African-American men have the highest incidence of and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing (n = 102) and targeted validation (n = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in ERF, an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed ERF deletions in 3% of primary prostate cancers and mutations or deletions in ERF in 3% to 5% of lethal castration-resistant prostate cancers. Knockdown of ERF confers increased anchorage-independent growth and generates a gene expression signature associated with oncogenic ETS activation and androgen signaling. Together, these results suggest that ERF is a prostate cancer tumor-suppressor gene. More generally, our findings support the application of systematic cancer genomic characterization in settings of broader ancestral diversity to enhance discovery and, eventually, therapeutic applications. Significance: Systematic genomic sequencing of prostate cancer in African-American men revealed new insights into prostate cancer, including the identifi cation of ERF as a prostate cancer gene; somatic copy-number alteration differences; and uncommon PIK3CA and PTEN alterations. This study highlights the importance of inclusion of underrepresented minorities in cancer sequencing studies.
Bibliographical noteFunding Information:
This work was supported by the NCI U01 CA162148 (L.A. Garra-way), the Department of Defense Prostate Cancer Research Program Physician Research Training Award W81XWH-14-1-0514 (F.W. Huang), Prostate Cancer Foundation Young Investigator Award (F.W. Huang), ASCO Young Investigator Award (F.W. Huang), the US NIH R01 CA116337 (M.A. Rubin), 5U01 CA111275-09 (J.M. Mosquera and M.A. Rubin), U54 HG003067 (S.Gabriel), R01CA154480 (J. Mesirov and P. Tamayo), R01CA121941 (J. Mesirov and P. Tamayo), U01CA176058 (J. Mesirov and P. Tamayo), R01CA109467 (J. Mesirov and P. Tamayo), U54 CA137788 (J.R. Osborne), the Starr Cancer Consortium (M.A. Rubin), and by a Stand Up To Cancer–Prostate Cancer Foundation Prostate Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT0712; M.A. Rubin and L.A. Garraway). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. This work was also supported in part by the Translational Research Program at WCM Pathology and Laboratory Medicine. This work was in part supported by the Department of Defense Prostate Cancer Research Program, DOD Award No. W81XWH-10-2-0056 and W81XWH-10-2-0046 PCRP Prostate Cancer Biorepository Network (PCBN). This work was supported by NCI grant P30CA016056 and the Pathology Network and Clinical Data Network Shared Resources at Roswell Park Cancer Institute.
© 2017 American Association for Cancer Research.