Genetic etiology of common familial colorectal cancer

常见家族性结直肠癌的遗传病因学

• 批准号: 7897217
• 负责人: Deborah Wood Neklason
• 金额: $ 8.95万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-12 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897217
• 关键词: 11q23; 3q21; 7q31; Address; Adenomatous Polyposis Coli; Affect; Agreement; Alleles; Cancer Etiology; Cancer Genetics Network; Candidate Disease Gene; Cessation of life; Chromosomes; Chromosomes, Human, Pair 7; Cohort Studies; Colon Carcinoma; Colonic Neoplasms; Colonic Polyps; Colorectal Cancer; Colorectal Neoplasms; Computer Analysis; DNA; Family; First Degree Relative; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genotype; Individual; Inherited; Link; Loss of Heterozygosity; Maps; Minor; Modeling; Mutation; Pathologic; Penetrance; Population; Predisposition; Premalignant; Relative (related person); Reporting; Research Priority; Resources; Risk; Risk Factors; Sample Size; Sampling; Short Tandem Repeat; Siblings; Signal Transduction; Susceptibility Gene; Syndrome; Universities; base; cancer genetics; cohort; genetic linkage analysis; genetic risk factor; kindred; member; public health relevance; tumor

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.

项目简介：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。来自癌症遗传学网络(CGN)、结肠肿瘤兄弟姐妹研究(CNSS)以及其他机构的受影响亲属配对研究报告称，患有结直肠癌(CRC)的一级亲属比其他人更容易发生共遗传。最近在CGN队列中发现了7q31上以前未被怀疑的区域，这些家庭有两个患有结直肠癌的兄弟姐妹(Nekraason等人，2008a)。其他研究也发现与9q22.33、3q21-24和11q23有一些小的峰，包括7q，这与研究一致(Daley等人，2008年；Djureinovic等人，2006年；Kemp等人，2006年；Nekraason等人，2008a；Wiesner等人，2003年)。这支持了一种范式，即常见的遗传性结肠癌源于一些外显性较低的易感基因，而不是导致众所周知的结肠癌综合征(如林奇综合征或家族性腺瘤性息肉病)的高渗透性等位基因。识别致病的中等外显性等位基因一直是一个问题，因为需要有足够的样本量的具有多个CRC成员的家系来获得统计能力。在这个应用程序中，我们计划通过合并两个基于CGN和CNSS的大型家族研究的资源来解决这个问题，并执行汇集的全基因组连锁分析。此外，对染色体7q31连锁信号的确认将通过在两个队列中进行7q的额外基因分型来进一步分析。合并分析将包括由凯斯西大学CNSS研究(Daley等人，2008；Wiesner等人，2003)收集的194个患有结肠癌的亲属的群体，并使用389个短串联重复序列(STR)标记的CIDR小组进行评估，以及由CGN收集的两个或更多患有结直肠癌的兄弟姐妹的83个亲属的群体，并使用1100个deCODE STR标记进行评估(Nekraason等人，2008a)。7q31基因座内的候选基因也将被评估胚系DNA的变化和配对的正常和肿瘤DNA的杂合性丢失(LOH)。我们假设，多个基因座与家族性结直肠癌有关；这些基因座可以通过对受影响的亲属对群体进行分层分析来增加统计能力来分离；通过评估与这些基因座相关联的特定群体，可以在这些基因座中识别出具有功能变化的基因。 公共卫生相关性：项目叙述结直肠癌(CRC)是工业化世界癌症死亡的第二大原因，寻找遗传危险因素一直是研究的重点。该项目将结合对结肠癌和癌前结肠息肉相关个体的两项大型研究，以确定常见的遗传风险因素。该项目还将专注于更好地定义之前在7号染色体上识别的区域，并检查该区域中导致这种风险增加的突变。