GWAS Identified Colorectal Cancer SNPs and Colorectal Polyp Risk

描述(申请人提供)：腺瘤性息肉，也被称为腺瘤，是公认的结直肠癌(CRC)的前驱病变。其他常见于结肠和直肠的息肉是增生性息肉(HPS)。长期以来，HPS一直被认为是良性病变。然而，最近的证据表明，HPS和与组织起源相关的锯齿状腺瘤可能会沿着单独的“锯齿状通路”进展为恶性肿瘤。有令人信服和一致的数据将高和低外显性基因与结直肠癌联系起来，很可能特定的基因或基因类型可能与不同的结直肠肿瘤途径有关。近年来，对结直肠癌的基因组研究取得了长足的进步，全基因组关联研究发现了位于人类基因组不同位置的10个结直肠癌易感基因座，这些基因座可能与某些类型的大肠息肉等前驱病变的发生和发展有关。在这一应用中，我们建议确定与以下相关的腺瘤和HPS的风险：1)通过GWAS鉴定的特定多态，包括8q24(Rs6983267)、18q21/Smad7(Rs4939827)、15q13/CRAC1(Rs4779584)、10p14(Rs10795668)、8q23.3/EIF3H(Rs16892766)、11q23(Rs3802842)、14q22.2/BMP4(Rs4444235)、16q22.1/cdh1(Rs9929218)、19q13.1/RHPN2(Rs10411210)、20p12.3(Rs9653)，以及2)使用SNP方法包含这些基因或基因组区域。这项研究是对一项名为“结肠癌路径：增生性息肉和腺瘤”(CA 097325)的研究的补充，该研究旨在比较腺瘤和腺瘤的流行病学危险因素和分子特征，目的是更多地了解结肠癌路径和锯齿状腺瘤路径的临床重要性。我们的研究人群包括1765例结肠镜检查确定的腺瘤病例、幽门螺杆菌病例和对照，他们是大型综合健康计划的成员。所有参与者都完成了涵盖人口统计学和结直肠癌风险因素的标准化访谈。此外，研究参与者提供了口腔细胞样本用于DNA分析，所有病例都正在接受标准化的病理检查，以确认诊断并进一步对其息肉的病理特征进行分类。这项拟议的项目将增加关于早期结直肠癌发生机制的知识体系，并有助于阐明对不同结直肠癌途径重要的基因。此外，通过将这些病变与已知的CRC易感基因联系起来，它还可能提供关于HPS和其他假设位于锯齿状通路上的息肉(包括固定性锯齿状息肉)的临床重要性的线索。 公共卫生相关性：项目简介大多数结直肠癌(CRC)起源于息肉，但对结直肠息肉重要的基因尚未完全确定，关于某些息肉(如增生性息肉(HPS))临床重要性的辩论仍在继续。最近关于结直肠癌的全基因组关联研究已经确定了10个与结直肠癌相关的基因座。通过检查这些与腺瘤和HPS相关的相同基因，我们将更多地了解与早期癌变有关的基因和机制，并进一步表征HPS的恶性潜能。

DESCRIPTION (provided by applicant): Adenomatous polyps, also referred to as adenomas, are well-established precursor lesions to colorectal cancer (CRC). Other polyps commonly found in the colon and rectum is hyperplastic polyps (HPs). HPs have long been considered benign lesions. However, recent evidence suggests that HPs and the histogenetically- related serrated adenomas may progress to malignancy along a separate "serrated pathway". There is compelling and consistent data that links both high and low penetrance genes to CRC, and it is likely that specific genes or genotypes may be associated with different colorectal neoplastic pathways. Recently, genomic studies of colorectal cancer have made great strides with genome-wide association studies (GWAS) identifying 10 CRC susceptibility loci at different sites in the human genome; these loci may be relevant to the genesis and progression of precursor lesions, such as certain types of colorectal polyps. In this application, we propose to determine the risk of adenomas and HPs associated with: 1) the specific polymorphisms identified through GWAS, including the following: 8q24 (rs6983267), 18q21/SMAD7 (rs4939827), 15q13/CRAC1 (rs4779584), 10p14 (rs10795668), 8q23.3/EIF3H (rs16892766), 11q23 (rs3802842), 14q22.2/BMP4 (rs4444235), 16q22.1/CDH1 (rs9929218), 19q13.1/RHPN2 (rs10411210), 20p12.3 (rs961253), and 2) the genes or regions of the genome that house these loci using a tagSNP approach. This research is ancillary to an existing study, "Colon cancer pathways: hyperplastic polyps and adenomas" (CA 097325), aimed at comparing the epidemiologic risk factors and molecular features of adenomas and HPs with the goal of learning more about the clinical importance of HPs and the serrated adenoma pathway. Our study population includes 1,765 colonoscopy-defined adenoma cases, HP cases, and controls who were members of a large integrated health plan. All participants completed standardized interviews covering demographics and colorectal-cancer risk factors. In addition, study participants provided buccal cell samples for DNA analysis, and all cases are undergoing a standardized pathology review to confirm the diagnosis and to further categorize the pathologic features of their polyps. This proposed project will increase the body of knowledge surrounding the mechanisms for early colorectal carcinogenesis and help elucidate the genes important to different colorectal cancer pathways. In addition, it may provide clues about the clinical importance of HPs and other polyps hypothesized to be on the serrated pathway, including sessile serrated polyps, by linking these lesions to known CRC susceptibility genes. PUBLIC HEALTH RELEVANCE: Project Narrative Most colorectal cancers (CRC) arise from polyps, but the genes important to colorectal polyps have not been fully characterized, and the debate about the clinical importance of some polyps, such as hyperplastic polyps (HPs) is ongoing. Recent genome wide association studies of CRC have indentified 10 loci that are associated with CRC. By examining these same loci in relation to adenomas and HPs we will learn more about genes and mechanisms involved in early carcinogenesis and further characterize the malignant potential of HPs.