Prostate Cancer (PCa) is the second most common cancer in men where advancements have been made for early detection using imaging techniques, however these are limited by lesion size. Immune surveillance has emerged as an effective approach for early detection and to monitor disease progression. In recent studies, we have shown that host peripheral blood immune cells undergo changes in DNA methylation in liver and breast cancer. In the current study, we examined the DNA methylation status of peripheral blood T cells of men with positive biopsy for PCa versus men with negative biopsy having benign prostate tissue, defined as controls. T cells DNA was isolated and subjected to Illumina Infinium methylation EPIC array and validated using Illumina amplicon sequencing and pyrosequencing platforms. Differential methylation of 449 CG sites between control and PCa T cell DNA showed a correlation with Gleason score (p < 0.05). Two hundred twenty-three differentially methylated CGs between control and PCa (∆ß +/− 10%, p < 0.05), were enriched in pathways involved in immune surveillance system. Three CGs which were found differentially methylated following DMP (Differentially methylated probes) analysis of ChAMP remained significant after BH (Benjamini-Hochberg) correction, of which, 2 CGs were validated. Predictive ability of combination of these 3 CGs (polygenic methylation score, PMS) to detect PCa had high sensitivity, specificity and overall accuracy. PMS also showed strong positive correlation with Gleason score and tumor volume of PCa patients. Results from the current study provide for the first-time a potential role of DNA methylation changes in peripheral T cells in PCa. This non-invasive methodology may allow for early intervention and stratification of patients into different prognostic groups to reduce PCa associated morbidity from repeat invasive prostate biopsies and design therapeutic strategy to reduce PCa associated mortality.

中文翻译：

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外周T细胞中前列腺癌的DNA甲基化特征。

前列腺癌（PCa）是男性中第二大最常见的癌症，其中使用成像技术进行早期检测已经取得了进步，但是这些受病灶大小的限制。免疫监测已成为一种早期发现和监测疾病进展的有效方法。在最近的研究中，我们已经表明，宿主外周血免疫细胞在肝癌和乳腺癌中会发生DNA甲基化的变化。在本研究中，我们检查了PCa活检阳性的男性与活检阴性的前列腺良性前列腺组织的男性外周血T细胞的DNA甲基化状态，将其定义为对照。分离T细胞DNA，并进行Illumina Infinium甲基化EPIC阵列，并使用Illumina扩增子测序和焦磷酸测序平台进行验证。对照和PCa T细胞DNA之间449个CG位点的甲基化差异显示与格里森评分相关（p <0.05）。对照和PCa之间的233个甲基化差异化CGs（∆ß +/- 10％，p <0.05）丰富了免疫监控系统所涉及的途径。经过BH（Benjamini-Hochberg）校正后，在ChAMP的DMP（差异甲基化探针）分析后发现差异甲基化的3个CG仍然显着，其中2个CG已得到验证。这三种CG（多基因甲基化评分，PMS）的组合检测PCa的预测能力具有很高的灵敏度，特异性和整体准确性。PMS还显示与PCa患者的Gleason评分和肿瘤体积密切相关。本研究的结果首次提供了PCa外周T细胞DNA甲基化变化的潜在作用。这种非侵入性方法可以允许将患者早期干预并分为不同的预后组，以减少重复侵入性前列腺活检所致PCa相关的发病率，并设计治疗策略以降低PCa相关的死亡率。