Androgen receptor mutations and polymorphisms in African American prostate cancer.
Androgen receptor mutations and polymorphisms in African American prostate cancer.
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DOI：
10.7150/ijbs.8974
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发表时间：
2014
影响因子：
9.2
通讯作者：
Attwood K
中科院分区：
文献类型：
--
作者：
Koochekpour S;Buckles E;Shourideh M;Hu S;Chandra D;Zabaleta J;Attwood K
雄激素受体（AR）在前列腺的正常发育、前列腺癌发生和前列腺癌（PCa）进展为晚期转移性疾病中起核心作用。患有PCa的非洲裔美国人（AA）男性表现出更大的肿瘤体积、更晚期的肿瘤分期和更高的Gleason评分。这可能部分与AA男性前列腺组织中的AR表达或活性有关，或者与AR的独特突变或多态性有关。在美国白人（CA）中，AR突变在器官局限性肿瘤中罕见或不常见，但在晚期、转移性或去势复发性疾病中发生率较高。在AA中，PCa中AR突变的患病率、临床和生物学意义尚不清楚。在这项研究中，我们调查了体细胞和生殖系AR突变的发生在原发性前列腺癌患者的AA相比，CA。由于E213（G/A）单核苷酸多态性（SNP）等位基因分布的数据非常有限，我们还评估了散发性前列腺癌患者和来自两个种族人群的无关健康个体。体细胞错义AR突变在AA中的检出率（17/200例）高于CA（2/100例）。在AA中，这些突变中的大多数（41.1%）来自Gleason 7肿瘤，一小部分（23.5%）来自Gleason 8肿瘤，其余（35.2%）来自Gleason 6肿瘤。从散发性前列腺癌患者的白色血细胞中提取的基因组DNA分析显示，AA中生殖系AR突变率也高于CA（约4倍）。就E213（G/A）SNP而言，E213 A等位基因在健康无关AA男性中的表达是CA男性的5.85倍。而在体细胞AR突变的AA中，E213 G等位基因的分布几乎与A等位基因相同。体细胞AR突变之一的沉默（即，597 Ser>Gly）在原代AA-PCa细胞系（例如，E006 AA）揭示了类似的AR突变可以同时与“功能获得”表型（细胞迁移和侵袭）和“功能丧失”表型（增殖）相关联。我们的数据表明，与CA相比，散发性PCa的体细胞突变形式或AA的生殖系突变形式的AR遗传变异的易感性更高。这些数据可能支持AR特异性超变基因表型与其他基因组合的观点，可能是PCa种族差异和AA作为高风险人群的潜在不同临床结局的促成因素。
The Androgen receptor (AR) plays a central role in the normal development of the prostate gland, in prostate carcinogenesis, and in the progression of prostate cancer (PCa) to advanced metastatic disease. African American (AA) men with PCa present with higher tumor volume, more advanced tumor stage, and higher Gleason score. This could be in part related to the AR expression or activity in the prostate tissue of AA men, or to unique mutations or polymorphisms of the AR. In Caucasian Americans (CAs), AR mutations are rare or infrequent in organ-confined tumors, but occur at a higher rate in advanced, metastatic, or castrate-recurrent disease. In AAs, the prevalence, clinical, and biological significance of AR mutations in PCa are unknown. In this study, we investigated the occurrence of somatic and germline AR mutations in patients with primary PCa in AAs compared with CAs. Due to very limited data available on allelic distribution of E213 (G/A) single nucleotide polymorphism (SNP), we also assessed this in patients with sporadic PCa and in unrelated healthy individuals from both ethnic populations. Somatic missense AR mutations were detected at a higher rate in AAs (17 out of 200 cases) than in CAs (2 out of 100 cases). In AAs, the majority of these mutations (41.1%) were from Gleason 7 tumors, a small portion (23.5%) from Gleason 8 tumors, and the rest (35.2%) from Gleason 6 tumors. Analysis of genomic DNAs extracted from white blood cells of patients with sporadic PCa revealed that the rate of germline AR mutations were also higher (~4 times) in AAs than in CAs. With respect to E213 (G/A) SNP, the E213 A-allele expression was 5.85 times higher in healthy unrelated AA men than in CA men. However, in AAs with somatic AR mutation, the E213 G-allele distribution was almost equal to the A-allele. Silencing of one of the somatic AR mutations (i.e., 597 Ser>Gly) in a primary AA-PCa cell line (e.g., E006AA) revealed that similar AR mutation can be associated simultaneously with both “gain-of-function” phenotype (cell migration and invasion) and a “loss-of-function” phenotype (proliferation). Our data demonstrated a higher susceptibility for genetic alterations in the AR in the form of somatic mutations in sporadic PCa or in the form of germline mutations in AAs as compared with CAs. These data may support the idea that AR-specific hypermutator phenotype in combination with other genes, might serve as a contributing factor to ethnic differences in PCa and potentially different clinical outcome in AAs as a high-risk population.
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3.8
作者：
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影响因子：
2.8
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通讯作者：
Rayford, W