Genomic Signatures of Gastric Adenocarcinoma By Tumor Location-Modified Laurén Classification: Highlighting the Molecular Heterogeneity of Mixed-Type Tumors.

Abstract

Tumor location-modified Laurén classification (mLC) of gastric adenocarcinoma (GAC) integrates Laurén histologic subtype and tumor location. mLC has been previously proposed and clinically validated as an independent prognostic indicator. However, the genomic signatures of GAC within the mLC system are unknown, particularly among mixed tumors. This study aimed to characterize the genomic signatures of GAC using the mLC system and to elucidate the genomic patterns of morphologically distinct components of mixed tumors. Treatment-naive GAC tumors were classified according to the mLC into 4 subgroups: proximal-intestinal, distal-intestinal, diffuse, and mixed types. The latter included 2 components: mixed-intestinal and mixed-signet ring. Sections of formalin-fixed, paraffin-embedded tissues were subjected to next-generation targeted sequencing. Tumors from 103 patients were included. The proximal-intestinal (n=28), distal-intestinal (n=34), and diffuse (n=25) subgroups exhibited distinct genomic alteration patterns. Among microsatellite stable cases, the proximal-intestinal subgroup was enriched for alterations in TP53, ERBB2, CDKN2A, and SMAD4, whereas the diffuse subgroup had significantly more alterations in CDH1 and ARID1A. The distal-intestinal subgroup had significantly more TP53 alterations than the diffuse subgroup. At the pathway level, both the proximal-intestinal and distal-intestinal subgroups had significantly higher TP53 pathway alterations than the diffuse subgroup. The proximal-intestinal subgroup had a significantly higher percentage of cell cycle, PI3K, and TGF-ß alterations than the diffuse subgroup. Both the mixed-intestinal and mixed-signet ring components of mixed tumors (n=16) exhibited alteration patterns that partially resembled those of the distal-intestinal and diffuse subgroups. The matched components of mixed tumors shared some, but not all, alterations. Overall, this study demonstrated distinct genomic patterns among the proximal-intestinal, distal-intestinal, and diffuse subgroups in the mLC system. The gene alteration patterns in the mixed-intestinal and mixed-signet ring components of mixed tumors exhibited partial similarities with both the distal-intestinal and diffuse subgroups. Furthermore, this study emphasizes how employing a multisampling approach can uncover the molecular heterogeneity of histologically distinct components of mixed-type tumors.