Somatic mutational profiles of stage II and III gastric cancer according to tumor microenvironment immune type

Abstract We aimed to determine somatic mutational profiles of stage II/III gastric cancers (GCs) according to their tumor microenvironment immune types (TMITs), which classify cancer based on co‐assessment of PD‐L1 expression and CD8 + tumor infiltrating lymphocytes. Eighty patients with stage II/III GC were classified as follows: TMIT I (PD‐L1 + /CD8 High ), TMIT II (PD‐L1 − /CD8 Low ), TMIT III (PD‐L1 + /CD8 Low ), and TMIT IV (PD‐L1 − /CD8 High ). Deep targeted sequencing using a panel of 170 cancer‐related genes was performed on an Illumina HiSeq‐2500 system. Most frequently mutated genes included GNAQ (41.3%), TP53 (38.8%), CREBBP (35.0%), and MAP3K1 (35.0%). PIK3CA mutations were observed more frequently in TMIT I (45.8%) and III (66.7%), than in II (12.0%) and IV (8.0%). Other genes with enriched mutations within TMIT I included ATM (33.3%), BRCA2 (33.3%), MAP3K4 (29.2%), and FLT4 (25.0%). FGFR3 , MAP3K1, and RUNX1 mutations were more frequently found in TMIT II. TMIT III had a unique somatic mutation profile harboring enriched mutations of histone modifiers including CREBBP and KMT2A , and we found FGFR2 amplification exclusively within TMIT IV. Fuzzy clustering analysis based on somatic mutation frequencies identified a hypermutated group (cluster 1) and a hypomutated group (cluster 2). Cluster 1 had significant associations with TMIT I, EBV + GCs, and MSI‐H GCs ( P = .023, .014, and .004), and had better overall survival ( P = .057) than Cluster 2. TMIT I, EBV + , and MSI‐H GCs were estimated to have greater tumor mutational burden ( P = .023, .003, and .015). By analyzing somatic mutation profiles according to TMIT classification, we identified TMIT‐specific genetic alterations that provide clues for biological linkage between GC genetics and microenvironment.