Journal article
Mediator kinase module proteins, genetic alterations and expression of super-enhancer regulated genes in colorectal cancer
Pharmacological reports, Vol.76(3), pp.535-556
06/01/2024
DOI: 10.1007/s43440-024-00589-2
PMID: 38602606
Abstract
BackgroundGenetic alterations are well characterized as contributors to the pathogenesis of cancers. Epigenetic abnormalities can lead to perturbations of the expression of genes in cancer cells without structural defects. Deregulation of proteins of the transcription machinery may result in perturbations of target genes. Mediator, a multiprotein component of the transcription machinery facilitates the function of RNA polymerase II, which transcribes most human genes. A part of the mediator with kinase activity, called the Mediator kinase module shows genetic alterations in a sub-set of colorectal cancers.MethodsData from publicly available genomic series of colorectal cancer patients were examined to determine alterations of Mediator kinase module component genes, including MED12, MED12L, MED13, MED13L, CDK8, CDK19, and CCNC. The prevalence of alterations in genomically defined colorectal cancer sub-sets was also interrogated. The effect of Mediator kinase module member gene expression on colorectal cancer relapse-free survival was investigated.ResultsMutations in genes of the Mediator kinase module were present in a small percentage of colorectal cancers, ranging between 2 to 10% for MED12 and MED13 and alternative units MED12L and MED13L and below 2% for kinases CDK8 and CDK19 and cyclin C. Amplifications of the CDK8 gene were observed in 3% to 5% of colorectal cancers. The highest prevalence of mutations was observed in MSI cancers and the equivalent CMS1 group, with other genomic groups showing much lower frequency. An association of higher expression of MED12 with inferior relapse-free survival was observed. In contrast, higher expression of cyclin C was associated with improved survival. Colorectal cancer cell lines with CDK8 amplifications displayed sensitivity to several small molecule inhibitors of the KRAS/PI3K pathway but not to BET inhibitors.ConclusionThe Mediator kinase module is deregulated in a sub-set of colorectal cancers with differences observed in genomically defined groups. These variations may result in differences in sensitivity to targeted therapies and may have to be taken into consideration as such therapies are developed.
Details
- Title: Subtitle
- Mediator kinase module proteins, genetic alterations and expression of super-enhancer regulated genes in colorectal cancer
- Creators
- Ioannis Voutsadakis - Essar Steel Algoma
- Resource Type
- Journal article
- Publication Details
- Pharmacological reports, Vol.76(3), pp.535-556
- Publisher
- Springer Nature
- DOI
- 10.1007/s43440-024-00589-2
- PMID
- 38602606
- ISSN
- 1734-1140
- eISSN
- 2299-5684
- Number of pages
- 22
- Language
- English
- Date published
- 06/01/2024
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984806504902771
Metrics
3 Record Views