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.

Exome sequencing of African-American prostate cancer reveals loss-of-function ERF mutations / Huang, Franklin W.; Mosquera, Juan Miguel; Garofalo, Andrea; Oh, Coyin; Baco, Maria; Amin-mansour, Ali; Rabasha, Bokang; Bahl, Samira; Mullane, Stephanie A.; Robinson, Brian D.; Aldubayan, Saud; Khani, Francesca; Karir, Beerinder; Kim, Eejung; Chimene-weiss, Jeremy; Hofree, Matan; Romanel, Alessandro; Osborne, Joseph R.; Kim, Jong Wook; Azabdaftari, Gissou; Woloszynska-read, Anna; Sfanos, Karen; De Marzo, Angelo M.; Demichelis, Francesca; Gabriel, Stacey; Van Allen, Eliezer M.; Mesirov, Jill; Tamayo, Pablo; Rubin, Mark A.; Powell, Isaac J.; Garraway, Levi A.. - In: CANCER DISCOVERY. - ISSN 2159-8274. - 7:9(2017), pp. 973-983. [10.1158/2159-8290.CD-16-0960]

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

Romanel, Alessandro;Demichelis, Francesca;
2017-01-01

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.
2017
9
Huang, Franklin W.; Mosquera, Juan Miguel; Garofalo, Andrea; Oh, Coyin; Baco, Maria; Amin-mansour, Ali; Rabasha, Bokang; Bahl, Samira; Mullane, Stephanie A.; Robinson, Brian D.; Aldubayan, Saud; Khani, Francesca; Karir, Beerinder; Kim, Eejung; Chimene-weiss, Jeremy; Hofree, Matan; Romanel, Alessandro; Osborne, Joseph R.; Kim, Jong Wook; Azabdaftari, Gissou; Woloszynska-read, Anna; Sfanos, Karen; De Marzo, Angelo M.; Demichelis, Francesca; Gabriel, Stacey; Van Allen, Eliezer M.; Mesirov, Jill; Tamayo, Pablo; Rubin, Mark A.; Powell, Isaac J.; Garraway, Levi A.
Exome sequencing of African-American prostate cancer reveals loss-of-function ERF mutations / Huang, Franklin W.; Mosquera, Juan Miguel; Garofalo, Andrea; Oh, Coyin; Baco, Maria; Amin-mansour, Ali; Rabasha, Bokang; Bahl, Samira; Mullane, Stephanie A.; Robinson, Brian D.; Aldubayan, Saud; Khani, Francesca; Karir, Beerinder; Kim, Eejung; Chimene-weiss, Jeremy; Hofree, Matan; Romanel, Alessandro; Osborne, Joseph R.; Kim, Jong Wook; Azabdaftari, Gissou; Woloszynska-read, Anna; Sfanos, Karen; De Marzo, Angelo M.; Demichelis, Francesca; Gabriel, Stacey; Van Allen, Eliezer M.; Mesirov, Jill; Tamayo, Pablo; Rubin, Mark A.; Powell, Isaac J.; Garraway, Levi A.. - In: CANCER DISCOVERY. - ISSN 2159-8274. - 7:9(2017), pp. 973-983. [10.1158/2159-8290.CD-16-0960]
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