Italian Institute for Genomic Medicine, IIGM, Turin, Italy; Department of Medical Sciences, University of Turin, Turin, Italy.
Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
J Thorac Oncol. 2019 Mar;14(3):527-539. doi: 10.1016/j.jtho.2018.10.163. Epub 2018 Nov 5.
Malignant pleural mesothelioma (MPM) is an aggressive tumor strongly associated with asbestos exposure. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive early diagnostic tests to monitor asbestos-exposed people.
We used a genome-wide methylation array to identify, in asbestos-exposed subjects, novel blood DNA methylation markers of MPM in 163 MPM cases and 137 cancer-free controls (82 MPM cases and 68 controls, training set; replication in 81 MPM cases and 69 controls, test set) sampled from the same areas.
Evidence of differential methylation between MPM cases and controls was found (more than 800 cytosine-guanine dinucleotide sites, false discovery rate p value (p) < 0.05), mainly in immune system-related genes. Considering the top differentially methylated signals, seven single- cytosine-guanine dinucleotides and five genomic regions of coordinated methylation replicated with similar effect size in the test set (p < 0.05). The top hypomethylated single-CpG (cases versus controls effect size less than -0.15, p < 0.05 in both the training and test sets) was detected in FOXK1 (Forkhead-box K1) gene, an interactor of BAP1 which was found mutated in MPM tissue and as germline mutation in familial MPM. In the test set, comparison of receiver operating characteristic curves and the area under the curve (AUC) of two models, including or excluding methylation, showed a significant increase in case/control discrimination when considering DNA methylation together with asbestos exposure (AUC = 0.81 versus AUC = 0.89, DeLong's test p = 0.0013).
We identified signatures of differential methylation in DNA from whole blood between asbestos exposed MPM cases and controls. Our results provide the rationale to further investigate, in prospective studies, the potential use of blood DNA methylation profiles for the identification of early changes related to the MPM carcinogenic process.
恶性胸膜间皮瘤（MPM）是一种与石棉暴露密切相关的侵袭性肿瘤。当目前的治疗方法获益有限时，患者通常被诊断出来，这突显了需要非侵入性的早期诊断测试来监测暴露于石棉的人群。
我们使用全基因组甲基化阵列，在来自同一地区的 163 例 MPM 病例和 137 例无癌症对照者（82 例 MPM 病例和 68 例对照者，训练集；81 例 MPM 病例和 69 例对照者，验证集）中，鉴定出石棉暴露者中 MPM 的新型血液 DNA 甲基化标志物。
在 MPM 病例和对照组之间发现了甲基化差异的证据（超过 800 个胞嘧啶-鸟嘌呤二核苷酸位点，错误发现率 p 值（p）<0.05），主要在免疫系统相关基因中。考虑到差异甲基化信号的顶端，在验证集中，7 个单胞嘧啶-鸟嘌呤二核苷酸和 5 个协同甲基化的基因组区域具有相似的效应大小（p<0.05）得到了复制。在 FOXK1（叉头框 K1）基因中检测到的最显著低甲基化单-CpG（病例与对照效应大小小于-0.15，在训练和验证集中均为 p<0.05）是 BAP1 的相互作用物，BAP1 在 MPM 组织中发生突变，并且是家族性 MPM 的种系突变。在验证集中，比较包括或不包括甲基化的两个模型的接收者操作特征曲线和曲线下面积（AUC），当考虑 DNA 甲基化与石棉暴露一起时，对病例/对照的区分有显著增加（AUC=0.81 与 AUC=0.89，DeLong 检验 p=0.0013）。
我们在石棉暴露的 MPM 病例和对照者的全血 DNA 中鉴定出了差异甲基化的特征。我们的结果为进一步在前瞻性研究中探索血液 DNA 甲基化谱在识别与 MPM 致癌过程相关的早期变化中的潜在用途提供了依据。
