Molecular characterization of intestinal (IS) and diffuse subtypes (DS) of gastric adenocarcinomas.

Abstract

60 Background: Gastric adenocarcinomas are histologically categorized into IS and DS. TCGA categorization suggests that IS is more common in tumors arising via the chromosomal instability pathway and DS is more common in genomically stable tumors. However, molecular differences between these subtypes are not well understood. Methods: Gastric adenocarcinomas were examined using NextGen sequencing (MiSeq platform on 47 genes or NextSeq on 592 genes), protein expression, and gene amplification techniques. For tumors sequenced with NextSeq, tumor mutational load (TML) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated on known MSI loci in target regions. Chi-square and t-tests were used for comparative analyses. Results: In total, 268 gastric adenocarcinomas with annotated histology (DS [n = 144]; IS [n = 124]) were analyzed. Patients with DS were younger than those with IS (mean age: 27y [DS] vs. 65y [IS], p < 0.0001). The majority of patients with DS were female (56% [DS] vs. 35% [IS], p = 0.0004). Most frequently mutated genes in DS were TP53 (44%), ARID1A (37%) , CDH1 (14%), BAP1 (8%), and PIK3CA (5%); whereas the most frequent mutations in IS were ARID1A (57%), TP53 (51%), CDKN2A (13%), MUTYH (13%), and PIK3CA (12%). IS had a higher rate of APC mutations (10% vs. 2%, p = 0.04), whereas DS had a higher rate of CDH1 (14% vs. 2%, p = 0.01). There was no difference in PD-L1 tumor expression (DS: 4%; IS: 8%). IS, when compared to DS, exhibited higher overexpression of TOP2A (90% vs 50%, p < 0.0001), TS (58% vs 28%, p < 0.0001), RRM1 (47% vs 22%, p = 0.0006), and Her2/neu (14% vs 1%, p < 0.0001), and greater Her2 amplification (19% vs 2%, p < 0.0001). Microsatellite instability was not detected in DS, and there was a trend toward a higher frequency of MSI-high in IS (6% [IS] vs. 0% [DS], p = 0.06), as well as a higher mean TML (10.3 vs. 6.6 mutation/megabase, p = 0.01). Conclusions: Significant molecular differences between IS and DS gastric adenocarcinomas were observed, a finding that indicates different carcinogenic pathways and biology, as well as potential differences in response to therapy. Low frequency mutations in several druggable genes may provide therapeutic options.