Clinical, Genomic, and Transcriptomic Data Profiling of Biliary Tract Cancer Reveals Subtype-Specific Immune Signatures.

Abstract

Biliary tract cancers (BTCs) are aggressive cancers that carry a poor prognosis. An enhanced understanding of the immune landscape of anatomically and molecularly defined subsets of BTC may improve patient selection for immunotherapy and inform immune-based combination treatment strategies. We analyzed deidentified clinical, genomic, and transcriptomic data from the Tempus database to determine the mutational frequency and mutational clustering across the three major BTC subtypes (intrahepatic cholangiocarcinoma [IHC], extrahepatic cholangiocarcinoma, and gallbladder cancer). We subsequently determined the relationship between specific molecular alterations and anatomical subsets and features of the BTC immune microenvironment. We analyzed 454 samples of BTC, of which the most commonly detected alterations were <i>TP53</i> (42.5%), <i>CDKN2A</i> (23.4%), <i>ARID1A</i> (19.6%), <i>BAP1</i> (15.5%), <i>KRAS</i> (15%), <i>CDKN2B</i> (14.2%), <i>PBRM1</i> (11.7%), <i>IDH1</i> (11.7%), <i>TERT</i> (8.4%), <i>KMT2C</i> (10.4%) and <i>LRP1B</i> (8.4%), and <i>FGFR2</i> fusions (8.7%). Potentially actionable molecular alterations were identified in 30.5% of BTCs including 39.1% of IHC. Integrative cluster analysis revealed four distinct molecular clusters, with cluster 4 predominately associated with <i>FGFR2</i> rearrangements and <i>BAP1</i> mutations in IHC. Immune-related biomarkers indicative of an inflamed tumor-immune microenvironment were elevated in gallbladder cancers and in cluster 1, which was enriched for <i>TP53</i>, <i>KRAS</i>, and <i>ATM</i> mutations. Multiple common driver genes, including <i>TP53</i>, <i>FGFR2</i>, <i>IDH1</i>, <i>TERT</i>, <i>BRAF</i>, and <i>BAP1</i>, were individually associated with unique BTC immune microenvironments. BTC subtypes exhibit diverse DNA alterations, RNA inflammatory signatures, and immune biomarkers. The association between specific BTC anatomical subsets, molecular alterations, and immunophenotypes highlights new opportunities for therapeutic development.