Genetic etiology of common familial colorectal cancer

项目概述结直肠癌（CRC）是工业化国家癌症死亡的第二大原因，寻找易感因素一直是研究的重点。来自癌症遗传网络（CGN）、结肠肿瘤同胞研究（CNSS）以及其他研究的受影响亲属对研究报告称，与未患结直肠癌（CRC）的一级亲属相比，结直肠癌（CRC）的一级亲属中共同遗传的遗传区域更常见。最近在有两个兄弟姐妹患有结直肠癌的CGN队列中发现了7q31上一个以前未被怀疑的区域（Neklason等，2008a）。其他研究也发现了与9q22.33、3q21-24和11q23之间的联系，其中有一些较小的峰值，包括7q，这在各研究中是一致的（Daley等人，2008；Djureinovic等人，2006；Kemp等人，2006；Neklason等人，2008a； Wiesner等人，2003）。这支持了一种范式，即常见的遗传性结肠癌是由一些低外显率的易感基因引起的，而不是由高外显率的等位基因引起的，这些等位基因导致了众所周知的结肠癌综合征，如Lynch综合征或家族性腺瘤性息肉病。确定中等外显率的致病等位基因是有问题的，因为有多个成员患有结直肠癌的亲属需要足够的样本量来进行统计。在本应用中，我们计划通过合并两个大型家族研究（CGN和CNSS）的资源来解决这个问题，并进行汇总的全基因组连锁分析。此外，将通过在两个队列中7q31位点的额外基因分型进一步分析染色体7q31连锁信号的确认。合并分析将包括凯斯西大学CNSS研究收集的194种结肠肿瘤患者（Daley et al., 2008; Wiesner et al., 2003），用389个短串联重复（STR）标记的CIDR小组进行评估；以及CGN收集的83种两个或两个以上兄弟姐妹患有结直肠癌的人群，用1100个deCODE STR标记进行评估（Neklason et al., 2008a）。7q31位点内的候选基因也将被评估生殖系DNA的改变和配对正常和肿瘤DNA的杂合性损失（LOH）。我们假设多个基因位点与家族性结直肠癌有关；通过对受影响的相对对群体进行分层分析，提高统计能力，可以分离出这些遗传位点；通过评估与这些基因座相连的特定种群，可以在这些基因座中识别出具有功能变化的基因。

DESCRIPTION (provided by applicant): Project Summary Colorectal cancer (CRC) is the second leading cause of cancer death in the industrialized world and the search for susceptibility factors has been a research priority. Affected relative pair studies from the Cancer Genetics Network (CGN), the Colon Neoplasia Sibling Study (CNSS) as well as others have reported genetic regions that are co-inherited more often in first-degree relatives with colorectal cancer (CRC) than those without. A previously unsuspected region on 7q31 was recently identified in the CGN cohort in kindreds with two siblings with CRC (Neklason et al., 2008a). Other studies also found linkages to 9q22.33, 3q21-24, and 11q23 with some minor peaks, including 7q, in agreement across studies (Daley et al., 2008; Djureinovic et al., 2006; Kemp et al., 2006; Neklason et al., 2008a; Wiesner et al., 2003). This supports the paradigm that common inherited colon cancer arises from a number of susceptibility genes of lower penetrance rather than highly penetrant alleles that cause the well described colon cancer syndromes, such as Lynch syndrome or Familial Adenomatous Polyposis. Identifying causative moderate penetrance alleles has been problematic because adequate sample size of kindreds with multiple members with CRC are needed for statistical power. In this application, we plan to address this problem by merging the resources of two large family based studies, CGN and CNSS, and perform a pooled whole genome linkage analysis. In addition, confirmation of the chromosome 7q31 linkage signal will be further analyzed by additional genotyping at 7q in both cohorts. The pooled analysis will include a population of 194 kindreds with colon neoplasias collected by the CNSS study at Case Western University (Daley et al., 2008; Wiesner et al., 2003) and evaluated with the CIDR panel of 389 short tandem repeat (STR) markers, and a population of 83 kindreds of two or more siblings with CRC collected by the CGN and evaluated with 1100 deCODE STR markers (Neklason et al., 2008a). Candidate genes within the 7q31 locus will also be evaluated for alterations in germline DNA and loss of heterozygosity (LOH) in paired normal and tumor DNA. We hypothesize that multiple genetic loci are responsible for familial colorectal cancers; that these genetic loci can be isolated by increasing the statistical power with stratified analysis of affected relative pair populations; and genes with functional changes can be identified within these loci by evaluating the specific populations that link to the loci. PUBLIC HEALTH RELEVANCE: Project Narrative Colorectal cancer (CRC) is the second leading cause of cancer death in the industrialized world and the search for inherited risk factors has been a research priority. This project will combine two large studies of related individuals with colon cancer and precancerous colonic polyps to identify genetic risk factors that are commonly inherited. The project will also focus on better defining a previously identified region on chromosome 7 and examine genes in region for mutations leading to this increased risk.