Šutić Maja, Motzek Antje, Bubanović Gordana, Linke Matthias, Sabol Ivan, Vugrek Oliver, Ozretić Petar, Brčić Luka, Seiwerth Sven, Debeljak Željko, Jakovčević Antonija, Janevski Zoran, Stančić-Rokotov Dinko, Vukić-Dugac Andrea, Jakopović Marko, Samaržija Miroslav, Zechner Ulrich, Knežević Jelena
Ruđer Bošković Institute, Division for Molecular Medicine, Zagreb, Croatia.
Institute for Human Genetics, Johannes Gutenberg-University Mainz, Mainz, Germany.
Transl Lung Cancer Res. 2019 Dec;8(6):1000-1015. doi: 10.21037/tlcr.2019.12.08.
Lung cancer is the leading cause of cancer-related death worldwide, with 5-year overall survival less than 15%. Therefore, it is essential to find biomarkers for early detection and prognosis. Aberrant DNA methylation is a common feature of human cancers and its utility is already recognized in cancer management. The aim of this study was to explore the diagnostic and prognostic value of the promoter methylation status of the and genes, key adaptor molecules in the activation of the innate immune response and apoptosis pathways.
A total of 50 non-small cell lung cancer (NSCLC) patients were enrolled in the study. Methylation of bisulphite converted DNA was quantified by pyrosequencing in fresh frozen malignant tissues and adjacent non-malignant tissues. Associations between methylation and lung function, tumor grade and overall survival were evaluated using receiver-operating characteristics (ROC) analysis and statistical tests of hypothesis.
Methylation level of tested genes is generally low but significantly decreased in tumor tissues (, P<0.0001; , P<0.0002), which correlates with increased protein expression. Three CpG sites were identified as promising diagnostic marker candidates; CpG11 (-63 position) in and CpG1 (-253 position) and 2 (-265 position) in . The association study showed that the methylation status of the CpG4 site (-34 position) in malignant and non-malignant tissues is associated with the overall survival (P=0.019) and the methylation status of CpG8 site (-92 position) is associated with TNM-stage (P=0.011).
The methylation status of the and promoters are promising prognostic biomarker candidates. However, presented results should be considered as a preliminary and should be confirmed on the larger number of the samples.
肺癌是全球癌症相关死亡的主要原因，5年总生存率低于15%。因此，寻找早期检测和预后的生物标志物至关重要。异常DNA甲基化是人类癌症的一个常见特征，其在癌症管理中的作用已得到认可。本研究的目的是探讨 和 基因启动子甲基化状态的诊断和预后价值，这两个基因是先天免疫反应和凋亡途径激活中的关键衔接分子。
本研究共纳入50例非小细胞肺癌（NSCLC）患者。通过焦磷酸测序对新鲜冷冻的恶性组织和相邻非恶性组织中经亚硫酸氢盐转化的DNA甲基化进行定量分析。使用受试者操作特征（ROC）分析和假设统计检验评估甲基化与肺功能、肿瘤分级和总生存率之间的关联。
所检测基因的甲基化水平总体较低，但在肿瘤组织中显著降低（ ，P<0.0001； ，P<0.0002），这与蛋白表达增加相关。确定了三个CpG位点作为有前景的诊断标志物候选位点； 中的CpG11（-63位）以及 中的CpG1（-253位）和2（-265位）。关联研究表明，恶性和非恶性组织中 基因CpG4位点（-34位）的甲基化状态与总生存率相关（P=0.019），CpG8位点（-92位）的甲基化状态与TNM分期相关（P=0.011）。
和 基因启动子的甲基化状态是有前景的预后生物标志物候选指标。然而，目前的结果应被视为初步结果，需要在更多样本上进行验证。
