The heritability and actionability of molecular therapies for biliary tract cancer are uncertain. Although associations between biliary tract cancer and BRCA germline variants have been reported, homologous recombination deficiency has not been investigated in BTCs.
Scientists from Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan sequenced germline variants in 27 cancer-predisposing genes in 1,292 biliary tract cancer cases and 37,583 controls without a personal and family history of cancer. We compared pathogenic germline variant frequencies between cases and controls and documented the demographic and clinical characteristics of carrier patients. In addition, whole-genome sequencing of 45 biliary tract cancers was performed to evaluate homologous recombination deficiency status.
Targeted sequencing identified 5,018 germline variants, which were classified into 317 pathogenic, 3,611 variants of uncertain significance, and 1,090 benign variants. Seventy-one BTC cases (5.5%) had at least one pathogenic variant among 27 cancer-predisposing genes. Pathogenic germline variants enriched in biliary tract cancers were in BRCA1, BRCA2, APC, and MSH6 (P < 0.00185). PALB2 variants were marginally associated with BTC (P = 0.01). APC variants were predominantly found in ampulla of Vater carcinomas. Whole-genome sequencing demonstrated that three biliary tract cancers with pathogenic germline variants in BRCA2 and PALB2 accompanied with loss of heterozygosity displayed HRD. Conversely, pathogenic germline variants without in homologous recombination-related genes showed homologous recombination proficient phenotypes.
This study described the heritability and the actionability of homologous recombination deficiency targeted treatments and provides possibilities for expanding therapeutic strategies and screening for BTCs. This study has been published in JOURNAL OF THEPATOLOGY in October 2022.
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