期刊
NATURE GENETICS
卷 44, 期 6, 页码 685-U107出版社
NATURE PORTFOLIO
DOI: 10.1038/ng.2279
关键词
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资金
- US National Human Genome Research Institute (NHGRI) [U54 HG003067]
- Kohlberg Foundation
- Starr Cancer Consortium
- Prostate Cancer Foundation
- US Department of Defense [PC101020, PC093372]
- Dana-Farber/Harvard Cancer Center Prostate Cancer SPORE (US National Institutes of Health (NIH)) [P50 CA090381]
- New Investigator Award [PC094516]
- US National Cancer Institute, Early Detection Research Network [U01CA111275, NCI EDRN]
- US National Cancer Institute [R01 CA125612]
- Pacific Northwest Prostate Cancer SPORE [P50CA097186]
- Swiss Science Foundation [PASMP3_134379/1]
- US NIH [DP2OD002750]
Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year(1). Overtreatment of indolent disease also results in significant morbidity(2). 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 promoters(9-11). Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis(12,13) 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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