Abstract 82: Molecular characterization of gallbladder cancer
Authors: Giraldo Nicolas A. , Mohanty Abhinita , Vanderbilt Chad , Brannon Rose , Benayed Ryma , Vakiani Efsevia , Abou-Alfa Ghassan , Harding James , Dika Imane El , Schultz Nikolaus , Li Bob , Berger Michael F. , Ladanyi Marc , O'Reilly Eileen , Jarnagin William , Basturk Olca , Arcila Maria 
Published: June 2022

Abstract
Introduction: Gallbladder carcinomas (GBC) are rare and aggressive neoplasms. Previous studies in small GBC cohorts have suggested potential molecular alterations associated with poor prognosis, however, a comprehensive understanding of the recurrent genetic events in this cancer type is very limited. In this study, we aim to characterize in detail the recurrent molecular alterations in GBC and their association with pathologic and clinical characteristics.
Material and Methods: We studied the prevalence of somatic mutations and copy number alterations (CNA) in n=244 GBC samples (54% primary, 56% metastatic), collected from 2014 to 2021, and sequenced with the targeted NGS panel MSK-IMPACT. We assessed the correlation of the recurrent genomic variants with several pathologic (e.g., T stage, N stage, grade, histologic subtypes) and clinical characteristics (e.g., clinical stage) using Fisher's exact test. We also used Cox Proportional-Hazards modeling to assess the correlation between genetic variants and patient overall survival (OS).
Results: The most common histologic subtypes in this GCB cohort included adenocarcinomas NOS (83%), carcinomas with squamous differentiation (9%), high-grade carcinomas (4%), and carcinomas with neuroendocrine differentiation (3%). Most patients were diagnosed with stage IV (65%) and stage III (11%) disease at the time of biopsy/resection, and the mean OS survival was 29.4 months. The most commonly mutated genes were TP53 (59%), SMAD4 (21%), ARID1A (19%), PIK3CA (10%), KRAS (7%), and ERBB2 (7%). Potentially recurrent oncogenic CNAs included deep deletions in CDKN2A (14%) and CDKN2B (14%), and amplifications in MDM2 (12%), ERBB2 (10%), CCNE1 (9%), MYC (7%), and KRAS (7%). RB1, PBRM1, and CTNNB1 variants were more common in cases with neuroendocrine differentiation, whereas alterations in IKZF1 and AGO2 were enriched in cases with squamous differentiation. The most significant event associated with shorted OS was chromosome 12q13-15 amplification i.e., CDK4 p=0.03 HR=2 [95% CI 1-3.6] and MDM2 p=0.05 HR=1.6 [1-2.5], which associated with a median OS of 20 months (vs. 34 months in the wild-type). Genomic variants associated with longer OS included ERBB2 (p=0.006 HR=0.2 [0.06-0.6]), KMT2C (p=0.03 HR=0.2 [0.1-0.9]) and KMT2D (p=0.01 HR=0.2 [0.04-0.7]) mutations, and CDK12 amplification (p=0.04 HR=0.4 [0.2-0.96]). Although ERBB2 amplification was not associated with prognosis, co-amplification of CDK12 and ERBB2 (chromosome 17q12) was frequently observed (Pearson correlation r=0.8).
Conclusions: This large-scale genomic analysis reveals recurrent genomic events potentially associated with prognosis in GBC, including single nucleotide variants in ERBB2, KMT2C, and KMT2D, in addition to CNAs in chromosome 12q13-15 and 17q12 regions. This effort will continue to include a detailed analysis of recurrent structural variants, loss of heterozygosity loci, and analysis of the microbiota in this GBC cohort.
Citation Format: Nicolas A. Giraldo, Abhinita Mohanty, Chad Vanderbilt, Rose Brannon, Ryma Benayed, Efsevia Vakiani, Ghassan Abou-Alfa, James Harding, Imane El Dika, Nikolaus Schultz, Bob Li, Michael F. Berger, Marc Ladanyi, Eileen O'Reilly, William Jarnagin, Olca Basturk, Maria Arcila. Molecular characterization of gallbladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 82.