African-American men have the highest incidence 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 3-5% 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.
Cancer discovery. 2017 May 17 [Epub ahead of print]
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 Azabdaftari, Anna 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
Medical Oncology, Dana-Farber Cancer Institute., Department of Pathology, Weill Cornell Medical College., Cancer Program, Broad Institute of Harvard and MIT., Centre for Integrative Biology, University of Trento., Department of Radiology, Memorial Sloan-Kettering Cancer Center., Pathology, Roswell Park Cancer Institute., Pharmacology and Therapeutics, Roswell Park Cancer Institute., Department of Pathology, Johns Hopkins University School of Medicine., Moores Cancer Center, University of California San Diego., Cancer Program, Broad Institute of MIT and Harvard., Caryl and Israel Englander Institute for Precision Medicine, Weil Cornell Medical College, NewYork-Presbyterian Hospital., Barbara Ann Karmanos Cancer Institute., Medical Oncology, Dana-Farber Cancer Institute .