Abstract

Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year1. Overtreatment of indolent disease also results in significant morbidity2. Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21)3,4 and PTEN (10q23)5,6, gains of AR (the androgen receptor gene)7,8 and fusion of ETS family transcription factor genes with androgen-responsive promoters9,10,11. Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis12,13 but have not been systematically analyzed in large cohorts. Here, we sequenced the exomes of 112 prostate tumor and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1. SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6–15% of tumors across multiple independent cohorts. Prostate cancers with mutant SPOP lacked ETS family gene rearrangements and showed a distinct pattern of genomic alterations. Thus, SPOP mutations may define a new molecular subtype of prostate cancer.

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Acknowledgements

We are grateful for the assistance of members of the Broad Institute Biological Samples Platform, Genetic Analysis Platform and Genome Sequencing Platform. We thank S. Banerjee for computational assistance, R. Kim and R. Leung for their critical contributions to the Weill Cornell Prostate Cancer Tumor Bank, P. Schraml, S. Dettwiler and M. Storz for assistance with the University Hospital Zurich cohort and biobank and the members of the University of Washington Rapid Autopsy Program. We thank the University of Michigan Prostate Cancer Special Program of Research Excellence (SPORE) (K. Pienta) for sample contribution to this study. We are also grateful to the individuals with prostate cancer and the families who contributed to these studies. This work was supported by the US National Human Genome Research Institute (NHGRI) Large Scale Sequencing Program (U54 HG003067 to the Broad Institute, E.S.L.), the Kohlberg Foundation (L.A.G.), the Starr Cancer Consortium (M.A.R., F.D. and L.A.G), the Prostate Cancer Foundation (M.A.R.), US Department of Defense Synergy Awards (PC101020 to F.D., L.A.G. and M.A.R. and PC093372 to T.W. and P.S.N.), the Dana-Farber/Harvard Cancer Center Prostate Cancer SPORE (US National Institutes of Health (NIH) P50 CA090381), a New Investigator Award (PC094516 to F.D.), the US National Cancer Institute, Early Detection Research Network (U01CA111275 and NCI EDRN to F.D. and M.A.R.), the US National Cancer Institute (R01 CA125612 to F.D. and M.A.R.), the Pacific Northwest Prostate Cancer SPORE (P50CA097186 to C.M. and P.S.N.), the Swiss Science Foundation (PASMP3_134379/1 to J.-P.T.) and a US NIH Director's New Innovator Award (DP2OD002750 to L.A.G.). S.C.B. is supported by a Medical Scientist Training Program (MSTP) grant from the US NIH. C.E.B. is supported by a Prostate Cancer Foundation Young Investigator Award.

Author information

Author notes

    • Christopher E Barbieri
    • , Sylvan C Baca
    •  & Michael S Lawrence

    These authors contributed equally to this work.

    • Gad Getz
    • , Mark A Rubin
    •  & Levi A Garraway

    These authors jointly directed this work.

Affiliations

  1. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.

    • Christopher E Barbieri
    • , Mirjam Blattner
    • , Sung-Suk Chae
    • , Gunther Boysen
    • , Kyung Park
    • , Naoki Kitabayashi
    • , Theresa Y MacDonald
    • , Karen Sheikh
    • , Terry Vuong
    • , Wasay M Hussain
    • , Juan Miguel Mosquera
    •  & Mark A Rubin
  2. Department of Urology, Weill Cornell Medical College, New York, New York, USA.

    • Christopher E Barbieri
    • , Ashutosh K Tewari
    •  & Mark A Rubin
  3. The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.

    • Sylvan C Baca
    • , Michael S Lawrence
    • , Jean-Philippe Theurillat
    • , Petar Stojanov
    • , Eliezer Van Allen
    • , Nicolas Stransky
    • , Elizabeth Nickerson
    • , Daniel Auclair
    • , Robert C Onofrio
    • , Candace Guiducci
    • , Kristian Cibulskis
    • , Andrey Sivachenko
    • , Scott L Carter
    • , Gordon Saksena
    • , Douglas Voet
    • , Alex H Ramos
    • , Wendy Winckler
    • , Michelle C Redman
    • , Kristin Ardlie
    • , Stacey B Gabriel
    • , Todd R Golub
    • , Matthew Meyerson
    • , Eric S Lander
    • , Gad Getz
    •  & Levi A Garraway
  4. Harvard Medical School, Boston, Massachusetts, USA.

    • Sylvan C Baca
    • , Alex H Ramos
    • , Philip W Kantoff
    • , Matthew Meyerson
    • , Eric S Lander
    •  & Levi A Garraway
  5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Sylvan C Baca
    • , Eliezer Van Allen
    • , Philip W Kantoff
    • , Matthew Meyerson
    •  & Levi A Garraway
  6. Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA.

    • Francesca Demichelis
    •  & Wasay M Hussain
  7. Centre for Integrative Biology, University of Trento, Trento, Italy.

    • Francesca Demichelis
  8. Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Thomas A White
    •  & Peter S Nelson
  9. Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.

    • Niels Rupp
    • , Peter J Wild
    •  & Holger Moch
  10. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Colm Morrissey
    •  & Peter S Nelson
  11. Department of Urology, University of Washington, Seattle, Washington, USA.

    • Colm Morrissey
    •  & Peter S Nelson
  12. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Todd R Golub
  13. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Todd R Golub
  14. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Todd R Golub
    • , Matthew Meyerson
    •  & Levi A Garraway
  15. Department of Biology, MIT, Cambridge, Massachusetts, USA.

    • Eric S Lander

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Contributions

S.C.B., M.S.L., P.S., W.M.H., E.V.A., N.S., K.C., A.S., S.L.C., G.S., D.V. and A.H.R. performed computational analyses. M.B., J.-P.T., T.A.W., S.-S.C., K.S., G.B., T.Y.M., K.P. and T.V. designed and performed experiments. E.N., D.A., R.C.O., C.G., W.W., M.C.R., K.A. and S.B.G. processed samples and supervised exome sequencing. J.M.M., K.P., N.K., A.K.T., N.R., P.J.W., H.M., C.M. and P.S.N. coordinated sample acquisition, processing, pathologic review and analysis. C.E.B., S.C.B., F.D., P.W.K., T.R.G., M.M., E.S.L., G.G., M.A.R. and L.A.G. designed the study. C.E.B., S.C.B., F.D., G.G., M.A.R. and L.A.G. analyzed the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mark A Rubin or Levi A Garraway.

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DOI

https://doi.org/10.1038/ng.2279

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