Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations

FW Huang, JM Mosquera, A Garofalo, C Oh, M Baco… - Cancer discovery, 2017 - AACR
FW Huang, JM Mosquera, A Garofalo, C Oh, M Baco, A Amin-Mansour, B Rabasha, S Bahl…
Cancer discovery, 2017AACR
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 …
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 identification 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. Cancer Discov; 7(9); 973–83. ©2017 AACR.
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