Department of Bioinformatics, The Basic Medical School of Chongqing Medical University, Chongqing, China.
Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Aging (Albany NY). 2020 Jul 28;12(14):14649-14676. doi: 10.18632/aging.103517.
Epigenetic alterations are crucial to oncogenesis and regulation of gene expression in non-small-cell lung carcinoma (NSCLC). DNA methylation (DNAm) biomarkers may provide molecular-level prediction of relapse risk in cancer. Identification of optimal treatment is warranted for improving clinical management of NSCLC patients. Using machine learning algorithm we identified 4 recurrence predictive CpG methylation markers (cg00253681/ART4, cg00111503/KCNK9, cg02715629/FAM83A, cg03282991/C6orf10) and constructed a risk score model that potently predicted recurrence-free survival and prognosis for patients with NSCLC (P = 0.0002). Integrating genomic, transcriptomic, proteomic and clinical data, the DNAm-based risk score was observed to significantly associate with clinical stage, cell proliferation markers, somatic alterations, tumor mutation burden (TMB) as well as DNA damage response (DDR) genes, and potentially predict the efficacy of immunotherapy. In general, our identified DNAm signature shows a significant correlation to TMB and DDR pathways, and serves as an effective biomarker for predicting NSCLC recurrence and response to immunotherapy. These findings demonstrate the utility of 4-DNAm-marker panel in the prognosis, treatment decision-making and evaluation of therapeutic responses for NSCLC.
表观遗传改变对非小细胞肺癌（NSCLC）的致癌作用和基因表达调控至关重要。DNA 甲基化（DNAm）生物标志物可能为癌症的复发风险提供分子水平的预测。为了改善 NSCLC 患者的临床管理，有必要确定最佳治疗方法。我们使用机器学习算法确定了 4 个复发预测性 CpG 甲基化标记物（cg00253681/ART4、cg00111503/KCNK9、cg02715629/FAM83A、cg03282991/C6orf10），并构建了一个风险评分模型，该模型能够有力地预测 NSCLC 患者的无复发生存率和预后（P = 0.0002）。整合基因组、转录组、蛋白质组和临床数据，发现基于 DNAm 的风险评分与临床分期、细胞增殖标志物、体细胞改变、肿瘤突变负荷（TMB）以及 DNA 损伤反应（DDR）基因显著相关，并可能预测免疫治疗的疗效。总的来说，我们鉴定的 DNAm 特征与 TMB 和 DDR 途径有显著的相关性，可作为预测 NSCLC 复发和对免疫治疗反应的有效生物标志物。这些发现证明了 4-DNAm 标记物面板在 NSCLC 的预后、治疗决策以及治疗反应评估中的效用。
