International Consortium for the Genetics of Biliary Tract Cancers Cholangiocarcinoma Genome Wide Association Study

国际胆道癌遗传学联盟胆管癌全基因组关联研究

• 批准号: 10608848
• 负责人: Christopher I. Amos
• 金额: $ 70.02万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-10 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608848
• 关键词: Africa; African; American; Asia; Asian; Asian ancestry; Asian population; Bile duct carcinoma; Biliary Tract Cancer; Biological; Cholangiocarcinoma; Cholelithiasis; Chromosome 6; Chronic viral hepatitis; Clinical; Collaborations; Collection; Complex; Consent; Cyst; DNA; DNA Sequence; Data; Development; Diagnosis; Disease; East Asian; Environmental Risk Factor; Epidemiology; Etiology; European; Exposure to; Fasciola hepatica; Frequencies; Future; Gene Targeting; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomic DNA; Genotype; Goals; Haplotypes; Heritability; Hispanic ancestry; Immune; Individual; Inflammatory; Inherited; Institution; International; Malignant Neoplasms; Mediating; Methods; Methylene Chloride; Modeling; Molecular; Occupational Exposure; Open Reading Frames; Organic solvent product; Outcome; Pathologic; Pathway interactions; Patients; Phase; Polymorphism Analysis; Population; Predisposition; Prevention strategy; Primary Prevention; Prognosis; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Publishing; Race; Radiology Specialty; Research; Risk; Risk Factors; Sampling; Single Nucleotide Polymorphism; Specimen; Susceptibility Gene; Toxin; Variant; bile duct; cancer prevention; cancer risk; cancer therapy; cancer type; cohort; density; epidemiology study; exome sequencing; expectation; follow-up; genetic variant; genome wide association study; genome-wide; genomic locus; improved; multi-ethnic; novel; primary sclerosing cholangitis; prospective; rare variant; recruit; repository; screening; sex; targeted sequencing; targeted treatment

Abstract/Project Summary Cholangiocarcinoma (CCA) is a highly lethal cancer that arises from the bile ducts and is often diagnosed at an advanced stage with very poor prognosis. Factors associated with development of CCA include inflammatory conditions of the bile ducts such as congenital cysts, gallstones, primary sclerosing cholangitis (PSC), chronic hepatitis from viral and other causes, and occupational exposure to toxins such as the organic solvents dichloromethane and 1,2-dichloropropane. In parts of Asia, liver fluke infestations of the bile ducts are a major risk factor. However, the majority of patients who develop CCA worldwide have no known major risk factor. Based on epidemiologic studies, it appears that CCA risk is due to a combination of genetic and environmental factors. Genome-wide association studies (GWAS) have identified genetic susceptibility loci for different cancer types, allowing development of risk models that can allow determination of an individual’s risk of cancer. GWAS have also provided valuable information on the biological and molecular pathways that contribute to risk of different cancers, allowing improved understanding of cancer development and progress in cancer prevention and treatment. Because CCA is a relatively less common cancer, it has been difficult to study large numbers of CCA patients and there have been no large CCA GWAS studies published, either for patients with de novo CCA or for CCA developing in patients with PSC. Although PSC patients are up to 150 times more likely to develop CCA than the general population, only 10-20% of PSC patients will progress to CCA. Variation in the risk of CCA among PSC patients may be caused by a complex interplay between genetic and environmental factors. Several studies indicate PSC has a strong genetic component; however, the impact of genetic factors in PSC-related CCA development is yet to be elucidated. We hypothesize that different host genetic variants are associated with CCA risk in de novo versus PSC-associated CCA cases. We have developed a large multi-institutional and multi-national collaboration to identify gene variants associated with CCA. The goal of this study is to use high-density single nucleotide polymorphism (SNP) analysis of genomic DNA from CCA patients and controls. In a first phase of the study, we have genotyped DNA from 2829 CCA patients, including 2412 of European and 417 of Asian descent. Of the European descent cases, 197 were PSC-associated. Comparing the results with controls from the PLCO cohort, we identified a variant in the HLA region on chromosome 6 that reached genome wide significance. A number of additional regions showed suggestive results. We now propose an expansion of this discovery phase to acquire, genotype and sequence DNA from an additional 7,267 CCA patients to confirm the validity of these suggestive results. We are also expanding recruitment efforts to enrich the cohort in samples from non-European patients. We will use sophisticated statistical genetic methods to analyze the results from the multi-ethnic cohort. Whole exome sequencing will also be used to identify rare variants associated with CCA.

摘要/项目摘要 胆管癌（CCA）是一种高度致命的癌症，是由胆管引起的，经常被诊断为 一个高级阶段，预后较差。与CCA发展相关的因素包括 胆管的炎症条件，例如先天性囊肿，胆结石，原发性硬化性胆管炎 （PSC），病毒和其他原因引起的慢性肝炎，以及职业暴露于毒素，例如有机 溶液二氯甲烷和1,2-二氯丙烷。在亚洲部分地区，胆管的肝氟侵染是 主要的危险因素。但是，大多数在全球范围内开发CCA的患者都没有已知的主要风险 因素。基于流行病学研究，CCA风险似乎是由于遗传和 环境因素。全基因组关联研究（GWAS）已确定了遗传易感性基因座 不同的癌症类型，允许开发可以确定个人风险的风险模型 癌症。 GWA还提供了有关生物和分子途径的有价值的信息 有助于不同癌症的风险，从而提高了对癌症发展和进步的了解 预防癌症和治疗。由于CCA是一个相对较少的癌症，因此很难研究 大量CCA患者，并且没有针对患者进行大量CCA GWAS研究 使用Noko CCA或PSC患者的CCA发育。尽管PSC患者最多150次 与普通人群相比，只有10-20％的PSC患者会发展到CCA。 PSC患者中CCA风险的差异可能是由于遗传和遗传之间的复杂相互作用引起的 环境因素。几项研究表明PSC具有强大的遗传成分。但是， 与PSC相关的CCA发育中的遗传因素尚未阐明。我们假设不同的主机 遗传变异与从头与PSC相关的CCA病例中的CCA风险有关。我们有 开发了大型的多机构和跨国合作，以识别与 CCA。这项研究的目的是使用基因组的高密度单核苷酸多态性（SNP）分析 CCA患者和对照组的DNA。在研究的第一阶段，我们从2829 CCA的基因分型DNA 患者，包括欧洲的2412例和417个亚洲血统。在欧洲血统案件中，有197例 PSC相关。将结果与PLCO队列的对照进行比较，我们确定了HLA中的一个变体 6号染色体的区域达到了基因组广泛的意义。显示了许多其他区域 暗示性结果。现在，我们提出了这个发现阶段的扩展以获取，基因型和序列 来自另外7,267名CCA患者的DNA确认这些暗示性结果的有效性。我们也是 扩大了招聘工作，以丰富非欧洲患者的样品中的同类群体。我们将使用 软化的统计遗传学方法分析了多种族队列的结果。整个外显子 测序还将用于识别与CCA相关的稀有变体。