ANDROGEN RECEPTOR AND PROSTATE CANCER RISK IN CHINESE

前列腺癌的一个独特特征是临床上常见的潜伏性病变，这些病变不会对健康构成威胁，但在组织学上与临床上重要的病变无法区分。确定预测晚期疾病的风险因素具有相当大的公共卫生意义。我们和其他人提供的证据表明，雄激素受体(AR)基因的CAG重复多态与美国白人晚期前列腺癌风险有关。我们建议进行流行病学和分子生物学相结合的研究，通过收集新加坡同种华人的病例和对照，以及筛选AR基因的体细胞突变，来评估AR基因与前列腺癌风险的关系。病例(约400例)将被组织学诊断为前列腺癌的发病病例，年龄45-74岁，发生在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(400名男性的年龄匹配随机样本)将从新加坡饮食与癌症队列研究的成员中挑选出来，该研究由NCI资助，持续以人群为基础，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，将测定和表征AR体细胞突变在晚期肿瘤中的发生率，以检查AR突变阳性的肿瘤患者与AR突变阴性的肿瘤患者组成的AR-CAG重复序列的分布是否不同。尽管AR突变在过去被认为在前列腺癌中很少发生，但新的数据表明，它可能会在晚期疾病中相当频繁地发生。到目前为止所分析的突变通常是“功能获得”类型的，可能会导致激素抵抗型疾病的进展。需要检验的主要假设是，较短的CAG等位基因编码更活跃的AR，进而通过增加癌基因和肿瘤抑制基因(包括AR基因本身)之间的前列腺癌体细胞突变率而增加晚期前列腺癌的风险。这项研究的结果将使对AR在前列腺癌易感性和进展中的作用的关键评估成为可能，并将使AR基因包括在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.