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BACKGROUND

Cancer evolution depends on epigenetic and genetic diversity. Historically, in multiple myeloma (MM), subclonal diversity and tumor evolution have been investigated mostly from a genetic perspective.

METHODS

Here, we performed an analysis of 42 MM samples from 21 patients by using enhanced reduced representation bisulfite sequencing (eRRBS). We combined several metrics of epigenetic heterogeneity to analyze DNA methylation heterogeneity in MM patients.

RESULTS

We show that MM is characterized by the continuous accumulation of stochastic methylation at the promoters of development-related genes. High combinatorial entropy change is associated with poor outcomes in our pilot study and depends predominantly on partially methylated domains (PMDs). These PMDs, which represent the major source of inter- and intrapatient DNA methylation heterogeneity in MM, are linked to other key epigenetic aberrations, such as CpG island (CGI)/transcription start site (TSS) hypermethylation and H3K27me3 redistribution as well as 3D organization alterations. In addition, transcriptome analysis revealed that intratumor methylation heterogeneity was associated with low-level expression and high variability.

CONCLUSIONS

We propose that disrupted DNA methylation in MM is responsible for high epigenetic and transcriptomic instability allowing tumor cells to adapt to environmental changes by tapping into a pool of evolutionary trajectories.

背景

癌症的进化取决于表观遗传和遗传多样性。在多发性骨髓瘤（MM）中，从历史上看，亚克隆多样性和肿瘤进化主要从遗传角度进行了研究。

方法

在这里，我们通过增强的简化重亚硫酸盐测序（eRRBS）对 21 名患者的 42 个 MM 样本进行了分析。我们结合了几种表观遗传异质性度量标准来分析 MM 患者的 DNA 甲基化异质性。

结果

我们表明，MM 的特征是与发育相关基因启动子处随机甲基化的不断积累。在我们的初步研究中，高组合熵变化与不良预后相关，并且主要取决于部分甲基化域（PMD）。这些 PMD 代表 MM 中患者间和患者内 DNA 甲基化异质性的主要来源，与其他关键的表观遗传异常（如 CpG 岛（CGI）/转录起始位点（TSS）过度甲基化和 H3K27me3 重新分布以及 3D 组织改变）相关。此外，转录组分析表明，肿瘤内甲基化异质性与低水平表达和高变异性相关。