It was unclear if molecular therapy for biliary tract cancer (BTC) was heritable and practicable. Homologous recombination deficit had not been researched in BTCs, despite the description of links between BTC and BRCA germline mutations.

In 1,292 instances of biliary tract cancer and 37,583 healthy controls without a personal or family history of cancer, researchers sequenced germline mutations in 27 cancer-predisposing genes. In addition, they evaluated the prevalence of harmful germline variants in cases and controls and described the demographic and clinical characteristics of carrier patients. To assess the homologous recombination deficit status, whole-genome sequencing of 45 biliary tract tumors was also carried out.

Over 5,018 germline variations were found using targeted sequencing, of which 317 were pathogenic, 3,611 were of unknown significance, and 1,090 were benign. Among the 27 cancer-predisposing genes, 71 BTC patients (5.5%) had at least one pathogenic mutation. BRCA1, BRCA2, APC, and MSH6 all had pathogenic germline mutations that were more prevalent in biliary tract malignancies (P<0.00185). Variants of PALB2 were just tangentially related to BTC (P = 0.01). Ampulla of Vater carcinomas was the most common site for APC mutations. Three biliary tract tumors with pathogenic germline mutations in BRCA2 and PALB2, together with loss of heterozygosity were shown to have HRD by whole-genome sequencing. On the other hand, pathogenic germline mutations that lacked genes involved in homologous recombination had symptoms that were efficient in the process.

The study presented opportunities for increasing therapy approaches and BTC screening by describing the heredity and actionability of homologous recombination deficit-focused therapeutics.