Gene/environment study of familial prostate cancer

前列腺癌是美国最常见的癌症，约占癌症发病率的30%。前列腺癌的病因尚不清楚，尽管家族因素、激素和饮食因素可能在疾病的发展中起作用。有证据表明，早发性前列腺癌可能归因于常染色体显性生殖系突变。据估计，每170人中就有一人可能携带前列腺癌基因的高风险等位基因，这种基因的携带者一生患病的风险为88%，非携带者一生患病的风险为5%。因此，识别该基因，了解其功能并确定其他暴露（遗传和/或环境）与该基因相互作用是非常重要的。据我们所知，迄今为止，有一些非基于人群的研究整合了(a)遗传易感性基因，(b)选定癌基因和肿瘤抑制基因的遗传改变，以及(c)环境暴露。使用我们在几个正在进行的NCI资助的遗传流行病学研究中开发的程序，我们建议：(1)建立一个以人群为基础的前列腺癌家庭登记处，包括524个年龄在70岁以下的先证家庭。我们将收集癌症家族史、饮食史、流行病学危险因素和血液样本的信息，这些信息来自所有先证者、其他前列腺癌患者亲属和信息丰富的未受影响的亲属。将从所有患癌亲属处收集肿瘤组织样本；(2)描述前列腺癌1q染色体的改变。其他与前列腺癌易感性相关的潜在基因座将被考虑进行研究。如果在本研究过程中克隆了前列腺癌易感基因，我们将测试该基因的突变，以估计其在人群中的频率和外显率；(3)评估易感基因的表达（或存在其他遗传改变）是否可能受到环境或宿主因素的改变；(4)为我们前列腺癌项目的化学预防试验（项目III）和替代终点生物标志物研究（项目II）提供一个特征良好的兄弟/男性表兄妹队列。通过该项目产生的数据将为识别前列腺癌的高危男性以及制定预防和早期发现方案提供依据。

Prostate cancer is the most common cancer diagnosed in the United States and accounts for about 30% of cancer incidence. Etiology of prostate cancer is unknown, although familial factors, hormones, and dietary factors may play a role in the development of the disease. There is evidence that early onset prostate cancer may be attributed to an autosomal dominant germline mutation. It is estimated that one person in 170 may carry high risk alleles of the prostate cancer gene and that carriers of this gene have a lifetime risk of disease of 88% and non- carriers a lifetime risk of 5%. It is, therefore, very important to identify the gene, understand how it functions and identify what other exposures (genetic and/or environmental) interact with this gene. To our knowledge, there are to date non population-based studies that integrate (a) inherited susceptibility genes, (b) genetic alterations in selected oncogenes and tumor suppressor genes, and (c) environmental exposures. Using procedures we have developed in several on-going NCI funded genetic epidemiology studies, we propose to: (1) develop a population-based prostate cancer family registry of 524 families of probands under age 70. We will collect information on family history of cancer, dietary history, epidemiologic risk factors, and blood samples, from all probands, other prostate cancer affected relatives, and informative unaffected relatives. Tumor tissue samples will be collected from all cancer affected relatives; (2) characterize alterations on chromosome 1q in prostate cancer. Other potential loci associated with prostate cancer susceptibility will be considered for study as they become known. In the event that the prostate cancer susceptibility gene is cloned during the course of this study, we will test for mutations in the gene in order to estimate in the population frequency and penetrance; (3) assess whether expression of susceptibility genes (or presence of other genetic alterations) may be modified by environmental or host factors; (4) provide a well-characterized cohort of brothers/male cousins for the chemoprevention trial (Project III) and surrogate endpoint biomarker studies (Project II) of our Prostate Cancer Program Project. Data generated though this project will provide the basis on which high risk men for prostate cancer can be identified and programs on prevention and early detection can be developed.