HIGH RISK FAMILIAL COLON CANCER

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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%的结肠癌有一些遗传基础，但已确定的基因仅占其中的5%。 我们的假设是，其他尚未定义的基因突变会增加患结肠癌的风险，通过对大家庭和兄弟姐妹对的遗传连锁研究，可以识别这些基因。 我们的研究项目有四个组成部分：1）确定没有已知的结肠癌遗传综合征之一的高危结肠癌家族的遗传易感性位点（或多个位点），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）高血压的临床特点通过体格检查和内窥镜检查对风险家族进行筛查，以精确定义连锁分析的表型，并澄清每种疾病基因和突变的突变率和表型，一旦这些被确定; 3）通过基因表达谱分析，确定高危和已知结肠癌综合征家族的分子特征（通过微阵列分析）正常和肿瘤性结肠组织，两者都有助于鉴定疾病基因，并且一旦基因诊断成为可能，4）通过对500对结直肠癌同胞的遗传连锁和非参数分析，确定常见的遗传易感位点。

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.