HIGH RISK FAMILIAL COLON CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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，但已识别的基因只占其中的5%。我们的假设是，其他尚未定义的基因突变会增加患结肠癌的风险，通过对大家族和兄弟姐妹对的基因连锁研究，可以识别这些基因。我们的研究项目包括四个部分：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系的遗传易感性基因座，并确定一个患有弱化性家族性腺瘤性息肉病的大家族的遗传修饰基因座；2)通过体检和内窥镜检查对高危家系进行临床特征分析，以便准确地确定连锁分析的表型，并在确定每个疾病基因和突变的外显性和表型后，允许澄清这些基因和突变；3)利用正常和肿瘤组织的基因表达谱(通过微阵列分析)建立高危和已知结肠癌综合征家系的分子特征，以帮助识别疾病基因，并在基因诊断可能的情况下，精确地阐明与每种类型的遗传易感性相关的分子表型；4)通过对500对结直肠癌同胞进行遗传连锁和非参数分析，确定共同的遗传易感基因。

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. 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.