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

• Published in: International journal of molecular sciences Vol. 25; no. 15; p. 8094
• Main Authors: Jasmine, Farzana, Almazan, Armando, Khamkevych, Yuliia, Bissonnette, Marc, Ahsan, Habibul, Kibriya, Muhammad G
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-08-2024
• Subjects: Aged; Antimitotic agents; Antineoplastic agents; Cancer; Cancer therapies; CDKN2A; Colorectal cancer; colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclin-dependent kinases; Developing countries; DNA Methylation; Epigenome; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Genetic research; Humans; Kinases; KRAS mutation; Male; Microsatellite Instability; Middle Aged; MSI; Mutation; Patients; proteasome inhibitor; Proto-Oncogene Proteins p21(ras) - genetics; Transcriptome; Tumors; Vascular endothelial growth factor; Villosol; Villosol; KRAS mutation; MSI; proteasome inhibitor; CDKN2A; VEGF; colorectal carcinoma; EGFR
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25158094

Kirsten Rat Sarcoma (
) 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
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
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
was more pronounced in tumors with the
mutation. A recent cell line study showed that there were higher
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-
therapy with Villosol in
-mutant CRC. Also, the more marked up-regulation of genes in the proteasome pathway in CRC tissue, especially with the
mutation and MSI, may suggest a potential role of a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) in selected CRC patients if necessary.