Characterization of tumor mutation burden (TMB) in gastrointestinal (GI) cancers.

Abstract

530Background: GI cancers are generally insensitive to immune checkpoint inhibitors (ICIs). Response to ICIs has been shown to correlate with TMB. Herein, we attempt to quantify TMB in GI cancers and its correlation with PD-1/PDL-1 expression. Methods: Tumor from various GI sites: right-sided and left-sided colon cancers (RT and LT), rectal cancer (RC), small bowel adenocarcinoma (SBA), gastric adenocarcinoma (GA), anal cancer (SCCA), hepatocellular carcinoma (HCC), esophageal adenocarcinoma and squamous cell carcinoma (EA and E-SCC), biliary cancer (BC), pancreatic adenocarcinoma (PA), and pancreatic neuroendocrine tumors (PNET), were analyzed by NextGen sequencing. TMB was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. MSI was assessed by fragment analysis. Correlation of PD-1/PD-L1 expression with TMB was calculated by student’s t test. Results: In total, 1375 tumors were examined. Among the different GI cancer types, RT and LT had the highest TMB (mean: 11.6 and 9.9 mutations [mut]/megabase [MB]), whereas BC and PA had the lowest levels (mean: 5.7 and 4.9 mut/MB) (Table). Overall primary tumors had higher TMB than metastases (mean: 8.3 vs. 6.5 mut/MB, p = 0.037). Using a cut-off of 17 mut/MB to define high vs. low TMB, high TMB was seen in all 24 MSI-H and 2 MSS colon tumors with POLE mutations, but not in other MSS colon tumors (n = 325, p < 0.0001). Similarly, among 6 GA tumors tested for MSI, high TMB was seen in 2 MSI-H while low TMB was seen in the 4 MSS tumors. Overall high TMB was seen most frequently in RT (12%), GA (11%), and SCCA (8%), and least frequently in PA (1.3%) and E-SCC (0%). PD-1 correlated with TMB in some tumor types (RT and RC), as did PD-L1 (RT and HCC). Conclusions: TMB varies among GI cancers. Forthcoming prognostic analysis to assess the correlation between TMB and response to ICIs in GI cancers is underway. [Table: see text]