Tumor DNA circulates in the plasma of cancer patients admixed with DNA from noncancerous cells. The genomic landscape of plasma DNA has been characterized in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome has not been extensively explored. Here, we performed next-generation sequencing (NGS) on plasma DNA with and without bisulfite treatment from mCRPC patients receiving either abiraterone or enzalutamide in the pre- or post-chemotherapy setting. Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically determined tumor fraction (r = –0.96; P < 10^–8) and characterized by hypermethylation of targets of the polycomb repressor complex 2 components. Further deconvolution of the PC1 top-correlated segments revealed that these segments are comprised of methylation patterns specific to either prostate cancer or prostate normal epithelium. To extract information specific to an individual’s cancer, we then focused on an orthogonal methylation signature, which revealed enrichment for androgen receptor binding sequences and hypomethylation of these segments associated with AR copy number gain. Individuals harboring this methylation pattern had a more aggressive clinical course. Plasma methylome analysis can accurately quantitate tumor fraction and identify distinct biologically relevant mCRPC phenotypes.

中文翻译：

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转移性前列腺癌的全基因组血浆 DNA 甲基化特征


肿瘤 DNA 在癌症患者的血浆中循环，与非癌细胞的 DNA 混合。血浆 DNA 的基因组景观已在转移性去势抵抗性前列腺癌 (mCRPC) 中得到表征，但血浆甲基化组尚未得到广泛探索。在这里，我们对在化疗前或化疗后接受阿比特龙或恩杂鲁胺治疗的 mCRPC 患者的血浆 DNA 进行了下一代测序 (NGS)，这些患者接受或未接受亚硫酸氢盐治疗。 mCRPC 血浆甲基化组的主成分分析表明，甲基化变异的主要贡献者（主成分一或 PC1）与基因组确定的肿瘤分数密切相关（ r = –0.96； P < 10 ^–8 ），并以靶标的高甲基化为特征多梳阻遏物复合物2个组分的。对 PC1 顶部相关片段的进一步去卷积表明，这些片段由前列腺癌或前列腺正常上皮特异的甲基化模式组成。为了提取特定于个体癌症的信息，我们随后关注正交甲基化特征，该特征揭示了雄激素受体结合序列的富集以及与AR拷贝数增加相关的这些片段的低甲基化。具有这种甲基化模式的个体具有更具侵袭性的临床病程。血浆甲基化组分析可以准确定量肿瘤部分并识别不同的生物学相关 mCRPC 表型。