Molecular Characterization of Undifferentiated-Type Gastric Carcinoma

Abstract

As the great majority of gastric cancers develop histologically differentiated, and a significant proportion of differentiated-type carcinomas progress to become undifferentiated, both histological types are likely to share several common genetic abnormalities, such as p53 mutations at advanced stages. However, a subset of gastric cancers develop as undifferentiated carcinomas, including signet-ring cell carcinoma and poorly differentiated adenocarcinoma, and the molecular pathogenesis of this tumor type remains largely unknown. To characterize the molecular features of undifferentiated-type gastric carcinomas that developed as undifferentiated-type, we examined for p53, APC, and epithelial (E)-cadherin gene mutations, microsatellite alterations including loss of heterozygosity (LOH) and microsatellite instability (MSI), and hypermethylation of the E-cadherin gene promoter in 26 early undifferentiated gastric carcinomas, consisting of 14 signet-ring cell carcinomas and 12 poorly differentiated adenocarcinomas. E-cadherin expression was evaluated immunohistochemically. p53 mutations were detected in only one poorly differentiated adenocarcinoma sample (3.8%; 1/26), whereas no APC or E-cadherin mutations were found. LOH was present only at D8S261 on the short arm of chromosome 8 in 2 of 14 (14%) informative tumors, both of which were poorly differentiated adenocarcinomas, and MSI was not observed in any of the tumors. No signet-ring cell carcinomas have been found to carry gene mutations or microsatellite alterations. In contrast, hypermethylation of the E-cadherin promoter occurred in 69% (18/26) of the tumors; 57% (8/14) of signet-ring cell carcinomas, and 83% (10/12) of poorly differentiated adenocarcinomas, and was significantly associated with loss or reduced expression of E-cadherin. Thus, whereas tumor suppressor gene mutation, LOH, and MSI were less common in undifferentiated-type early gastric carcinomas, epigenetic inactivation of E-cadherin via promoter hypermethylation may be an early critical event in the development of undifferentiated tumors.

A protein and mRNA expression-based classification of gastric cancer

“…A few studies have reported TP53 mutations as a late event in the development of poorly cohesive gastric cancer, which was our rationale for using cases of 'gastric cancer with aberrant E-cadherin expression' before 'gastric cancer with aberrant p53 expression' to assign a group for clinical applicability. 47,48 The frequency of this subset best correlates with the gastric cancer-stable group (genomically stable) reported in the Cancer Genome Atlas, 6 and the microsatellite stable/epithelial-mesenchymal transition subtype of the Asian Cancer Research Group. 7 This group constituted 21% of the entire cohort similar to the 20% and 15.3% reported in these studies.…”

“Crawling-type” adenocarcinoma of the stomach: a distinct entity preceding poorly differentiated adenocarcinoma

“…In previous reports, the frequency of p53 mutation in the early phase was 37-41 % in welldifferentiated adenocarcinomas, and only 0-4 % in poorly differentiated adenocarcinomas [26][27][28][29]. These reports indicate that p53 mutation is an early event in tumorigenesis for well-differentiated adenocarcinoma, while the mutation is rare in poorly differentiated adenocarcinoma.…”

RASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cancer

“…(Tamura, 2002). Ecadherin is inactivated through any combinations of gene mutation, loss of heterozygosity (LOH), and promoter hypermethylation in gastric cancer, especially that of undifferentiated histological type (Tamura et al, 2001). Recent evidences of frequent silencing of hMLH1, p16, RUNX3, and other tumour suppressor and tumour-related genes by promoter hypermethylation suggests that epigenetic alterations play the most important role in gastric carcinogenesis (Tamura, 2004).…”