MOLECULAR GENETIC STUDY--COLORECTAL CANCER EPIDEMIOLOGY

这里提出的研究旨在应用技术 为了进一步阐明遗传缺陷的作用， 环境影响和基因组不稳定性在青光眼病因中的作用 确定人群中的结直肠癌。80个家庭，已确认身份 来自以人群为基础的癌症登记，具有高发病率 很可能是遗传原因的结直肠癌，将是 包括在遗传连锁研究中。与突出候选基因的连锁 将进行检测，特别是最近检测到的易感基因 2号染色体被称为FCC，意为家族性结肠癌。我们将努力 旨在使用遗传连锁分析来精炼 这种2号染色体基因，便于定位克隆。躯体变化 在肿瘤中来自连锁家庭的个体将被检查以 对基因-基因相互作用影响的可能性进行检验 致癌途径。癌前病变(息肉)的躯体改变 来自具有特定环境风险因素的无关个人 还将进行检查，以检测可能的相关性。一个新认识的人 全基因组的体细胞变化现象，称为RER，用于复制 错误，将特征为来自候选连锁家族的肿瘤 以及来自环境评估病例的息肉中。已发表的研究 这表明RER基本上存在于所有由 Fcc基因缺陷。约15%的结肠癌来自随机系列 表现出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(S)上可能显著参与了 所有结肠肿瘤中这部分的病因学。我们建议进一步 用于确定RER频率和作用的分子分析 大肠肿瘤及其与遗传性缺陷或 环境影响。我们将研究分子机制 潜在的RER，因为了解这一点可能会导致筛查 患有生殖系FCC缺陷的个体，可能有助于识别 促进它的环境因素。这个合作社的L项目 努力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族。 包括在本提案中。项目2是以下项目的中心工作 检测大肠息肉的基因-环境交互作用。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.