Abstract：
Consensus molecular subtypes (CMSs) are emerging as critical factor for prognosis and treatment of colorectal cancer. Gene regulators, including chromatin regulator, RNA-binding protein and transcriptional factor, are critical modulators of cancer hallmark, yet little is known regarding the underlying functional mechanism in CMSs. Herein, we identified a core set of 235 functional gene regulators (FGRs) by integrating genome, epigenome, transcriptome and interactome of CMSs. FGRs exhibited significant multi-omics alterations and impacts on cell lines growth, as well as significantly enriched cancer driver genes and pathways. Moreover, common FGRs played different roles in the context of CMSs. In accordance with the immune characteristics of CMSs, we found that the anti-tumor immune pathways were mainly activated by FGRs (e.g. STAT1 and CREBBP) in CMS1, while inhibited by FGRs in CMS2-4. FGRs mediated aberrant expression of ligands, which bind to receptor on immune cells, and modulated tumor immune microenvironment of subtypes. Intriguingly, systematic exploration of datasets using genomic and transcriptome co-similarity reveals the coordinated manner in FGRs act in CMSs to orchestrate their pathways and patients\' prognosis. Expression signatures of the FGRs revealed an optimized CMS classifier, which demonstrated 88% concordance with the gold-standard classifier, but avoiding the influence of sample composition. Overall, our integrative analysis identified FGRs to regulate core tumorigenic processes/pathways across CMSs.
摘要：
共识分子亚型（CMSs）正在成为结直肠癌预后和治疗的关键因素。基因调节因子,包括染色质调节剂，RNA结合蛋白和转录因子,是癌症标志的关键调节剂，然而，关于CMS的潜在功能机制知之甚少。在这里，我们通过整合基因组确定了235个功能基因调节因子（FGR）的核心集，表观基因组,CMSs的转录组和相互作用组。FGR表现出显著的多组学改变和对细胞系生长的影响，以及显著丰富的癌症驱动基因和途径。此外，常见的FGR在CMS中扮演不同的角色。根据CMSs的免疫特性,我们发现CMS1中的抗肿瘤免疫途径主要被FGRs（如STAT1和CREBBP）激活，而在CMS2-4中被FGRs抑制。FGR介导配体的异常表达，与免疫细胞上的受体结合，和调节肿瘤免疫微环境的亚型。有趣的是，使用基因组和转录组共相似性对数据集进行系统探索，揭示了FGR在CMS中的协调方式，以协调其途径和患者预后。FGR的表达特征揭示了优化的CMS分类器，与黄金标准分类器有88%的一致性，但避免样品成分的影响。总的来说,我们的综合分析确定FGRs可以调节CMS中的核心致瘤过程/途径。
