GENETIC LINKAGE IN COLORECTAL CANCER FAMILES

描述（由申请人提供）：结直肠癌（CRC）是一种常见的严重疾病，在家庭中聚集，因此与普通人群相比，具有受影响兄弟姐妹的个体的风险几乎增加3倍。很少，如果有的话，所观察到的家庭聚集尚未解释共享的环境暴露。 已知的遗传综合征，如遗传性非息肉病性结直肠癌（HNPCC）和家族性腺瘤性息肉病（FAP）被认为占不到2%的病例。未确定的易感基因座可能是重要的，在许多剩余的非综合征家族性结直肠癌。 我们的目标是确定新的CRC易感基因位点收集通过结肠癌合作家庭登记（结肠CFR）。Colon CFR是1997年发起的一个由NCI支持的联盟，为CRC遗传流行病学的跨学科研究建立了全面的合作基础设施。六个合作登记处收集了CRC肿瘤标本，血液样本和多病例家庭的流行病学信息。从Colon CFR以及使用相同方案的其他研究中心招募的未显示携带HNPCC或FAP易感突变的CRC家族将纳入两阶段基因图谱策略。 首先，我们将使用499个家庭中的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相关的证据;将确定区域进行随访。 其次，来自499个家庭的个体将使用初始扫描所建议的基因组区域中更密集间隔的微卫星标记进行基因分型。参数和非参数联系方法将评估CRC联系的证据。 这项工作的优势包括使用现有的CRC家族收集，丰富的初步数据（包括筛选已知突变），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族与美国和英国的其他CRC连锁研究相结合，以积累广泛的资源，进一步提高了解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.