePinho
  15. Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Ronald A DePinho
    •  & Lynda Chin
  16. Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA.

    • Lynda Chin
  17. Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jose Baselga
  18. Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Eric S Lander
  19. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

    • Eric S Lander

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Contributions

A.J.B., M.S.L., A.H.R., Y.D., K.C., A.S., T.P., R.J., D.V., G.S., R.G.V. and N. Stransky performed computational analysis. J. Barretina, J. Baselga, J.J., J.T., D.B.S., E.V., D.Y.C., W.G.K. and S.S. provided samples for analysis. A.J.B., L.E.B., Y.M. and W.S. performed laboratory experiments. A.T.B., Y.H., M.W., N.S., R.A.D., W.C.H., C.S.F. and S.O. provided expert guidance regarding the analysis. C.S., M.P., L.C., L.A.G., S.G. and E.S.L. supervised and designed the sequencing effort. A.J.B., M.S.L., E.S.L., G.G. and M.M. designed the study, analyzed the data and prepared the manuscript. All coauthors reviewed and commented on the manuscript.

Competing interests

M.M., L.A.G. and E.S.L. are equity-holding founding advisors of Foundation Medicine. M.M. and L.A.G. consult for Novartis. M.M. is also a patent holder on the use of EGFR mutations in lung cancer licensed to Genzyme Genetics. W.S., Y.M. and M.W. are employees of Novartis.

Corresponding authors

Correspondence to Gad Getz or Matthew Meyerson.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1 and 2, Supplementary Tables 2, 3 and 5 and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 1

    Non-synonymous Mutations and Insertions/Deletions Identified Within Coding Genes

  2. 2.

    Supplementary Table 4

    Somatic Rearrangements Identified with dRanger Algorithm

About this article

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DOI

https://doi.org/10.1038/ng.936

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