GWAS Identified Colorectal Cancer SNPs and Colorectal Polyp Risk

描述（由申请人提供）：腺瘤性息肉，也称为腺瘤，是结直肠癌（CRC）的明确前驱病变。在结肠和直肠中常见的其他息肉是增生性息肉（HP）。HP长期以来被认为是良性病变。然而，最近的证据表明，HP和组织遗传学相关的锯齿状腺瘤可能沿着单独的“锯齿状途径”发展为恶性肿瘤。有令人信服的和一致的数据表明，高和低转移率基因与CRC相关，并且特定的基因或基因型可能与不同的结直肠肿瘤途径相关。最近，结直肠癌的基因组研究取得了很大进展，全基因组关联研究（GWAS）在人类基因组的不同位点确定了10个CRC易感基因座;这些基因座可能与前驱病变的发生和进展有关，例如某些类型的结直肠息肉。在本申请中，我们建议确定与以下相关的腺瘤和HP的风险：1）通过GWAS鉴定的特定多态性，包括以下：8q24（rs6983267），18q21/SMAD7（rs4939827），15q13/CRAC 1（rs 4779584），10页14（rs10795668），8q23.3/EIF3H（rs16892766），11q23（rs3802842），14q22.2/BMP 4（rs 4444235）、16q22.1/CDH 1（rs 9929218）、19q13.1/RHPN 2（rs 10411210）、20p12.3（rs 961253），和2）使用tagSNP方法的容纳这些基因座的基因组的基因或区域。这项研究是一项现有研究的辅助，“结肠癌途径：增生性息肉和腺瘤”（CA 097325），旨在比较腺瘤和HP的流行病学风险因素和分子特征，目的是更多地了解HP和锯齿状腺瘤途径的临床重要性。我们的研究人群包括1，765例结肠镜检查确定的腺瘤病例，HP病例和对照组，他们都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，研究参与者提供了颊细胞样本进行DNA分析，所有病例都进行了标准化病理学检查，以确认诊断并进一步对息肉的病理特征进行分类。这个项目将增加围绕早期结直肠癌发生机制的知识体系，并有助于阐明不同结直肠癌途径的重要基因。此外，通过将这些病变与已知的CRC易感基因联系起来，它可以提供关于HP和其他息肉的临床重要性的线索，假设这些息肉位于锯齿状通路上，包括无蒂锯齿状息肉。 公共卫生相关性：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表征，关于某些息肉（如增生性息肉（HP））的临床重要性的争论仍在进行中。最近的CRC全基因组关联研究已经确定了10个与CRC相关的基因座。通过研究这些相同的基因座与腺瘤和HP的关系，我们将了解更多有关早期癌变的基因和机制，并进一步表征HP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.