Exome sequencing of African-American prostate cancer reveals loss-of-function ERF mutations

Franklin W. Huang, Juan Miguel Mosquera, Andrea Garofalo, Coyin Oh, Maria Baco, Ali Amin-Mansour, Bokang Rabasha, Samira Bahl, Stephanie A. Mullane, Brian D. Robinson, Saud Aldubayan, Francesca Khani, Beerinder Karir, Eejung Kim, Jeremy Chimene-Weiss, Matan Hofree, Alessandro Romanel, Joseph R. Osborne, Jong Wook Kim, Gissou AzabdaftariAnna Woloszynska-Read, Karen Sfanos, Angelo M. De Marzo, Francesca Demichelis, Stacey Gabriel, Eliezer M. Van Allen, Jill Mesirov, Pablo Tamayo, Mark A. Rubin, Isaac J. Powell, Levi A. Garraway

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)973-983
Number of pages11
JournalCancer discovery
Volume7
Issue number9
DOIs
StatePublished - Sep 2017

ASJC Scopus subject areas

  • Oncology

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