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，起源于胆管，通常在 晚期预后很差与CCA发展相关的因素包括 胆管炎性疾病，如先天性囊肿、胆结石、原发性硬化性胆管炎 (PSC)病毒性和其他原因引起的慢性肝炎，以及职业性接触毒素，如有机 溶剂二氯甲烷和1，2-二氯丙烷。在亚洲部分地区，肝吸虫感染的胆管是 一个主要的风险因素。然而，世界范围内发生CCA的大多数患者没有已知的主要风险 因子根据流行病学研究，CCA风险似乎是由于遗传和 环境因素全基因组关联研究（GWAS）已经确定了遗传易感性位点， 不同的癌症类型，允许开发风险模型，可以确定个人的风险 癌症。GWAS还提供了关于生物和分子途径的有价值的信息， 有助于不同癌症的风险，使人们更好地了解癌症的发展和进展， 癌症预防和治疗。由于CCA是一种相对不太常见的癌症，因此一直难以研究 大量的CCA患者，并且没有大型CCA GWAS研究发表，无论是患者 原发性CCA或PSC患者中发生CCA。虽然PSC患者高达150倍， PSC患者比一般人群更容易发展为CCA，只有10-20%的PSC患者会发展为CCA。 PSC患者中CCA风险的变化可能是由遗传和基因之间复杂的相互作用引起的。 环境因素一些研究表明PSC具有很强的遗传成分;然而， PSC相关CCA发展中的遗传因素尚待阐明。我们假设不同的宿主 与PSC相关CCA病例相比，遗传变异与新发CCA风险相关。我们有 开发了一个大型的多机构和多国合作，以确定与以下疾病相关的基因变异 CCA。本研究的目的是利用高密度单核苷酸多态性（SNP）分析基因组 来自CCA患者和对照的DNA。在研究的第一阶段，我们对来自2829个CCA的DNA进行了基因分型。 患者，包括2412名欧洲人和417名亚洲人后裔。在欧洲血统的病例中， PSC相关。将结果与PLCO队列的对照组进行比较，我们确定了HLA中的一个变体， 6号染色体上的区域，达到全基因组意义。一些其他地区显示， 暗示性的结果。我们现在建议将这个发现阶段扩展到获取、基因分型和测序 来自另外7，267名CCA患者的DNA，以确认这些提示性结果的有效性。我们也 扩大招募工作，以丰富来自非欧洲患者的样本。我们将使用 复杂的统计遗传学方法来分析多种族队列的结果。全外显子组 测序也将用于鉴定与CCA相关的罕见变异。