BACKGROUND Lung (LC), prostate (PCa) and colorectal (CRC) cancers are the most incident in males worldwide. Despite recent advances, optimal population-based cancer screening methods remain an unmet need. Due to its early onset, cancer specificity and accessibility in body fluids, aberrant DNA promoter methylation might be a valuable minimally invasive tool for early cancer detection. Herein, we aimed to develop a minimally invasive methylation-based test for simultaneous early detection of LC, PCa and CRC in males, using liquid biopsies. RESULTS Circulating cell-free DNA was extracted from 102 LC, 121 PCa and 100 CRC patients and 136 asymptomatic donors' plasma samples. Sodium-bisulfite modification and whole-genome amplification was performed. Promoter methylation levels of APCme, FOXA1me, GSTP1me, HOXD3me, RARβ2me, RASSF1Ame, SEPT9me and SOX17me were assessed by multiplex quantitative methylation-specific PCR. SEPT9me and SOX17me were the only biomarkers shared by all three cancer types, although they detected CRC with limited sensitivity. A "PanCancer" panel (FOXA1me, RARβ2me and RASSF1Ame) detected LC and PCa with 64% sensitivity and 70% specificity, complemented with "CancerType" panel (GSTP1me and SOX17me) which discriminated between LC and PCa with 93% specificity, but with modest sensitivity. Moreover, a HOXD3me and RASSF1Ame panel discriminated small cell lung carcinoma from non-small cell lung carcinoma with 75% sensitivity, 88% specificity, 6.5 LR+ and 0.28 LR-. An APCme and RASSF1Ame panel independently predicted disease-specific mortality in LC patients. CONCLUSIONS We concluded that a DNA methylation-based test in liquid biopsies might enable minimally invasive screening of LC and PCa, improving patient compliance and reducing healthcare costs. Moreover, it might assist in LC subtyping and prognostication.

中文翻译：

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使用DNA甲基化面板对血液基活检中的主要男性癌症类型进行早期检测。

背景技术肺癌（LC），前列腺癌（PCa）和结直肠癌（CRC）是全世界男性中最常见的疾病。尽管有最新进展，基于人群的最佳癌症筛查方法仍未得到满足。由于其早期发作，癌症特异性和在体液中的可及性，异常的DNA启动子甲基化可能是用于早期癌症检测的有价值的微创工具。在本文中，我们旨在开发一种基于微创甲基化的测试，用于使用液体活检同时早期检测男性的LC，PCa和CRC。结果从102例LC，121例PCa和100例CRC患者和136例无症状供体血浆中提取了循环无细胞DNA。进行了亚硫酸氢钠修饰和全基因组扩增。APCme，FOXA1me，GSTP1me，HOXD3me，RARβ2me，RASSF1Ame，SEPT9me和SOX17me通过多重定量甲基化特异性PCR进行评估。SEPT9me和SOX17me是所有三种癌症类型共有的唯一生物标志物，尽管它们以有限的敏感性检测到CRC。“ PanCancer”面板（FOXA1me，RARβ2me和RASSF1Ame）检测到LC和PCa的灵敏度为64％，特异性为70％，补充了“ CancerType”面板（GSTP1me和SOX17me），该方法区分了LC和PCa，特异性为93％，但适度灵敏度。此外，HOXD3me和RASSF1Ame小组以75％的敏感性，88％的特异性，6.5 LR +和0.28 LR-的灵敏度将小细胞肺癌与非小细胞肺癌区分开来。APCme和RASSF1Ame小组独立预测LC患者的疾病特异性死亡率。结论我们得出结论，在液体活检中进行基于DNA甲基化的测试可以实现LC和PCa的微创筛查，从而提高患者依从性并降低医疗保健成本。此外，它可能有助于LC的分型和预后。