Prevalence and Potential Clinical Relevance of Germline Pathogenic Variants in Korean Biliary Tract Cancer
Jun-Ha Jang1,2, Jong Eun Park3, Jung Won Chun4,5
1Targeted Therapy Branch, National Cancer Center, Goyang, Korea.
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.