GENETIC LINKAGE IN COLORECTAL CANCER FAMILES

描述(申请人提供)：结直肠癌(CRC)是一种常见的严重疾病，聚集在家庭中，因此，与普通人群相比，有受影响兄弟姐妹的个人的风险几乎增加了3倍。几乎没有，如果有的话，观察到的家族聚集性还没有被共同的环境暴露所解释。已知的遗传综合征，如遗传性非息肉病、结直肠癌(HNPCC)和家族性腺瘤性息肉病(FAP)，被认为占病例的不到2%。未确定的易感基因可能在许多剩余的非综合征型家族性结直肠癌中很重要。 我们的目标是确定通过结肠癌合作家庭登记处(Colon CFR)收集的新的CRC易感基因。Colon CFR是一个由NCI支持的联盟，成立于1997年，已经为CRC遗传流行病学的跨学科研究建立了一个全面的合作基础设施。六个合作登记机构已经从多个病例家庭收集了结直肠癌肿瘤标本、血液样本和流行病学信息。从结肠CFR以及使用相同方案的其他地点招募的CRC家庭，如果没有显示出携带HNPCC或FAP易感突变，将被包括在两阶段基因图谱策略中。 首先，我们将使用499个家系中的844个受影响的亲属对进行全基因组连锁分析。将对大约400个微卫星标记进行基因分型，并使用参数和非参数方法评估与CRC有关的证据；将为后续行动确定区域。 其次，来自499个家庭的个体将使用初始扫描建议的基因组区域中更密集的微卫星标记进行基因分型。参数和非参数关联方法将评估CRC关联的证据。 这项工作的优势包括使用现有的CRC家族集合，丰富的初步数据(包括对已知突变的筛查)，以及研究人员之间成功的合作历史。未来的一个关键目标是将这些家系与美国和英国的其他CRC连锁研究的家系结合起来，以积累广泛的资源，并进一步增强了解CRC遗传易感性的能力。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a common, serious disease that clusters in families, such that individuals with an affected sibling are at almost 3-fold increased risk compared to those in the general population. Little, if any, of the observed familial clustering has yet been explained by shared environmental exposures. Known genetic syndromes such as hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) are thought to account for less than 2% of cases. Unidentified susceptibility loci are probably important in much of the remaining non-syndromic familial colorectal cancer. We aim to identify novel CRC susceptibility loci collected via the Colon Cancer Cooperative Family Registry (Colon CFR). The Colon CFR is an NCI-supported consortium initiated in 1997 that has established a comprehensive collaborative infrastructure for interdisciplinary studies in CRC genetic epidemiology. Six cooperating registries have collected CRC tumor specimens, blood samples, and epidemiologic information from multiple-case families. Recruited CRC families from the Colon CFR, as well as from an additional site using identical protocols, who are not shown to carry HNPCC- or FAP-predisposing mutations will be included in a two-stage gene-mapping strategy. First, we will perform a genome-wide linkage analysis using 844 affected relative pairs in 499 families. Approximately 400 microsatellite markers will be genotyped and assessed for evidence of linkage to CRC using parametric and non-parametric methods; regions will be identified for follow-up. Second, individuals from 499 families will be genotyped using more densely-spaced microsatellite markers in genomic regions suggested by the initial scan. Parametric and non-parametric linkage methods will assess evidence for CRC linkage. Strengths of this effort include the use of an existing CRC family collection, a wealth of preliminary data (including screening for known mutations), and a successful collaborative history among investigators. A key future aim is to combine these families with those of other CRC linkage studies in the US and UK to amass an extensive resource with further increased power to understand CRC genetic susceptibility.