MYC is deregulated in more than 50% of all cancers. While MYC amplification is the most common MYC-deregulating event, many other alterations can increase MYC activity. We thus systematically investigated MYC pathway activity across different tumor types. Using a logistic regression framework, we established tumor type-specific, transcriptomic-based MYC activity scores that can accurately capture MYC activity. We show that MYC activity scores reflect a variety of MYC-regulating mechanisms, including MYCL and/or MYCN amplification, MYC promoter methylation, MYC mRNA expression, lncRNA PVT1 expression, MYC mutations and viral integrations near the MYC locus. Our MYC activity score incorporates all of these mechanisms, resulting in better prognostic predictions compared to MYC amplification status, MYC promoter methylation and MYC mRNA expression in several cancer types. In addition, we show that tumor proliferation and immune evasion are likely contributors to this reduction in survival. Lastly, we developed a MYC activity signature for liquid tumors in which MYC translocation is commonly observed, suggesting that our approach can be applied to different types of genomic alterations. In conclusion, we developed a MYC activity score that captures MYC pathway activity and is clinically relevant. Implications: By using cancer type specific MYC activity profiles, we were able to assess MYC activity across many more tumor types than previously investigated. The range of different MYC-related alterations captured by our MYC activity score can be used to facilitate the application of future MYC inhibitors and aid physicians to pre-select patients for targeted therapy.

中文翻译：

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MYC 活动推断捕获了人类癌症中异常 MYC 通路激活的多种机制

MYC 在超过 50% 的所有癌症中被解除管制。虽然 MYC 扩增是最常见的 MYC 解除调节事件，但许多其他改变可以增加 MYC 活性。因此，我们系统地研究了不同肿瘤类型的 MYC 通路活性。使用逻辑回归框架，我们建立了肿瘤类型特异性、基于转录组的 MYC 活动评分，可以准确捕捉 MYC 活动。我们发现 MYC 活性评分反映了多种 MYC 调节机制，包括 MYCL 和/或 MYCN 扩增、MYC 启动子甲基化、MYC mRNA 表达、lncRNA PVT1 表达、MYC 突变和 MYC 基因座附近的病毒整合。我们的 MYC 活动评分包含了所有这些机制，与 MYC 扩增状态相比，可以做出更好的预后预测，几种癌症类型中的 MYC 启动子甲基化和 MYC mRNA 表达。此外，我们表明肿瘤增殖和免疫逃避可能是导致这种存活率降低的原因。最后，我们为液体肿瘤开发了 MYC 活性特征，其中通常观察到 MYC 易位，这表明我们的方法可以应用于不同类型的基因组改变。总之，我们开发了一个 MYC 活性评分，该评分捕捉 MYC 通路活性并具有临床相关性。启示：通过使用癌症类型特异性 MYC 活性谱，我们能够评估比以前研究的更多肿瘤类型的 MYC 活性。