GWAS Identified Colorectal Cancer SNPs and Colorectal Polyp Risk

GWAS 鉴定的结直肠癌 SNP 和结直肠息肉风险

• 批准号: 8114992
• 负责人: POLLY A NEWCOMB
• 金额: $ 8.54万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114992
• 关键词: 11q23; 16q22.1; 19q13.1; 8q24; Adenomatous Polyps; BMP4; Benign; Biological; Biological Assay; CDH1 gene; Cancer-Predisposing Gene; Candidate Disease Gene; Cells; Clinical; Colon; Colon Carcinoma; Colonoscopy; Colorectal; Colorectal Cancer; Colorectal Polyp; DNA; DNA analysis; Data; Diagnosis; Environment; Epidemiology; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Genotype; Goals; Health; Health Planning; Housing; Human Genome; Hyperplastic Polyp; Individual; Interview; Knowledge; Learning; Lesion; Light; Link; MADH7 gene; Malignant - descriptor; Malignant Neoplasms; Molecular; Parents; Participant; Pathologic; Pathology; Pathway interactions; Penetrance; Polyps; Population Study; Predisposition; Reader; Rectal Hyperplastic Polyp; Rectum; Research; Risk; Risk Factors; Sampling; Serrated Adenoma; Site; adenoma; base; cancer risk; carcinogenesis; case control; demographics; genetic analysis; genome wide association study; insight; member; neoplastic; public health relevance; sound

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.

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。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”进展为恶性肿瘤。有令人信服且一致的数据将高外显率基因和低外显率基因与结直肠癌联系起来，并且特定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长足的进步，全基因组关联研究（GWAS）确定了人类基因组不同位点的 10 个结直肠癌易感位点；这些位点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 风险：1) 通过 GWAS 鉴定的特定多态性，包括以下内容：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）， 2) 使用 tagSNP 方法确定容纳这些基因座的基因或基因组区域。这项研究是现有研究“结肠癌途径：增生性息肉和腺瘤”(CA 097325)的辅助研究，旨在比较腺瘤和 HP 的流行病学危险因素和分子特征，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 名结肠镜检查确定的腺瘤病例、HP 病例以及大型综合健康计划成员的对照组。所有参与者都完成了涵盖人口统计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进行DNA分析，所有病例都在接受标准化病理学检查，以确认诊断并进一步对其息肉的病理特征进行分类。该项目将增加有关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，它还可以提供有关 HP 和假设位于锯齿状通路上的其他息肉（包括无蒂锯齿状息肉）的临床重要性的线索。 公共健康相关性：项目叙述大多数结直肠癌 (CRC) 源自息肉，但对结直肠息肉重要的基因尚未完全表征，并且关于某些息肉（例如增生性息肉 (HP)）的临床重要性的争论仍在继续。最近的 CRC 全基因组关联研究已确定了 10 个与 CRC 相关的位点。通过检查与腺瘤和 HP 相关的相同基因座，我们将更多地了解参与早期癌发生的基因和机制，并进一步表征 HP 的恶性潜力。