Multilevel prioritization of gene regulators associated with consensus molecular subtypes of colorectal cancer.

Publisher: Oxford University Press Country of Publication: England NLM ID: 100912837 Publication Model: Print Cited Medium: Internet ISSN: 1477-4054 (Electronic) Linking ISSN: 14675463 NLM ISO Abbreviation: Brief Bioinform Subsets: MEDLINE

Publication: Oxford : Oxford University Press
Original Publication: London ; Birmingham, AL : H. Stewart Publications, [2000-

Gene Expression Regulation, Neoplastic*; Biomarkers, Tumor/*genetics ; Colorectal Neoplasms/*genetics ; Gene Expression Profiling/*methods ; Genes, Regulator/*genetics; Algorithms ; Biomarkers, Tumor/metabolism ; Colorectal Neoplasms/classification ; Colorectal Neoplasms/metabolism ; Consensus ; Gene Regulatory Networks ; Genomics/methods ; Humans ; Kaplan-Meier Estimate ; Mutation ; Prognosis ; Signal Transduction/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Tumor Microenvironment/genetics

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.
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Keywords: colorectal cancer; consensus molecular subtype; gene regulator; multi-omics feature

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Date Created: 20210415 Date Completed: 20211122 Latest Revision: 20211122

20250114

10.1093/bib/bbab077

33855351