Whole-genome sequencing of cholangiocarcinoma to reveal distinct profiles of patients with underlying cirrhosis or inflammatory disorders.

340 Background: Cholangiocarcinoma (CCA) is a lethal malignancy with limited treatment options. Molecular profiling of these tumours has revealed a number of actionable mutations and four clusters have been defined through integrative genomic analysis. We sought to explore whole genome sequencing (WGS) data in 20 patients enriched for CCA arising in the setting of cirrhosis or inflammatory disorders. Methods: A previously established Biliary Tract Cancer (BTC) database at the Princess Margaret Cancer Centre (PMCC)/University Health Network (UHN) was used to identify patients of clinical interest including long-term survivors, those with germ-line mutations, and those with chronic inflammatory disorders. WGS and bioinformatic analyses were performed at the Ontario Institute for Cancer Research. Results: The 20 resected samples included 12 patients (pts) with intrahepatic CCA, 7 perihilar CCA, and 1 distal CCA. 8 pts were alive > 8 years post resection and one patient harboured a germline MLH1 pathogenic variant (MLH1 G67R). 3 pts had documented cirrhosis (hepatitis B n = 2, haemochromatosis n = 1); other inflammatory disorders (n = 4) included ulcerative colitis (UC) without documented PSC (n = 1), PSC alone (n = 1), UC with PSC (n = 1), and ankylosing spondylitis (n = 1). The remaining cases were randomly selected. The predominant COSMIC single base substitution (SBS) mutational signatures were 1, 8 and 5, and the median TMB was 1.75 mutations per MB (0.73-33.23). The pt with an MLH1 mutation exhibited a TMB of 33.23 with predominance of SBS26. Actionable variants were enriched in the 8 pts who are alive and disease free including 2 predicted FGFR fusions and mutations in IDH1 (n = 1), BRAF V600E (n = 1), and BAP1 (n = 1). TP53 mutations (n = 7) were present exclusively in patients with cirrhosis or inflammatory disorders and the median survival in the group was 12 months (3 -21 months). Although SBS signatures were similar in this group, in the two cases of UC, SBS17 (unknown etiology) was evident. SBS17 was also dominant in one case where the TMB was 13 mutations per MB and the patient died within 3 months of diagnosis. A somatic case of homologous recombination deficiency, with no causative genetic alteration identified, was evident in a further patient receiving maintenance rituximab for a coexisting stage 4 mantle cell lymphoma. Conclusions: WGS may provide additional biological information in CCA particularly in patients with underlying inflammatory disorders, where TP53 mutations are prevalent and mutational signatures are distinct.