An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma Based on mRNA, microRNA, and DNA Methylation Biomarkers.
An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma Based on mRNA, microRNA, and DNA Methylation Biomarkers.
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DOI：
10.1097/jto.0000000000000560
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发表时间：
2015-07
期刊：
影响因子：
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通讯作者：
Harris CC
中科院分区：
文献类型：
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作者：
Robles AI;Arai E;Mathé EA;Okayama H;Schetter AJ;Brown D;Petersen D;Bowman ED;Noro R;Welsh JA;Edelman DC;Stevenson HS;Wang Y;Tsuchiya N;Kohno T;Skaug V;Mollerup S;Haugen A;Meltzer PS;Yokota J;Kanai Y;Harris CC
高达30%的I期肺癌患者在治疗性手术后5年内复发。我们试图通过结合表观遗传生物标志物来改善现有的蛋白质编码基因和microRNA表达预后分类器。在两个独立收集的I期肺腺癌队列中进行DNA甲基化全基因组筛选和HOXA9启动子甲基化焦磷酸测序分析。在两个队列中，通过Cox回归和Kaplan-Meier生存分析评估HOXA9启动子甲基化单独和联合mRNA和miRNA生物标志物的预后价值。胚胎干细胞中Polycomb标记的基因启动子在肿瘤中重新甲基化，并识别预后不良的患者。HOXA9位点在I期肿瘤中从头甲基化（P < 0.0005）。高HOXA9启动子甲基化与较差的癌症特异性生存（风险比[HR]， 2.6, P = 0.02）和无复发生存（风险比[HR]， 3.0, P = 0.01）相关，并在IA期和IB期分层分析中确定高危患者。四种蛋白质编码基因（XPO1, BRCA1, HIF1α, dcl1）， miR-21表达和HOXA9启动子甲基化分别与预后独立相关(风险比，2.8,P = 0.002，风险比，2.3,P = 0.01，风险比，2.4；P = 0.005)，并且，当联合时，确定高风险，治疗naïve， I期患者（HR, 10.2; P = 3 × 10−5）。所有关联在两个独立收集的队列中得到证实。由三种类型的基因组和表观基因组数据组成的预后分类器可能有助于指导复发风险高的I期肺癌患者的术后管理。
Up to 30% Stage I lung cancer patients suffer recurrence within 5 years of curative surgery. We sought to improve existing protein-coding gene and microRNA expression prognostic classifiers by incorporating epigenetic biomarkers. Genome-wide screening of DNA methylation and pyrosequencing analysis of HOXA9 promoter methylation were performed in two independently collected cohorts of Stage I lung adenocarcinoma. The prognostic value of HOXA9 promoter methylation alone and in combination with mRNA and miRNA biomarkers was assessed by Cox regression and Kaplan-Meier survival analysis in both cohorts. Promoters of genes marked by Polycomb in Embryonic Stem Cells were methylated de novo in tumors and identified patients with poor prognosis. The HOXA9 locus was methylated de novo in Stage I tumors (P < 0.0005). High HOXA9 promoter methylation was associated with worse cancer-specific survival (Hazard Ratio [HR], 2.6; P = 0.02) and recurrence-free survival (HR, 3.0; P = 0.01), and identified high-risk patients in stratified analysis of Stage IA and IB. Four protein-coding gene (XPO1, BRCA1, HIF1α, DLC1), miR-21 expression and HOXA9 promoter methylation were each independently associated with outcome (HR, 2.8; P = 0.002; HR, 2.3; P = 0.01; and HR, 2.4; P = 0.005, respectively), and, when combined, identified high-risk, therapy naïve, Stage I patients (HR, 10.2; P = 3x10−5). All associations were confirmed in two independently collected cohorts. A prognostic classifier comprising three types of genomic and epigenomic data may help guide the postoperative management of Stage I lung cancer patients at high risk of recurrence.