Abstract C106: New therapeutic strategy by integrative analysis of germline, somatic genetic alterations and tumor mutational burden (TMB) in deficient mismatch repair (dMMR) gastric cancer

Abstract

Abstract Background: The prevalence of microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) and Lynch syndrome with germline MMR mutations in gastric cancer (GC), are 5% and 1.6%, respectively. According to TCGA data, BRCA mutations, one of DNA Damage Response (DDR) pathway genes, occur in about 10% of GC (BRCA1 2.7%, BRCA2 7%), but the incidence is increased in MSI-H GC (BRCA1 16%, BRCA2 34%). Our study focused on integrative analysis of germline and somatic genetic alterations according to dMMR status for new therapeutic strategy. Methods: Retrospective comparison analysis of advanced gastric cancer patients between 20 dMMR and 48 proficient MMR (pMMR) was performed using targeted next-generation sequencing (NGS) for somatic genetic alterations and Global Screening Array (Illumina©) to detect germline alterations. PD-L1 expression using immunohistochemistry 22C3 pharmDx was evaluated. TMB was calculated based on somatic nonsynonymous missense mutations and DDR genes were compared. DNA pyrosequencing was used to determine promoter methylation status of MLH1 gene. Results: dMMR was associated with higher TMB (median 64 mut/Mb, IQR 54 -73 vs. 42 mut/Mb, IQR 34 - 50, P<0.001), but not with PD-L1 overexpression (p=0.7). The promoter methylation of MLH1 gene was observed in 50% of total dMMR (n=10/20), and had higher TMB (73 mut/Mb, IQR 63 - 88) compared to MLH1 unmethylated dMMR group (57 mut/Mb, IQR 52 – 62) (P<0.001). Germline or somatic gene alterations associated with MMR expression were not different between dMMR and pMMR (p=0.7, p=0.3, respectively). Somatic DDR alterations were elevated in dMMR compared to pMMR (median 45 mut vs. 36 mut, P=0.004), and in high TMB group with > 50 mut/Mb (n=29, p<0.001). In dMMR group, highly mutated ATM (E166D), CDK12 (E711Q, E716Q, R712T, R713T), PARLB2 (Q559R), STAG2 (V343L) and SMARCA4 (A314P) were observed, implying dMMR GC patients’ sensitivity to PARP inhibitor. Conclusions: There were no differences in germline variations according to MMR status, suggesting no beneficial information from germline testing in advanced GC without family history. However, we observed elevated DDR gene alterations in dMMR GC with higher TMB. These findings may be applicable in strategies to combine immune checkpoint inhibitors with PARP inhibitors in patient with dMMR and/or higher TMB GC. Citation Format: Garden Lee, Jihyun Hwang, Sejung Park, Woo Sun Kwon, Jinseul Park, Jii Bum Lee, Choong-kun Lee, Hyun Cheol Chung, Sun Young Rha. New therapeutic strategy by integrative analysis of germline, somatic genetic alterations and tumor mutational burden (TMB) in deficient mismatch repair (dMMR) gastric cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C106. doi:10.1158/1535-7163.TARG-19-C106