COLON CANCER RISK AND PREVENTION CLINIC

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。本研究的目的是确定高危家族性结肠癌的遗传病因和临床特征。据估计，20-30%的结肠癌有一定的遗传基础，但已确定的基因只占其中的5%。我们的假设是，其他尚未定义的基因突变会导致患结肠癌的风险增加，通过对大家庭和兄弟姐妹的遗传联系研究，可以识别这些基因。我们的研究项目有四个组成部分：1)确定没有已知结肠癌遗传综合征的高危结肠癌家族的遗传易感性位点（或位点），并确定具有减毒家族性腺瘤性息肉病的大家族的遗传修饰位点；2)通过物理和内镜检查对高危家族进行临床表征，以便精确定义表型进行连锁分析，一旦确定每个疾病基因和突变，就可以澄清外显率和表型；3)通过正常和肿瘤结肠组织的基因表达谱（通过微阵列分析）建立高危和已知结肠癌综合征家族的分子特征，既有助于疾病基因的鉴定，一旦有可能进行遗传诊断，精确阐明与每种遗传易感性相关的分子表型；4)对500对结直肠癌兄弟姐妹进行遗传连锁和非参数分析，确定共同遗传易感位点。

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. The objective of this study is to determine the genetic etiology and clinical characteristics of high-risk familial colon cancer. It is estimated that 20-30% of all colon cancers have some hereditary basis but the identified genes account for only 5% of these. Our hypothesis is that mutations in additional, yet to be defined, genes cause an increased risk of developing colon cancer, and by genetic linkage studies of large families and sibling pairs, these genes can be identified. There are four components to our research project: 1) Determine the genetic susceptibility locus (or loci) of high-risk colon cancer families that do not have one of the known inheritied syndromes of colon cancer and determine genetic modifier loci in a large family with attenuated familial adenomatous polyposis; 2) Clincally characterize the high-risk families with physical and endoscopic examination in order to precisely define the phenotype for linkage analysis and to allow clarification of the penetrance and phenotype of each disease gene and mutation once these are identified; 3) establish molecular characteristics of the high-risk and known colon cancer syndrome families with gene expression profiling (by microarray analysis) of normal and neoplastic colon tissue, both to assist in identification of disease genes, and once genetic diagnosis is possible, to precisely clarify the molecular phenotypes associated with each type of genetic predisposition; 4) Determine common genetic susceptibility loci by genetic linkage and nonparametric analysis of 500 sibling pairs with colorectal cancer.