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

• Type of Material: Article
• Authors: Kabir Mody, Mayo Clinic; Prerna Jain, Tempus Labs Inc; Sherif M El-Refai, Tempus Labs Inc; Nilofer S Azad, Johns Hopkins University; Daniel J Zabransky, Johns Hopkins University; Marina Baretti, Johns Hopkins University; Rachna T Shroff, University of Arizona; Katiee R Kelley, University of California San Francisco; Anthony B El-Khouiery, USC Norris Comprehensive Cancer Center; Adam J Hockenberry, Tempus Labs Inc; Denise Lau, Tempus Labs Inc; Gregory Lesinski, Emory University; Mark Yarchoan, Johns Hopkins University
• Language: English
• Date: 2022-06-01
• Publisher: LIPPINCOTT WILLIAMS & WILKINS
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by American Society of Clinical Oncology
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1200/PO.21.00510
• Title of Journal or Parent Work: JCO PRECISION ONCOLOGY
• Volume: 6
• Start Page: e2100510
• End Page: e2100510
• Keywords: Life Sciences & Biomedicine; Oncology; Science & Technology; PEMBROLIZUMAB; CHOLANGIOCARCINOMA
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

PURPOSEBiliary 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.METHODSWe 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.RESULTSWe analyzed 454 samples of BTC, of which the most commonly detected alterations were TP53 (42.5%), CDKN2A (23.4%), ARID1A (19.6%), BAP1 (15.5%), KRAS (15%), CDKN2B (14.2%), PBRM1 (11.7%), IDH1 (11.7%), TERT (8.4%), KMT2C (10.4%) and LRP1B (8.4%), and FGFR2 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 FGFR2 rearrangements and BAP1 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 TP53, KRAS, and ATM mutations. Multiple common driver genes, including TP53, FGFR2, IDH1, TERT, BRAF, and BAP1, were individually associated with unique BTC immune microenvironments.CONCLUSIONBTC 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.