Analysis of clinicopathological and molecular features of crawling-type gastric adenocarcinoma

Abstract

Background: Crawling-type adenocarcinoma (CRA) is an important gastric cancer (GC) subtype that exhibits a specific histological pattern and has characteristic clinicopathological findings. Despite its characteristic histology, little is known about the molecular characteristics of CRA. Methods: We examined 254 GC cases, including 51 cases of CRA and 126 cases having conventional differentiated adenocarcinomas (CDAs). Results for immunohistochemistry (mucin phenotype; Muc5AC, Muc6, Muc2 and CD10, CDX-2, MLH-1 and β-catenin), mutation analysis ( TP53 , KRAS and BRAF ), microsatellite instability (BAT25, BAT26, D2S123, D5S346 and D17S250), DNA methylation status by a two-panel method ( RUNX3 , MINT31 , LOX, NEUROG1 , ELMO1 and THBD ), MLH-1 promoter methylation, and allelic imbalance (AI; 1p, 3p, 4p, 5q, 8p, 9p, 13q, TP53, 18q and 22q) were examined. Results: CRAs were more likely to occur in the middle third of the stomach, in younger patients and to be macroscopically depressed. Nuclear accumulation of β-catenin and loss of MLH-1 expression were less frequent among CRA cases compared to CDA cases. At a molecular level, CRA is often characterized by the deletion mutation c.529_546 (18-base pair deletion at codon 177-182 in exon 5), in the TP53 gene (10 cases). Although the low methylation epigenotype was significantly more frequent for CRAs compared to CDAs, multiple AIs were more often seen in CRAs relative to CDAs. Conclusions: The results demonstrated that TP53 mutations, particularly c.529_546del, and multiple AIs are closely associated with CRA carcinogenesis. Our results suggest that CRA is an independent entity of GC in terms of clinicopathologic and molecular findings.