MOLECULAR GENETIC STUDY--COLORECTAL CANCER EPIDEMIOLOGY

这里提出的研究旨在应用以下技术： 分子遗传学进一步阐明遗传缺陷的作用， 环境影响和基因组的不稳定性 在特定人群中的结肠直肠癌。80个家庭，已查明 从基于人群的癌症登记处， 结肠直肠癌，可能是遗传病因，将是 包括在遗传连锁研究中。与突出候选基因的连锁 将进行测试，特别是最近检测到的易感基因， 2号染色体，家族性结肠癌的FCC。着力 针对使用遗传连锁分析来精确定位 这个2号染色体基因，以便于定位克隆。体细胞变化 将检查来自连锁家族中个体的肿瘤中的 基因-基因相互作用可能影响 致癌途径癌前病变（息肉）的躯体变化 来自具有特征性环境风险因素的无关个体 也将被检查以检测可能的相关性。一个新认识的 全基因组的体细胞变化现象，称为RER，用于复制 错误，将在来自候选连锁家族的肿瘤中表征 以及环境评估案例中的珊瑚虫。发表的研究 这表明RER存在于基本上所有肿瘤中， FCC基因的缺陷大约15%的结肠肿瘤来自“随机”系列 显示RER，表明FCC基因的生殖系或体细胞缺陷 在2号染色体上或相关基因可能显著参与了 所有结肠肿瘤的这一部分的病因。我们建议进一步 用于确定RER的频率和作用的分子分析 结直肠肿瘤及其与遗传缺陷的关系， 环境影响。我们将研究分子机制 基础RER，因为了解这一点可能会导致筛选测试， 有生殖系FCC缺陷的个人，并可能有助于识别 环境因素，促进它。该合作社的项目l effort是一项家族性结直肠癌的遗传流行病学研究， 这将包括确定遗传连锁家庭 包括在本提案中。项目2的核心工作是 研究结直肠息肉中的基因-环境相互作用。这是 项目3。

The studies proposed here are aimed at applying the techniques of molecular genetics to further elucidate the roles of inherited defects, environmental influences and genomic instability in the etiology of colorectal cancers in a defined population. Eighty families, identified from population-based cancer registries, with a high incidence of colorectal cancer that is likely to be of genetic etiology, will be included in genetic linkage studies. Linkage to prominent candidate genes will be tested, particularly the recently detected predisposing gene on chromosome 2, called FCC for familial colon cancer. Efforts will be directed toward using genetic linkage analysis to refine the location of this chromosome 2 gene, to facilitate positional cloning. Somatic changes in the tumors from individuals in the linkage families will be examined to test for the possibility of gene-gene interactions influencing the carcinogenic pathway. Somatic changes in precancerous lesions (polyps) from unrelated individuals with characterized environmental risk factors will also be examined to detect possible correlations. A newly recognized phenomenon of genome-wide somatic change, called RER, for replication error, will be characterized in tumors from the candidate linkage families and in the polyps from environmentally assessed cases. Published studies suggest that RER is found in essentially all tumors resulting from a defect in the FCC gene. About 15% of all colon tumors from "random" series exhibit RER, suggesting that germline or somatic defects in the FCC gene on chromosome 2 or related gene(s) may be significantly involved in the etiology of this fraction of all colon tumors. We propose further molecular analyses for defining the frequency and role of RER in colorectal neoplasia and its association with inherited defects or environmental influences. We will examine the molecular mechanism underlying RER, as understanding of this may lead to a screening test for individuals with germline FCC defects and may help to identify environmental factors that promote it. Project l of this cooperative effort is a genetic epidemiological study of familial colorectal cancer that will include the ascertainment of the genetic linkage families included in the present proposal. Project 2 is the central effort for examining gene-environment interactions in colorectal polyps. This is Project 3.