A Prognostic DNA Methylation Signature for Stage I Non-Small-Cell Lung Cancer
A Prognostic DNA Methylation Signature for Stage I Non-Small-Cell Lung Cancer
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DOI：
10.1200/jco.2012.48.5516
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发表时间：
2013-11-10
影响因子：
45.3
通讯作者：
Esteller, Manel
中科院分区：
文献类型：
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作者：
Sandoval, Juan;Mendez-Gonzalez, Jesus;Esteller, Manel
目的非小细胞肺癌（NSCLC）是一种临床预后仅有微小改善的肿瘤。这个问题对于I期患者至关重要，因为没有可用的生物标志物指示哪些高危患者应该接受辅助化疗。我们的目的是找到DNA甲基化标志物，可以在这方面有所帮助。患者和MethodsA DNA甲基化微阵列，分析450，000个CpG位点被用来研究肿瘤DNA从444例非小细胞肺癌患者，其中包括237 I期肿瘤。在143例I期NSCLC患者的独立队列中，通过单甲基化焦磷酸测序分析验证了预后DNA甲基化标志物。结果发现队列中10，000个最可变的DNA甲基化位点的无监督聚类确定了无复发生存期较短的高危I期NSCLC患者（RFS;风险比[HR]，2.35; 95% CI，1.29至4.28; P = .004）。来自发现队列的显著甲基化位点的验证队列中的研究发现，五个基因的超甲基化与I期NSCLC中较短的RFS显著相关：HIST 1H 4F、PCDHGB 6、NPBWR 1、ALX 1和HOXA 9。一个签名的基础上的高甲基化事件的数量区分高风险和低风险的I期NSCLC患者（HR，3.24; 95%CI，1.61至6.54; P = .001）。对最佳DNA甲基化生物标志物的分析提高了标准分期以外的预后准确性。(C)2013年美国临床肿瘤学会
PurposeNon-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard.Patients and MethodsA DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC.ResultsUnsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high-and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001).ConclusionThe DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging. (C) 2013 by American Society of Clinical Oncology