Identification of a novel germline missense mutation of the androgen receptor in African American men with familial prostate cancer.
Identification of a novel germline missense mutation of the androgen receptor in African American men with familial prostate cancer.
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DOI：
10.1038/aja.2010.5
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发表时间：
2010-05
影响因子：
2.9
通讯作者：
Koochekpour, Shahriar
中科院分区：
文献类型：
--
作者：
Hu, Si-Yi;Liu, Tao;Liu, Zhen-Zhen;Ledet, Elisa;Velasco-Gonzalez, Cruz;Mandal, Diptasri M.;Koochekpour, Shahriar
种族、家族史和年龄是公认的前列腺癌 (PCa) 危险因素。雄激素受体（AR）依赖性信号传导是前列腺癌发生及其进展为转移性疾病的重要因素。我们研究了非裔美国人 AR 基因组变化与家族性 PCa 相关的可能性，非裔美国人的发病率和死亡率高于白人，临床上疾病表现也更具侵袭性。研究人员对参与路易斯安那州立大学健康科学中心前列腺癌遗传连锁研究的 30 个高危非裔美国人和白种人家庭的 60 名患者的基因组 DNA 进行了研究。使用外显子特异性聚合酶链反应、双向自动测序和限制性酶基因分型来分析 AR 基因编码区的突变。我们在一个有早发性疾病史的非裔美国家庭的三名 PCa 患者的 DNA 结合域中发现了种系 AR (A1675T) (T559S) 替代突变。本研究描述了一个有家族性 PCa 病史的非洲裔美国家庭中的第一个 AR 种系突变。 AR (T559S) 突变可能通过改变 AR DNA 结合亲和力和/或其对雄激素、非雄激素类固醇或抗雄激素的反应而导致该疾病。需要进行更多研究来确定 AR (A1675T) 等位基因对非裔美国人早发性和/或家族性 PCa 的频率和贡献。
Race, family history and age are the unequivocally accepted risk factors for prostate cancer (PCa). Androgen receptor (AR)-dependent signaling is an important element in prostate carcinogenesis and its progression to metastatic disease. We examined the possibility of genomic changes in the AR in association with familial PCa in African Americans who have a higher incidence and mortality rate and a clinically more aggressive disease presentation than Caucasians. Genomic DNAs of 60 patients from 30 high-risk African American and Caucasian families participating in the Louisiana State University Health Sciences Center genetic linkage study of PCa were studied. Exon-specific polymerase-chain reaction, bi-directional automated sequencing and restriction enzyme genotyping were used to analyze for mutations in the coding region of the AR gene. We identified a germline AR (A1675T) (T559S) substitution mutation in the DNA-binding domain in three PCa-affected members of an African-American family with a history of early-onset disease. The present study describes the first AR germline mutation in an African-American family with a history of familial PCa. The AR (T559S) mutation may contribute to the disease by altering AR DNA-binding affinity and/or its response to androgens, non-androgenic steroids or anti-androgens. Additional studies will be required to define the frequency and contribution of the AR (A1675T) allele to early-onset and/or familial PCa in African Americans.
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