The recent identification of recurrently mutated epigenetic regulator genes (ERGs) supports their critical role in tumorigenesis. We conducted a pan-cancer analysis integrating (epi)genome, transcriptome, and DNA methylome alterations in a curated list of 426 ERGs across 33 cancer types, comprising 10,845 tumor and 730 normal tissues. We found that, in addition to mutations, copy number alterations in ERGs were more frequent than previously anticipated and tightly linked to expression aberrations. Novel bioinformatics approaches, integrating the strengths of various driver prediction and multi-omics algorithms, and an orthogonal in vitro screen (CRISPR-Cas9) targeting all ERGs revealed genes with driver roles within and across malignancies and shared driver mechanisms operating across multiple cancer types and hallmarks. This is the largest and most comprehensive analysis thus far; it is also the first experimental effort to specifically identify ERG drivers (epidrivers) and characterize their deregulation and functional impact in oncogenic processes.

中文翻译：

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表观遗传驱动基因的泛癌多组学分析和正交实验评估。


最近对反复突变的表观遗传调节基因（ERG）的鉴定支持了它们在肿瘤发生中的关键作用。我们对涵盖 33 种癌症类型（包括 10,845 个肿瘤组织和 730 个正常组织）的 426 个 ERG 的精选列表进行了整合（表观）基因组、转录组和 DNA 甲基化组改变的泛癌症分析。我们发现，除了突变之外，ERG 中的拷贝数改变比之前预期的更频繁，并且与表达畸变密切相关。新颖的生物信息学方法，整合了各种驱动预测和多组学算法的优势，以及针对所有 ERG 的正交体外筛选 (CRISPR-Cas9)，揭示了在恶性肿瘤内部和之间具有驱动作用的基因，以及跨多种癌症类型和共享驱动机制。标志。这是迄今为止规模最大、最全面的分析；这也是第一个专门识别 ERG 驱动因素（epidrivers）并表征其在致癌过程中的放松管制和功能影响的实验工作。