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Abstract：
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.
摘要：
Kirsten大鼠肉瘤（KRAS）是大肠癌（CRC）中最常见的突变癌基因。我们以前报道过微卫星不稳定性(MSI)之间的相互作用，DNA启动子甲基化,和基因表达。在这项研究中,我们寻找KRAS突变之间的关联,基因表达，和甲基化可能有助于精准医学。在配对的CRC肿瘤和周围健康组织中进行全基因组基因表达和DNA甲基化。结果提示(a)在具有KRAS突变的患者中,CRC中许多主要基因通路的失调程度显著更大,（b）这些失调的基因通路的上调和下调可能与相应的低甲基化和高甲基化相关，和(c)CDKN2A的上调在具有KRAS突变的肿瘤中更为明显。最近的细胞系研究表明,在5-FU抗性CRC细胞中存在较高的CDKN2A水平,并且这些可以被Villosol下调。我们的发现表明，在KRAS突变型CRC中，Villosol对抗CDKN2A治疗有更好的反应。此外，CRC组织中蛋白酶体途径的基因上调更明显，尤其是KRAS突变和MSI,可能表明蛋白酶体抑制剂(硼替佐米，Carfilzomib,或艾沙佐米）在必要时用于选定的CRC患者。
