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Kirsten Rat Sarcoma (<i>KRAS</i>) 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 <i>KRAS</i> 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 <i>KRAS</i> 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 <i>CDKN2A</i> was more pronounced in tumors with the <i>KRAS</i> mutation. A recent cell line study showed that there were higher <i>CDKN2A</i> 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-<i>CDKN2A</i> therapy with Villosol in <i>KRAS</i>-mutant CRC. Also, the more marked up-regulation of genes in the proteasome pathway in CRC tissue, especially with the <i>KRAS</i> mutation and MSI, may suggest a potential role of a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) in selected CRC patients if necessary.