Despite considerable efforts, the mechanisms linking genomic alterations to the transcriptional identity of cancer cells remain elusive. Integrative genomic analysis, using a network-based approach, identified 407 master regulator (MR) proteins responsible for canalizing the genetics of individual samples from 20 cohorts in The Cancer Genome Atlas (TCGA) into 112 transcriptionally distinct tumor subtypes. MR proteins could be further organized into 24 pan-cancer, master regulator block modules (MRBs), each regulating key cancer hallmarks and predictive of patient outcome in multiple cohorts. Of all somatic alterations detected in each individual sample, >50% were predicted to induce aberrant MR activity, yielding insight into mechanisms linking tumor genetics and transcriptional identity and establishing non-oncogene dependencies. Genetic and pharmacological validation assays confirmed the predicted effect of upstream mutations and MR activity on downstream cellular identity and phenotype. Thus, co-analysis of mutational and gene expression profiles identified elusive subtypes and provided testable hypothesis for mechanisms mediating the effect of genetic alterations.

尽管付出了相当大的努力，但将基因组改变与癌细胞转录身份联系起来的机制仍然难以捉摸。使用基于网络的方法进行综合基因组分析，确定了 407 种主调节蛋白 (MR) 蛋白，它们负责将癌症基因组图谱 (TCGA) 中 20 个队列中的个体样本的遗传学转化为 112 个转录不同的肿瘤亚型。MR 蛋白可以进一步组织成 24 个泛癌主调节块模块 (MRB)，每个模块调节关键癌症标志并预测多个队列中的患者结果。在每个单独样本中检测到的所有体细胞改变中，预计 >50% 会诱导异常的 MR 活性，从而深入了解将肿瘤遗传学和转录同一性联系起来的机制，并建立非癌基因依赖性。遗传和药理学验证分析证实了上游突变和 MR 活性对下游细胞身份和表型的预测影响。因此，突变和基因表达谱的共同分析确定了难以捉摸的亚型，并为介导遗传改变影响的机制提供了可检验的假设。