Prevalence and Potential Clinical Relevance of Germline Pathogenic Variants in Korean Biliary Tract Cancer.

PURPOSE: This study aimed to identify germline pathogenic/likely pathogenic variants in DNA damage repair genes associated with increased cancer risk in Korean patients with biliary tract cancer and characterize their population-specific patterns.

MATERIALS AND

METHODS

In this retrospective multicenter cohort study, we performed germline whole-exome sequencing in 172 Korean patients diagnosed with intrahepatic cholangiocarcinoma (n = 83) or gallbladder cancer (n = 89) between June 2001 and February 2022. Germline variants were analyzed in 210 hereditary cancer genes, and the germline landscape of this cohort was compared with that of global cohorts.

RESULTS

Pathogenic/likely pathogenic variants were identified in 24 of 172 (14.0%) patients, predominantly in DNA damage repair genes (18 of 24 [75.0%]). BRCA2 was among the most frequently altered genes, harboring two distinct pathogenic variants (2 of 24 [8.3%]; both cases of intrahepatic cholangiocarcinoma). Of the 24 carriers, five (20.8%) harbored Tier 1-2 variants of potential, tumor-confirmation-dependent therapeutic relevance. Notably, 15 of 24 (62.5%) carriers reported no family cancer history. In population-stratified comparisons across nine biliary tract cancer cohorts (n = 4,018), PMS2 showed a Korean-enriched signal after accounting for heterogeneous gene coverage, whereas TP53 showed only a directional, non-significant increase after multiple-testing correction.

CONCLUSION

The study findings provide reference data for genetic counseling in East Asian patients with biliary tract cancer and suggest that germline testing may warrant consideration regardless of family history.