Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations.
Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations.
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DOI：
10.1158/2159-8290.cd-16-0960
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发表时间：
2017-09
期刊：
影响因子：
28.2
通讯作者：
Garraway LA
中科院分区：
文献类型：
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作者：
Huang FW;Mosquera JM;Garofalo A;Oh C;Baco M;Amin-Mansour A;Rabasha B;Bahl S;Mullane SA;Robinson BD;Aldubayan S;Khani F;Karir B;Kim E;Chimene-Weiss J;Hofree M;Romanel A;Osborne JR;Kim JW;Azabdaftari G;Woloszynska-Read A;Sfanos K;De Marzo AM;Demichelis F;Gabriel S;Van Allen EM;Mesirov J;Tamayo P;Rubin MA;Powell IJ;Garraway LA
非裔美国男性前列腺癌的发病率和死亡率最高。这种差异是否存在生物学基础仍不清楚。对非裔美国男性的局部原发性激素初治前列腺癌进行外显子组测序 (n = 102) 和靶向验证 (n = 90)，发现了一些以前在这种情况下未观察到的基因突变，包括 5% 的病例中 ERF（一种 ETS 转录抑制因子）中反复出现的功能丧失突变。对现有前列腺癌队列的分析显示，3% 的原发性前列腺癌存在 ERF 缺失，3-5% 的致死性去势抵抗性前列腺癌存在 ERF 突变或缺失。 ERF 的敲低会增加不依赖锚定的生长，并产生与致癌 ETS 激活和雄激素信号传导相关的基因表达特征。总之，这些结果表明 ERF 是前列腺癌肿瘤抑制基因。更一般地说，我们的研究结果支持在更广泛的祖先多样性的环境中应用系统的癌症基因组表征，以增强发现并最终促进治疗应用。
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.