Grant Details
Grant Number: |
5U01CA275065-02 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: |
2024 |
Abstract
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.
Publications
Independent of Primary Sclerosing Cholangitis and Cirrhosis, Early Adulthood Obesity Is Associated with Cholangiocarcinoma.
Authors: Hatia R.I.
, Eluri M.
, Hawk E.T.
, Shalaby A.
, Karatas E.
, Shalaby A.
, Abdelhakeem A.
, Abdel-Wahab R.
, Chang P.
, Rashid A.
, et al.
.
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2023-10-02 00:00:00.0; 32(10), p. 1338-1347.
PMID: 37540502
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