DNMT3A overexpression is associated with aggressive behavior and enteroblastic differentiation of gastric adenocarcinoma.

Gastric adenocarcinoma (GA) with enteroblastic differentiation is a subset of gastric cancer with poor prognosis. RNA-Seq data of The Cancer Genome Atlas of GA (TCGA-STAD) revealed a positive correlation between SALL4, a representative enteroblastic marker, and DNMT3A expression. Here, we conducted immunohistochemical analysis of GA to clarify the clinicopathological significance of DNMT3A expression and its correlation with enteroblastic differentiation. Of the 346 cases of solitary GA analyzed, 120 (34.7%) showed unequivocal DNMT3A nuclear expression. DNMT3A expression was associated with Lauren's intestinal type, papillary and tubular architectures, high frequency of lymphatic and vascular invasion, and lymph node metastasis (each, P < 0.01). Log-rank test revealed that DNMT3A-positive cases recurred more frequently with a predilection for liver metastasis (P < 0.01) and showed poorer overall and recurrence-free survival (each, P < 0.05). With respect to surrogate markers of molecular subtypes, DNMT3A-positive cases more frequently showed p53 overexpression (P < 0.001). Consistent with the results of TCGA data analysis, DNMT3A-positive cases exhibited enteroblastic morphology (18.3% vs. 0.9%, P < 0.001) and expressed enteroblastic markers, SALL4 (32.5% vs. 3.1%, P < 0.001) and glypican-3 (22.5% vs. 4.4%, P < 0.001) more frequently than did DNMT3A-negative cases. Additionally, GAs showing enteroblastic differentiation, morphologically or immunohistochemically, expressed DNMT3A with significantly higher frequency and intensity than did conventional GAs (P < 0.001). Our findings suggest DNMT3A as a potential therapeutic target for this conventional therapy-refractory cancer subtype.