Background:

Gastric adenocarcinomas are histologically categorized into intestinal (IS) and diffuse types (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, 296 gastric adenocarcinomas with annotated histology (DS [n = 181]; IS [n = 115]) were analyzed. Patients with DS were younger than those with IS (mean age: 58y [DS] vs. 67y [IS], p < 0.0001). The majority of patients with DS were female (51% [DS] vs. 35% [IS], p = 0.0051). Most frequently mutated genes in IS were ARID1A (70%), TP53 (57%), ATRX (20%), NF1 (15%); whereas the most frequent mutations in DS were TP53 (45%), ARID1A (30%), CDH1 (12%), BAP1 (7%), and RNF43 (5%). IS had a higher rate of ARID1A (70% vs. 30%, p=0.025), ATRX (20% vs. 0, p=0.028), NF1 (15% vs. 0, p=0.005), APC (13% vs. 2%, p=0.007), CDKN2A (13% vs. 0, p=0.008) and KRAS (11% vs. 2%, p=0.017) mutations; whereas DS had a higher rate of CDH1 (12% vs. 0, p = 0.0049). There was no difference in PD-L1 tumor expression (DS: 3%; IS: 9%). IS, when compared to DS, exhibited higher overexpression of TOP2A (95% vs. 56%, p < 0.0001), TS (67% vs. 30%, p < 0.0001), RRM1 (50% vs. 22%, p < 0.001), and Her2/neu (15% vs. 1%, p < 0.0001), as well as greater Her2 amplification (29% vs. 3%, p < 0.0001). MSI was seen in 5% of DS and 13% of IS, whereas high-TML is seen in 4% of DS and 8% of IS.

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.