FAMILIAL FACTORS IN THE DEVELOPMENT OF COLON AND OTHER CANCERS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。这一建议是基于这样一种假设，即结直肠癌（CRC）和其他癌症主要发生在高风险人群中，这一人群是由携带特定基因定义的，这些基因赋予了腺瘤性结肠息肉形成的易感性。此外，确定这组个体将导致通过靶向和筛查那些风险最大的个体来降低结直肠癌死亡率的成本效益策略。遗传易感性对结直肠癌的发展是公认的。虽然大多数结肠癌和其他癌症是散发性的，但人们越来越认识到，很大一部分癌症是由于遗传易感性造成的。已经确定的是，一些已知的结肠癌易感基因的种系突变赋予了早发性结肠肿瘤的显著风险。该项目的最终目标是验证结肠息肉形成的易感性是由一个主要的易感性等位基因决定的预测。该研究的目标是：(1)建立一个300对成年兄弟姐妹的队列，他们要么患有结肠息肉，要么患有结肠癌；(2)对多达600名兄弟姐妹进行柔性乙状结肠镜检查，以确定结肠息肉的存在与否；(3)采集全血进行DNA提取、白细胞储存、血清储存；(4)开发多态标记作为少量结肠息肉易感性候选基因位点的试点项目。2001年，位于约翰霍普金斯大学的美国国立卫生研究院遗传疾病研究中心（CIDR）批准了我们的研究，对350个标记进行全基因组扫描。基因分型工作于2001年9月在CIDR开始。研究人员还发表了一篇论文，排除了COX2位点作为结肠肿瘤的候选基因。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal is based on the hypothesis that colorectal cancer (CRC) and other cancers principally occur in a high risk group that is defined by the carriage of specific genes that confer susceptibility to formation of adenomatous colon polyps. Additionally, identification of this group of individuals would lead to a cost effective strategy for reducing CRC mortality by targeting and screening those individuals who are at greatest risk. Genetic susceptibility for the development of CRC is well recognized. While the majority of colon and other cancers are sporadic, there is growing recognition that a significant proportion of cancer is due to inherited susceptibility. It is well established that germline mutations of some of the already known colon cancer susceptibility genes confer a marked risk of early onset colon neoplasia. The ultimate goal of this project is to test the prediction that susceptibility to colon polyp formation is determined by a major susceptibility allele. The goals of the study are: (1) to develop a cohort of 300 adult sibling pairs who are concordant for either colon polyps and/or colon cancer; (2) to perform flexible sigmoidoscopy on up to 600 siblings to determine the presence or absence of colon polyps; (3) to collect whole blood for DNA extraction, white blood cell storage, and serum storage; and (4) to develop polymorphic markers as a pilot project for a small number of candidate gene loci for colon polyp susceptibility. In 2001, the NIH Center for Inherited Disease Research (CIDR) located at Johns Hopkins University approved our study for a 350 marker genome-wide scan. Genotyping work began at CIDR in September 2001. The study investigators also published a paper excluding the COX2 locus as a candidate gene for colon neoplasia.