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Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer

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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Figure 1: Significantly mutated genes in aggressive primary prostate cancer.
Figure 2: Recurrent somatic alterations in FOXA1 and MED12.
Figure 3: Structural and functional studies of recurrent SPOP alterations in prostate cancer.
Figure 4: SPOP mutation defines a distinct genetic subclass 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.

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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.

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Correspondence to Mark A Rubin or Levi A Garraway.

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Barbieri, C., Baca, S., Lawrence, M. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet 44, 685–689 (2012). https://doi.org/10.1038/ng.2279

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