美国哥伦比亚大学Andrea Califano等研究人员合作发现，模块化的核心调节因子可调控癌症的转录身份。这一研究成果于2021年1月11日在线发表在国际学术期刊《细胞》上。
通过使用基于网络的方法进行综合基因组分析，研究人员确定了407个主要调节因子（MR）蛋白，这些蛋白将来自癌症基因组图谱（TCGA）中20个队列的单样本遗传基因转化为112种转录上不同的肿瘤亚型。MR蛋白可以进一步组织为24个全癌的核心调节模块（MRB），每个模块都可调节关键的癌症标志并预测多个队列中的患者预后。
在每个个体样品中检测到的所有体细胞变化中，预计> 50％会诱导MR异常活动，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，并建立了非癌基因依赖性。遗传和药理学验证试验证实了上游突变和MR活性对下游细胞特性和表型的预期影响。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。
据介绍，尽管人们付出了巨大的努力，将基因组改变与癌细胞的转录同一性联系起来的机制仍然难以捉摸。
附：英文原文
Title: A modular master regulator landscape controls cancer transcriptional identity
Author: Evan O. Paull, Alvaro Aytes, Sunny J. Jones, Prem S. Subramaniam, Federico M. Giorgi, Eugene F. Douglass, Somnath Tagore, Brennan Chu, Alessandro Vasciaveo, Siyuan Zheng, Roel Verhaak, Cory Abate-Shen, Mariano J. Alvarez, Andrea Califano
Issue&Volume: 2021-01-11
Abstract: Despite considerable efforts, the mechanisms linking genomic alterations to the transcriptionalidentity of cancer cells remain elusive. Integrative genomic analysis, using a network-basedapproach, identified 407 master regulator (MR) proteins responsible for canalizingthe genetics of individual samples from 20 cohorts in The Cancer Genome Atlas (TCGA)into 112 transcriptionally distinct tumor subtypes. MR proteins could be further organizedinto 24 pan-cancer, master regulator block modules (MRBs), each regulating key cancerhallmarks and predictive of patient outcome in multiple cohorts. Of all somatic alterationsdetected in each individual sample, >50% were predicted to induce aberrant MR activity,yielding insight into mechanisms linking tumor genetics and transcriptional identityand establishing non-oncogene dependencies. Genetic and pharmacological validationassays confirmed the predicted effect of upstream mutations and MR activity on downstreamcellular identity and phenotype. Thus, co-analysis of mutational and gene expressionprofiles identified elusive subtypes and provided testable hypothesis for mechanismsmediating the effect of genetic alterations.
DOI: 10.1016/j.cell.2020.11.045
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31617-2