Germline pathogenic variants in a cohort of individuals with biliary tract cancer.

559 Background: Biliary tract cancers (BTC) are rare but have been implicated in hereditary cancer conditions such as Lynch syndrome (LS) and BRCA1 and BRCA2. Data from paired somatic and germline genetic testing on BTC have shown that ~5% may be related to germline pathogenic variants in BRCA1 and BRCA2. Identification of these germline pathogenic variants (PV) often provide patients with an opportunity for personalized treatment including platinum-based chemotherapies, PARP inhibitors and/or immunotherapy. Germline testing also provides crucial data to relatives regarding cancer risk and access to increased cancer surveillance and risk-reducing surgeries. Current guidelines recommend germline genetic testing when the likelihood of identifying a PV is >5%. The contribution of germline PV in BTC has not been described in a diverse patient population. Methods: In this prospective clinic-based study, individuals with BTC were referred by their oncologist for genetic counselling and testing. The majority of individuals were enrolled based on participation in the Legresley Biliary Registry, which recruits all individuals with BTC. Blood was sent for germline multi-gene panel testing. Results: Germline genetic testing was performed for 139 individuals. Average age of diagnosis was 57.8 years (range 28-84). The majority of individuals were diagnosed with intrahepatic cholangiocarcinoma (CCA) (54.7%), followed by extrahepatic CCA (20.9%) and gallbladder cancer (10.1%). The majority of individuals were male (56.1%). The population was ethnically diverse with 55% European, 24% Asian, 9% Middle Eastern/North African and 6% African. A minority of individuals had a previous cancer (18%) and 24.5% met current provincial eligibility criteria. Germline testing was complete on 136 individuals. 25/136 (14.7%) PV were identified in 20 individuals. 8/136 (5.9%) of the cohort carried PV in genes known to increase the risk for BTC ( BRCA1, BRCA2 and LS genes), 9/136 (6.6%) carried PV in other genes with clinically actionability (e.g. PALB2, ATM ), and 8/136 (5.9%) carried heterozygous PV in genes for recessive diseases. Variants of uncertain significance were identified in 42/136 (30.9%) and negative results were identified in 74/136 (54.4%). Personal and/or family history was not suggestive of the associated cancer condition in 9/16 (56%) of the PV cohort. Tumor profiling by whole genome sequencing on some individuals with PV found corresponding somatic mutational signatures, consistent with variant pathogenicity. Conclusions: Detection rates for PV in a diverse BTC cohort was up to 14.7%, including 5.9% among genes known to increase the risk for BTC. The majority of PV were found in individuals lacking personal and/or family history suggestive of the associated hereditary cancer condition. These results suggest that guidelines should be updated to recommend universal germline genetic testing for individuals with BTC.