ANDROGEN RECEPTOR AND PROSTATE CANCER RISK IN CHINESE

前列腺癌的一个独特特征是临床潜伏性病变的流行，这些病变不构成健康威胁，但在组织学上与临床重要病变无法区分。 识别预测晚期疾病的风险因素具有相当大的公共卫生意义。我们和其他研究人员提供的证据表明，雄激素受体（AR）基因CAG重复多态性与美国白人晚期前列腺癌风险相关。 我们建议在这里结合流行病学/分子研究，以评估AR基因型和前列腺癌的风险之间的关系，通过组装的情况下，控制遗传同质的中国新加坡，并通过筛选AR基因的体细胞突变。 病例（约400例）为组织学诊断的前列腺癌偶发病例，年龄45-74岁，发生于1993年1月1日至1998年12月31日的6年期间的新加坡住宅区居民中。 对照组（年龄匹配的400名男性随机样本）将从新加坡饮食与癌症队列研究的成员中选择，该研究是一项由国家癌症研究所资助的正在进行的基于人群的队列研究，共有60，000名中国男性和女性，他们是住宅区居民，基线时年龄为45-74岁。 在分子组分中，将确定和表征晚期肿瘤中AR体细胞突变的患病率，以检查体细胞AR突变阳性肿瘤患者的组成性AR-CAG重复序列的分布是否与AR突变阴性肿瘤患者不同。 虽然过去认为AR突变很少发生在前列腺肿瘤中，但新的数据表明它可能在晚期疾病中频繁发生。 到目前为止分析的突变通常是“功能获得”类型的，并且可能有助于激素抵抗性疾病的进展。 待检验的主要假设是，较短的CAG等位基因编码更活跃的AR，反过来通过增加肿瘤和肿瘤抑制基因（包括AR基因本身）中的前列腺体细胞突变率来增加晚期前列腺癌的风险。 这项研究的结果将能够对AR在前列腺癌易感性和进展中的作用进行关键评估，并将允许将AR基因纳入前列腺癌发展的多基因模型中。

A unique feature of prostate cancer is the prevalence of clinically latent lesions that do not pose a health threat, and yet are histologically indistinguishable from clinically important lesions. Identification of risk factors that predict advanced disease carries considerable public health significance. We, and others, have provided evidence that the CAG repeat polymorphism in the androgen receptor (AR) gene is associated with advanced prostate cancer risk in US whites. We propose here a combined epidemiologic/molecular study to evaluate the relationship between AR genotypes and prostate cancer risk, by assembling cases and controls among genetically homogeneous Chinese of Singapore, and by screening for somatic mutations in the AR gene. Cases (approximately 400) will be histologically diagnosed incident cases of prostate cancer, aged 45-74 years, occurring among housing estate residents of Singapore in the 6-year period between Jan. 1, 1993 and Dec. 31, 1998. Controls (an aged-matched random sample of 400 men) will be selected from members of the Singapore Cohort Study of Diet and Cancer, an NCI-funded, ongoing population-based cohort of 60,000 Chinese men and women, who are housing estate residents and aged 45-74 years at baseline. In the molecular component, the prevalence of AR somatic mutations in advanced tumors will be determined and characterized, to check whether the distribution of constitutional AR-CAG repeats of patients with somatic AR mutation-positive tumors differ from those with AR mutation-negative tumors. Although AR mutations were considered in the past to occur rarely in prostate tumors, new data indicate that it might occur quite frequently in advanced disease. The mutations so far analyzed, are often of the "gain-of-function" kind, and might contribute to the progression to hormone resistant disease. The main hypothesis to be tested is that shorter CAG alleles code for more active ARs that in turn increase advanced prostate cancer risk by increasing the rate of prostate somatic mutations among onco- and tumor suppressor genes, including the AR gene itself. Results from this study will enable the critical assessment of the role of the AR in prostate cancer predisposition and progression, and will allow the inclusion of the AR gene in a multigenic model of prostate cancer development.