Altered oncomodules underlie chromatin regulatory factors driver mutations.
Chromatin regulatory factors (CRFs), are known to be involved in tumorigenesis in several cancer types. Nevertheless, the molecular mechanisms through which driver alterations of CRFs cause tumorigenesis remain unknown. Here, we developed a CRFs Oncomodules Discovery approach, which mines several sources of cancer genomics and perturbaomics data. The approach prioritizes sets of genes significantly miss-regulated in primary tumors (oncomodules) bearing mutations of driver CRFs. We applied the approach to eleven TCGA tumor cohorts and uncovered oncomodules potentially associated to mutations of five driver CRFs in three cancer types. Our results revealed, for example, the potential involvement of the mTOR pathway in the development of tumors with loss-of-function mutations of MLL2 in head and neck squamous cell carcinomas. The experimental validation that MLL2 loss-of-function increases the sensitivity of cancer cell lines to mTOR inhibition lends further support to the validity of our approach. The potential oncogenic modules detected by our approach may guide experiments proposing ways to indirectly target driver mutations of CRFs.
Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain.
Joan
J
Frigola
Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain.
Ane
A
Iturbide
Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
Nuria
N
Lopez-Bigas
Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain.
Sandra
S
Peiro
Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain.
Abel
A
Gonzalez-Perez
D063646:Carcinogenesis / Q000235:genetics*; D002843:Chromatin / Q000378:metabolism*; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000235:genetics; D066264:Datasets as Topic; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D002843:Chromatin; D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
CRFs Oncomodules Discovery; CRFs oncogenic modules; chromatin regulatory factors; indirect targeted therapeutic strategies; oncogenic modules scoring system