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Cholangiocarcinoma News

Molecular Epidemiology of Cholangiocarcinoma: Identifying New Inherited Variants

December 2021, Vol 2, No 4

Cholangiocarcinoma (CCA) involves genetic heterogeneity, highlighting the need to identify new inherited variants, as discussed at the 3rd Annual CCA Summit in Session II, “Molecular Epidemiology of CCA.”

Lewis Roberts, MBChB, PhD, of the Mayo Clinic in Rochester, MN, described the epidemiology and risk factors, genomic heterogeneity, mutations, inherited germline variants of known cancer genes, and the discovery of new inherited variants in CCA. The incidence of CCA is increasing, he said, with the highest rates seen in Asia. The rise in intrahepatic CCA has been seen particularly in industrialized countries.

Liver fluke and viral hepatitis, host genetics, environment, and lifestyle factors affect the risk for CCA. The strongest evidence in the prevention of CCA has been with statins, and with aspirin plus statins.

A gradient of genetic aberrations can be seen across hepatocellular carcinoma, CCA, and pancreatic cancer; TP53 mutation is seen in all 3 cancers, IDH1/2 and FGFR2 mutations are mostly seen in CCA, and KRAS mutations are increasing from hepatocellular carcinoma to CCA to pancreatic cancer. Substantial heterogeneity exists in the integrated subclassifications in CCAs, using different analyses.

The frequency of FGFR2 rearrangements and IDH1 mutations varies by ethnicity, with increased FGFR2 frequency seen in African Americans; increased IDH1 mutations in Hispanics, Europeans, and South Asians; and similar frequencies observed in an East Asian population.

Gene alterations affect outcomes in patients with intrahepatic CCA. Patients with clinical low-risk, genetic high-risk CCA have significantly worse overall survival versus patients with clinical low-risk, genetic low-risk CCA. Similarly, patients with clinical high-risk and genetic high-risk CCA have significantly worse overall survival versus patients with clinical high-risk, genetic low-risk CCA.

“Individuals with what appears to be sporadic cancer, many of those individuals do carry inherited or germline high-risk known oncogenic tumor mutations or aberrations,” said Dr Roberts.

Dr Roberts discussed the bile duct cancer genome-wide association study. Such studies are designed to investigate common gene variants across the genome, which may facilitate the identification of unexpected, important associations in the development of CCA. The use of whole-genome sequencing and family studies may help the identification of rare gene variants associated with CCA risk.

“The percentage of risk for CCA attributed to inherited predisposition has yet to be determined,” Dr Roberts said. “We are hoping to accomplish a large cohort genome-wide association study in biliary tract cancer, particularly in cholangiocarcinoma, to detect meaningful associations between individual gene variants in these cancers.”

Known CCA risk factors involve many mechanisms, including inflammation, liver and bile duct injury from toxins, and underlying genetic predisposition. CCA risk may be influenced by many genes in different cellular pathways.

Dr Roberts explained that by understanding these genetic risk factors, researchers can identify patients at the highest risk and improve early diagnosis. Based on approximately 1000 European extrahepatic samples and 1000 European intrahepatic samples, there are some suggestive regions, but none has reached significance. Therefore, more samples are needed.

“We remain on a quest to identify gene variants that don’t have strong effect but cumulatively are likely associated with increasing risk of cholangiocarcinoma,” Dr Roberts suggested. “That’s what we are doing with the genome-wide association study, and we are making progress. Hopefully, we will have more information to share in future years.”

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