Department of Rheumatology and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, China.
Int J Biol Sci. 2020 Mar 25;16(11):1785-1797. doi: 10.7150/ijbs.39046. eCollection 2020.
N6-methyladenosine (mA) RNA methylation is dynamically and reversibly regulated by methyl-transferases ("writers"), binding proteins ("readers"), and demethylases ("erasers"). The mA is restored to adenosine and thus to achieve demethylation modification. The abnormality of mA epigenetic modification in cancer has been increasingly attended. However, we are rarely aware of its diagnostic, progressive and prognostic performance in lung adenocarcinoma (LUAD). The expression of 13 widely reported mA RNA regulators in LUAD and normal samples were systematically analyzed. There were 12 mA RNA methylation genes displaying aberrant expressions, and an 11-gene diagnostic score model was finally built (Diagnostic score =0.033KIAA1429+0.116HNRNPC+0.115RBM15-0.067 METTL3-0.048ZC3H13-0.221WTAP+0.213YTHDF1-0.132YTHDC1-0.135* FTO+0.078YTHDF2+0.014ALKBH5). Receiver operating characteristic (ROC) analysis was performed to demonstrate superiority of the diagnostic score model (Area under the curve (AUC) was 0.996 of training cohort, P<0.0001; AUC was 0.971 of one validation cohort-GSE75037, P<0.0001; AUC was 0.878 of another validation cohort-GSE63459, P<0.0001). In both training and validation cohorts, YTHDC2 was associated with tumor stage (P<0.01), while HNRNPC was up expressed in progressed tumor (P<0.05). Besides, WTAP, RBM15, KIAA1429, YTHDF1, and YTHDF2 were all up expressed for TP53 mutation. Furthermore, using least absolute shrinkage and selection operator (lasso) regression analysis, a ten-gene risk score model was built. Risk score=0.169ALKBH5-0.159FTO+0.581HNRNPC-0.348 YTHDF2-0.265YTHDF1-0.123YTHDC2+0.434RBM15+0.143KIAA1429-0.200WTAP-0.310METTL3. There existed correlation between the risk score and TNM stage (P<0.01), lymph node stage (P<0.05), gender (P<0.05), living status (P<0.001). Univariate and multivariate Cox regression analyses of relevant clinicopathological characters and the risk score revealed risk score was an independent risk factor of lung adenocarcinoma (HR: 2.181, 95%CI (1.594-2.984), P<0.001). Finally, a nomogram was built to facilitate clinicians to predict outcome. mA epigenetic modification took part in the progression, and provided auxiliary diagnosis and prognosis of LUAD.
N6-甲基腺苷（mA）RNA 甲基化受甲基转移酶（“写入器”）、结合蛋白（“读取器”）和去甲基酶（“橡皮擦”）的动态和可逆调节。mA 被恢复为腺苷，从而实现去甲基化修饰。癌症中 mA 表观遗传修饰的异常已经越来越受到关注。然而，我们很少意识到它在肺腺癌（LUAD）中的诊断、进展和预后表现。系统分析了 13 种广泛报道的 mA RNA 调节剂在 LUAD 和正常样本中的表达。有 12 个 mA RNA 甲基化基因显示异常表达，并最终构建了一个 11 基因诊断评分模型（诊断评分=0.033KIAA1429+0.116HNRNPC+0.115RBM15-0.067METTL3-0.048ZC3H13-0.221WTAP+0.213YTHDF1-0.132YTHDC1-0.135FTO+0.078YTHDF2+0.014ALKBH5）。进行了接收者操作特征（ROC）分析，以证明诊断评分模型的优越性（训练队列的曲线下面积（AUC）为 0.996，P<0.0001；验证队列-GSE75037 的 AUC 为 0.971，P<0.0001；验证队列-GSE63459 的 AUC 为 0.878，P<0.0001）。在训练和验证队列中，YTHDC2 与肿瘤分期相关（P<0.01），而 HNRNPC 在进展性肿瘤中表达上调（P<0.05）。此外，WTAP、RBM15、KIAA1429、YTHDF1 和 YTHDF2 均因 TP53 突变而上调表达。此外，使用最小绝对收缩和选择算子（lasso）回归分析，构建了一个十基因风险评分模型。风险评分=0.169ALKBH5-0.159FTO+0.581HNRNPC-0.348YTHDF2-0.265YTHDF1-0.123YTHDC2+0.434RBM15+0.143KIAA1429-0.200WTAP-0.310*METTL3。风险评分与 TNM 分期（P<0.01）、淋巴结分期（P<0.05）、性别（P<0.05）、生存状态（P<0.001）之间存在相关性。相关临床病理特征和风险评分的单因素和多因素 Cox 回归分析表明，风险评分是肺腺癌的独立危险因素（HR：2.181，95%CI（1.594-2.984），P<0.001）。最后，构建了一个列线图，以方便临床医生预测结果。mA 表观遗传修饰参与了 LUAD 的进展，并为其提供了辅助诊断和预后。
