Disease progression and therapeutic resistance are hallmarks of advanced stage prostate cancer (PCa), which remains a major cause of cancer-related mortality around the world. Longitudinal studies, coupled with the use of liquid biopsies, offer a potentially new and minimally invasive platform to study the dynamics of tumour progression. Our aim was to investigate the dynamics of personal DNA methylomic profiles of metastatic PCa (mPCa) patients, during disease progression and therapy administration. Forty-eight plasma samples from 9 mPCa patients were collected, longitudinally, over 13–21 months. After circulating cell-free DNA (cfDNA) isolation, DNA methylation was profiled using the Infinium MethylationEPIC BeadChip. The top 5% most variable probes across time, within each individual, were utilised to study dynamic methylation patterns during disease progression and therapeutic response. Statistical testing was carried out to identify differentially methylated genes (DMGs) in cfDNA, which were subsequently validated in two independent mPCa (cfDNA and FFPE tissue) cohorts. Individual cfDNA global methylation patterns were temporally stable throughout the disease course. However, a proportion of CpG sites presented a dynamic temporal pattern that was consistent with clinical events, including different therapies, and were prominently associated with genes linked to immune response pathways. Additionally, study of the tumour fraction of cfDNA identified > 2000 DMGs with dynamic methylation patterns. Longitudinal assessment of cfDNA methylation in mPCa patients unveiled dynamic patterns associated with disease progression and therapy administration, thus highlighting the potential of using liquid biopsies to study PCa evolution at a methylomic level.

中文翻译：

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转移性前列腺癌个体 cfDNA 甲基化组模式的纵向分析

疾病进展和治疗耐药性是晚期前列腺癌 (PCa) 的标志，这仍然是全球癌症相关死亡率的主要原因。纵向研究，加上液体活检的使用，为研究肿瘤进展的动态提供了一个潜在的新的微创平台。我们的目的是研究转移性 PCa (mPCa) 患者在疾病进展和治疗期间的个人 DNA 甲基化谱动态。在 13-21 个月内纵向收集了 9 名 mPCa 患者的 48 份血浆样本。循环游离 DNA (cfDNA) 分离后，使用 Infinium MethylationEPIC BeadChip 分析 DNA 甲基化。在每个人中，随时间变化最多的前 5% 的探针，用于研究疾病进展和治疗反应期间的动态甲基化模式。进行了统计测试以鉴定 cfDNA 中的差异甲基化基因 (DMG)，随后在两个独立的 mPCa（cfDNA 和 FFPE 组织）队列中进行了验证。在整个疾病过程中，个体 cfDNA 全局甲基化模式在时间上是稳定的。然而，一部分 CpG 位点呈现出与临床事件（包括不同疗法）一致的动态时间模式，并且与与免疫反应途径相关的基因显着相关。此外，对 cfDNA 肿瘤部分的研究确定了 > 2000 个具有动态甲基化模式的 DMG。