Association of KRAS Mutation and Gene Pathways in Colorectal Carcinoma: A Transcriptome- and Methylome-Wide Study and Potential Implications for Therapy.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Colorectal Neoplasms*/genetics ; Colorectal Neoplasms*/drug therapy ; Colorectal Neoplasms*/pathology ; Colorectal Neoplasms*/metabolism ; Proto-Oncogene Proteins p21(ras)*/genetics ; DNA Methylation* ; Mutation* ; Gene Expression Regulation, Neoplastic*/drug effects ; Transcriptome*; Humans ; Male ; Female ; Middle Aged ; Aged ; Gene Expression Profiling ; Microsatellite Instability ; Epigenome ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism

Kirsten Rat Sarcoma ( KRAS ) is the most commonly mutated oncogene in colorectal carcinoma (CRC). We have previously reported the interactions between microsatellite instability (MSI), DNA promoter methylation, and gene expression. In this study, we looked for associations between KRAS mutation, gene expression, and methylation that may help with precision medicine. Genome-wide gene expression and DNA methylation were done in paired CRC tumor and surrounding healthy tissues. The results suggested that (a) the magnitude of dysregulation of many major gene pathways in CRC was significantly greater in patients with the KRAS mutation, (b) the up- and down-regulation of these dysregulated gene pathways could be correlated with the corresponding hypo- and hyper-methylation, and (c) the up-regulation of CDKN2A was more pronounced in tumors with the KRAS mutation. A recent cell line study showed that there were higher CDKN2A levels in 5-FU-resistant CRC cells and that these could be down-regulated by Villosol. Our findings suggest the possibility of a better response to anti- CDKN2A therapy with Villosol in KRAS -mutant CRC. Also, the more marked up-regulation of genes in the proteasome pathway in CRC tissue, especially with the KRAS mutation and MSI, may suggest a potential role of a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) in selected CRC patients if necessary.

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P20 CA210305 United States CA NCI NIH HHS; P30 ES027792 United States ES NIEHS NIH HHS; P20CA210305 United States GF NIH HHS; P30ES027792 United States GF NIH HHS

Keywords: CDKN2A; EGFR; KRAS mutation; MSI; VEGF; Villosol; colorectal carcinoma; proteasome inhibitor

EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
0 (KRAS protein, human)
0 (Cyclin-Dependent Kinase Inhibitor p16)

Date Created: 20240810 Date Completed: 20240810 Latest Revision: 20240830

20240830

PMC11311678

10.3390/ijms25158094

39125664