Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Mod Pathol. 2016 Feb;29(2):182-93. doi: 10.1038/modpathol.2015.144. Epub 2016 Jan 15.
Gastric cancers are the most frequent gastric malignancy and usually arise in the sequence of Helicobacter pylori-associated chronic gastritis. CpG methylation is a central mechanism of epigenetic gene regulation affecting cancer-related genes, and occurs early in gastric carcinogenesis. DNA samples from non-metaplastic gastric mucosa with variable levels of gastritis (non-metaplastic mucosa), intestinal metaplasia, or gastric cancer were screened with methylation arrays for CpG methylation of cancer-related genes and 30 gene targets were further characterized by high-definition bisulfite next-generation sequencing. In addition, data from The Cancer Genome Atlas were analyzed for correlation of methylation with gene expression. Overall, 13 genes had significantly increased CpG methylation in gastric cancer vs non-metaplastic mucosa (BRINP1, CDH11, CHFR, EPHA5, EPHA7, FGF2, FLI1, GALR1, HS3ST2, PDGFRA, SEZ6L, SGCE, and SNRPN). Further, most of these genes had corresponding reduced expression levels in gastric cancer compared with intestinal metaplasia, including novel hypermethylated genes in gastric cancer (FLI1, GALR1, SGCE, and SNRPN), suggesting that they may regulate neoplastic transformation from non-malignant intestinal metaplasia to cancer. Our data suggest a tumor-suppressor role for FLI1 in gastric cancer, consistent with recently reported data in breast cancer. For the genes with strongest methylation/expression correlation, namely FLI1, the expression was lowest in microsatellite-unstable tumors compared with other gastric cancer molecular subtypes. Importantly, reduced expression of hypermethylated BRINP1 and SGCE was significantly associated with favorable survival in gastric cancer. In summary, we report novel methylation gene targets that may have functional roles in discrete stages of gastric carcinogenesis and may serve as biomarkers for diagnosis and prognosis of gastric cancer.
胃癌是最常见的胃部恶性肿瘤，通常源于幽门螺杆菌相关的慢性胃炎。CpG 甲基化是一种影响癌症相关基因的表观遗传基因调控的核心机制，发生在胃癌发生的早期。使用甲基化阵列筛选具有不同程度胃炎（非化生黏膜）、肠化生或胃癌的非化生胃黏膜的 DNA 样本，对 30 个基因靶标进行了进一步的高分辨率亚硫酸氢盐下一代测序。此外，还对癌症基因组图谱的数据进行了分析，以确定甲基化与基因表达的相关性。总体而言，与非化生黏膜相比，胃癌中有 13 个基因的 CpG 甲基化显著增加（BRINP1、CDH11、CHFR、EPHA5、EPHA7、FGF2、FLI1、GALR1、HS3ST2、PDGFRA、SEZ6L、SGCE 和 SNRPN）。此外，与肠化生相比，这些基因在胃癌中的表达水平大多降低，包括胃癌中新型高甲基化基因（FLI1、GALR1、SGCE 和 SNRPN），提示它们可能调节从非恶性肠化生到癌症的肿瘤转化。我们的数据表明 FLI1 在胃癌中具有肿瘤抑制作用，与最近在乳腺癌中报道的数据一致。对于甲基化/表达相关性最强的基因，即 FLI1，与其他胃癌分子亚型相比，在微卫星不稳定肿瘤中表达最低。重要的是，高甲基化 BRINP1 和 SGCE 的表达降低与胃癌的良好生存显著相关。总之，我们报告了一些新的甲基化基因靶标，它们可能在胃癌发生的不同阶段发挥功能作用，并可能作为胃癌诊断和预后的生物标志物。
