PDF(Sci-hub)
Abstract：
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.
摘要：
具有肠母细胞分化的胃腺癌（GA）是预后不良的胃癌的一个子集。GA的癌症基因组图谱（TCGA-STAD）的RNA-Seq数据揭示了SALL4之间的正相关性，和DNMT3A表达。这里,我们对GA进行了免疫组化分析，以阐明DNMT3A表达的临床病理意义及其与肠母细胞分化的相关性。在分析的346例孤立性GA中，120(34.7%)显示明确的DNMT3A核表达。DNMT3A表达与Lauren肠型相关,乳头状和管状结构，高频率的淋巴和血管侵袭，和淋巴结转移(每个，P<0.01)。Log-rank检验显示，DNMT3A阳性病例复发频率更高，易患肝转移（P<0.01），总体生存率和无复发生存率较差（每个，P<0.05)。关于分子亚型的替代标记，DNMT3A阳性病例更频繁地显示p53过表达(P<0.001)。与TCGA数据分析结果一致，DNMT3A阳性病例表现为肠母细胞形态(18.3%vs.0.9%，P<0.001）并表达肠母细胞标记，SALL4（32.5%vs.3.1%,P<0.001）和磷脂酰肌醇蛋白聚糖-3（22.5%vs.4.4%,P<0.001）比DNMT3A阴性病例更常见。此外,显示肠母细胞分化的GAs，形态学或免疫组织化学，DNMT3A的表达频率和强度明显高于常规GA（P<0.001）。我们的发现表明DNMT3A是这种常规治疗难治性癌症亚型的潜在治疗靶点。
