Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fucheng Rd, Haidian District, Beijing, 100142, People's Republic of China.
Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, 90095, USA.
BMC Cancer. 2021 May 25;21(1):610. doi: 10.1186/s12885-021-08389-0.
Few studies have examined prognostic outcomes-associated molecular signatures other than overall survival (OS) for gastric cancer (GC). We aimed to identify DNA methylation biomarkers associated with multiple prognostic outcomes of GC in an epigenome-wide association study.
Based on the Cancer Genome Atlas (TCGA), DNA methylation loci associated with OS (n = 381), disease-specific survival (DSS, n = 372), and progression-free interval (PFI, n = 383) were discovered in training set subjects (false discovery rates < 0.05) randomly selected for each prognostic outcome and were then validated in remaining subjects (P-values < 0.05). Key CpGs simultaneously validated for OS, DSS, and PFI were further assessed for disease-free interval (DFI, n = 247). Gene set enrichment analyses were conducted to explore the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways simultaneously enriched for multiple GC prognostic outcomes. Methylation correlated blocks (MCBs) were identified for co-methylation patterns associated with GC prognosis. Based on key CpGs, risk score models were established to predict four prognostic outcomes. Spearman correlation analyses were performed between key CpG sites and their host gene mRNA expression.
We newly identified DNA methylation of seven CpGs significantly associated with OS, DSS, and PFI of GC, including cg10399824 (GRK5), cg05275153 (RGS12), cg24406668 (MMP9), cg14719951(DSC3), and cg25117092 (MED12L), and two in intergenic regions (cg11348188 and cg11671115). Except cg10399824 and cg24406668, five of them were also significantly associated with DFI of GC. Neuroactive ligand-receptor interaction pathway was suggested to play a key role in the effect of DNA methylation on GC prognosis. Consistent with individual CpG-level association, three MCBs involving cg11671115, cg14719951, and cg24406668 were significantly associated with multiple prognostic outcomes of GC. Integrating key CpG loci, two risk score models performed well in predicting GC prognosis. Gene body DNA methylation of cg14719951, cg10399824, and cg25117092 was associated with their host gene expression, whereas no significant associations between their host gene expression and four clinical prognostic outcomes of GC were observed.
We newly identified seven CpGs associated with OS, DSS, and PFI of GC, with five of them also associated with DFI, which might inform patient stratification in clinical practices.
很少有研究除总生存期 (OS) 以外的预后相关分子特征来研究胃癌 (GC)。我们旨在通过全基因组关联研究鉴定与 GC 多种预后结局相关的 DNA 甲基化生物标志物。
基于癌症基因组图谱 (TCGA)，我们在训练集 (每个预后结局随机选择 n = 381) 中发现了与 OS、疾病特异性生存 (DSS，n = 372) 和无进展间隔 (PFI，n = 383) 相关的 DNA 甲基化位置，并在其余对象中进行了验证 (P 值 < 0.05)。同时验证 OS、DSS 和 PFI 的关键 CpG 进一步评估了疾病无复发生存期 (DFI，n = 247)。我们进行了基因集富集分析，以探索与多个 GC 预后结局同时富集的基因本体论和京都基因与基因组百科全书途径。我们鉴定了与 GC 预后相关的共甲基化模式的甲基化相关块 (MCB)。基于关键 CpG，我们建立了风险评分模型来预测四个预后结局。我们进行了 Spearman 相关分析，以研究关键 CpG 位点与其宿主基因 mRNA 表达之间的关系。
我们新鉴定了与 GC 的 OS、DSS 和 PFI 显著相关的七个 CpG 的 DNA 甲基化，包括 cg10399824 (GRK5)、cg05275153 (RGS12)、cg24406668 (MMP9)、cg14719951 (DSC3) 和 cg25117092 (MED12L)，以及两个位于基因间区的 cg11348188 和 cg11671115。除了 cg10399824 和 cg24406668 之外，其余五个 CpG 也与 GC 的 DFI 显著相关。神经活性配体-受体相互作用途径被认为在 DNA 甲基化对 GC 预后的影响中起着关键作用。与个别 CpG 水平的关联一致，涉及 cg11671115、cg14719951 和 cg24406668 的三个 MCB 与 GC 的多个预后结局显著相关。整合关键 CpG 位点，两个风险评分模型在预测 GC 预后方面表现良好。cg14719951、cg10399824 和 cg25117092 的基因体 DNA 甲基化与其宿主基因表达相关，而宿主基因表达与 GC 的四个临床预后结局之间没有显著相关性。
我们新鉴定了与 GC 的 OS、DSS 和 PFI 相关的七个 CpG，其中五个与 DFI 相关，这可能为临床实践中的患者分层提供信息。
