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Grant Details

Grant Number: 1U01CA275065-01A1 Interpret this number
Primary Investigator: Roberts, Lewis
Organization: Mayo Clinic Rochester
Project Title: International Consortium for the Genetics of Biliary Tract Cancers Cholangiocarcinoma Genome Wide Association Study
Fiscal Year: 2023


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.



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