A modular master regulator landscape controls cancer transcriptional identity

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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. A network-based integrative genomic analysis of 20 The Cancer Genome Atlas cohorts characterizes conserved master regulator blocks underlying cancer hallmarks across different tumor types, providing insights into the connection between genetic alterations and tumor transcriptional identity.

Original languageEnglish (US)
Pages (from-to)334-351.e20
JournalCell
Volume184
Issue number2
DOIs
StatePublished - Jan 21 2021
Externally publishedYes

Keywords

  • cancer genetics
  • cancer systems biology
  • genomic alteration
  • integrative genomics
  • multiomics
  • network analysis
  • pan-cancer analysis
  • transcriptional regulation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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