Genomic characterization of cholangiocarcinoma with autoimmune etiologies.

Abstract

531 Background: Chronic inflammation from autoimmune conditions is a well-recognized risk factor for cholangiocarcinoma in the Western world. Cholangiocarcinomas in the setting of autoimmune disease have earlier age-of-onset and worse prognosis. Currently, their biology is inadequately understood, and the risks and benefits of immunotherapy approaches in this population are unknown. We describe the clinical and genomic characteristics of a cohort of cholangiocarcinoma patients with autoimmune etiologies. Methods: In a prospective cohort of 43 patients with mismatch repair proficient cholangiocarcinoma, we performed whole-genome sequencing (WGS, n=43) and total RNA sequencing (RNA-seq, n=28). Among this cohort, 15 patients had cholangiocarcinoma with autoimmune etiologies, including primary sclerosing cholangitis (PSC, n=10), ulcerative colitis (UC, n=6), ankylosing spondylitis (AS, n=1), and Crohn’s disease (CD, n=3). Results: Patients with autoimmune conditions had a 6.46-fold higher Tumour Mutational Burden (TMB) ( P = 0.0010), characterized by higher load of indels ( P = 0.0006). TMB was greater than 10 mutations per megabase in 4 of 15 patients with autoimmune conditions and 0 of 28 patients in those without ( P = 0.0111). Autoimmune patients exhibited an enrichment in mutational signatures 5 ( P = 0.0154), 17 ( P = 0.0004), 28 ( P = 0.028) and 30 ( P = 0.0164). Despite a higher TMB, autoimmune tumours have similar patterns of driver mutations. Differential gene expression of bulk RNA-seq analysis revealed comparable transcriptional markers of immunogenicity, but autoimmune cancers are enriched in pathways involved with cell proliferation and cell-cycle checkpoints. One patient with PSC/UC was treated with gemcitabine, cisplatin, and durvalumab with a partial response, while another with Crohn’s disease had durvalumab added to gemcitabine and cisplatin at progression and experienced stable disease with a decreased CA19-9. Neither experienced immune-related adverse events. Conclusions: Cholangiocarcinoma with autoimmune etiologies have unique genomic features characterized by elevated TMB. Chemo-immunotherapy may be a novel therapeutic option in this subgroup of patients and warrants further study.