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)是一种发生于胆管的高度致命的癌症，通常被诊断为 晚期，预后非常差。与发展CCA相关的因素包括 胆管炎性状况，如先天性囊肿、胆结石、原发性硬化性胆管炎 (PSC)，病毒和其他原因造成的慢性肝炎，以及职业接触毒素，如有机 溶剂二氯甲烷和1，2-二氯丙烷。在亚洲部分地区，肝吸虫感染胆管 是一个主要的风险因素。然而，全球大多数罹患CCA的患者都没有已知的重大风险。 因素。根据流行病学研究，CCA的风险似乎是由遗传和 环境因素。全基因组关联研究(GWAs)已确定遗传易感基因 不同的癌症类型，允许开发风险模型，从而可以确定个人的风险 癌症的威胁。Gwas还提供了有关生物和分子途径的宝贵信息 有助于不同癌症的风险，使人们能够更好地了解癌症的发展和进展 癌症防治。由于CCA是一种相对较少见的癌症，因此一直难以研究。 大量的CCA患者，而且还没有发表针对患者的大型CCA GWAS研究 对于PSC患者的新生CCA或发生CCA。尽管PSC患者高达150次 与普通人群相比，PSC患者更有可能发展为CCA，只有10%-20%的PSC患者会进展为CCA。 PSC患者中CCA风险的变化可能是由基因和基因之间的复杂相互作用引起的 环境因素。多项研究表明，PSC具有很强的遗传成分；然而， PSC相关CCA发生的遗传因素尚不清楚。我们假设不同的宿主 与PSC相关的CCA病例相比，基因变异与新生CCA的风险相关。我们有 开展了一项大型多机构和多国家合作，以确定与 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患者和对照组的DNA。在研究的第一阶段，我们对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。在欧洲人后裔的案例中，197人是 PSC关联。将结果与PLCO队列中的对照组进行比较，我们发现了人类白细胞抗原的一个变异体 6号染色体上具有全基因组意义的区域。一些额外的地区显示 具有启发性的结果。我们现在建议将这一发现阶段扩展到获取、基因型和序列 来自另外7267名CCA患者的DNA以确认这些提示性结果的有效性。我们也是 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来自多种族队列的结果。完整的外显子 测序也将用于识别与CCA相关的罕见变异。