Introduction: 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. Methods: 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. Results: Evidence of differential methylation between MPM cases and controls was found (more than 800 cytosine‐guanine dinucleotide sites, false discovery rate p value (pfdr) < 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 (pfdr < 0.05). The top hypomethylated single‐CpG (cases versus controls effect size less than ‐0.15, pfdr < 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). Conclusions: 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.

中文翻译：

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外周血 DNA 甲基化作为石棉暴露受试者恶性胸膜间皮瘤的潜在生物标志物

简介：恶性胸膜间皮瘤 (MPM) 是一种侵袭性肿瘤，与石棉暴露密切相关。当目前的治疗方法获益有限时，患者通常会被诊断出来，这突出了无创早期诊断测试以监测石棉暴露人群的必要性。方法：我们使用全基因组甲基化阵列在暴露于石棉的受试者中鉴定了 163 个 MPM 病例和 137 个无癌对照（82 个 MPM 病例和 68 个对照，训练集；在 81 MPM 病例和 69 个对照、测试集）从相同区域采样。结果：发现 MPM 病例和对照之间存在差异甲基化的证据（超过 800 个胞嘧啶-鸟嘌呤二核苷酸位点，错误发现率 p 值 (pfdr) < 0.05），主要是在免疫系统相关基因中。考虑到最高的差异甲基化信号，七个单胞嘧啶-鸟嘌呤二核苷酸和五个协调甲基化的基因组区域在测试集中以相似的效应大小复制（pfdr < 0.05）。在 FOXK1 (Forkhead-box K1) 基因中检测到最高的低甲基化单 CpG（病例与对照的效应大小小于 ‐0.15，pfdr < 0.05）在 FOXK1（Forkhead-box K1）基因中检测到，该基因是在 MPM 中发现突变的 BAP1 的相互作用物组织和作为家族性 MPM 中的种系突变。在测试集中，接受者操作特征曲线和包括或不包括甲基化在内的两种模型的曲线下面积 (AUC) 的比较显示，当考虑 DNA 甲基化和石棉暴露时，病例/对照区分显着增加 (AUC = 0.81相对于 AUC = 0.89，DeLong 检验 p = 0.0013）。结论：我们确定了石棉暴露 MPM 病例和对照之间全血 DNA 差异甲基化的特征。我们的结果为在前瞻性研究中进一步调查血液 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。