ANDROGEN RECEPTOR AND PROSTATE CANCER RISK IN CHINESE

前列腺癌的一个独特特征是临床潜伏病变的流行，不构成健康威胁，但在组织学上与临床重要病变难以区分。识别预测晚期疾病的危险因素具有相当大的公共卫生意义。我们和其他人已经提供了证据，证明雄激素受体（AR）基因中的CAG重复多态性与美国白人晚期前列腺癌风险相关。在此，我们提出一项流行病学/分子联合研究，通过收集遗传同质的新加坡华人的病例和对照，以及筛选AR基因的体细胞突变，来评估AR基因型与前列腺癌风险之间的关系。在1993年1月1日至1998年12月31日的6年间，大约400例组织学诊断为前列腺癌的病例，年龄在45-74岁之间，发生在新加坡住宅区的居民中。对照（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nci资助的，正在进行的以人口为基础的队列，包括6万名中国男性和女性，他们是住宅区居民，基线年龄为45-74岁。在分子成分方面，将确定和表征晚期肿瘤中AR体细胞突变的患病率，以检查AR体细胞突变阳性肿瘤患者的构象AR- cag重复序列分布是否与AR突变阴性肿瘤患者不同。尽管过去认为AR突变在前列腺肿瘤中很少发生，但新的数据表明，它可能在晚期疾病中发生得相当频繁。到目前为止分析的突变通常是“功能获得”类型的，并且可能导致激素抗性疾病的进展。要验证的主要假设是，较短的CAG等位基因编码更活跃的AR，进而通过增加癌和肿瘤抑制基因（包括AR基因本身）之间的前列腺体细胞突变率来增加晚期前列腺癌的风险。这项研究的结果将有助于评估AR在前列腺癌易感性和进展中的作用，并允许将AR基因纳入前列腺癌发展的多基因模型。

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.