BRAF mutations in tumors with MSI+ CIMP+ are 10 folds
more frequent than tumors without these phenotypes (20), 70-80% BRAF mutation frequencies have been reported in sporadic MSI+, CIMP+ and MLH1-methylated CRC and polyps (21). The BRAF oncogene gene has been linked to MSI pathway in tumorigenesis (22). BRAF mutation frequencies in MSI+ are much higher than MSI- tumors, and the higher frequencies have been seen Inhibitors,research,lifescience,medical in tumors showing methylation of the MLH1 promoter proximal region and in tumors with infiltrating lymphocytes (20). It has been reported in various studies that 100% of the carcinomas with BRAF mutations, methylation of hMLH1 occurred. Samowitz et al. have speculated about a fact, that MSI colorectal tumors that develop from hyperplastic polyps frequently Inhibitors,research,lifescience,medical show BRAF mutations and the Tofacitinib order methylator phenotype (CIMP), including the methylation of hMLH1 (23). According to Domingo et al, the inactivation of hMLH1 by methylation is reacted to the activation of BRAF, suggesting that specific modulation in the RAS/RAF system could occur depending on hMLH1 methylation status in CRC (24). Koinuma K et al. reported an association between BRAF mutations
Inhibitors,research,lifescience,medical and promoter methylation of the hMLH1 repair gene, where hMLH1 has been Inhibitors,research,lifescience,medical found to be altered in 80% of the cases of MSI sporadic CRC (25). BRAF mutations were reported to show prognostic significance in MSI – but not in MSI+ CRC (26). In various previous studies it has been reported that BRAF mutations in MSI-sporadic CRC are more frequently detected as compared with microsatellite -stable CRC
(up to 50% vs. 12% respectively) Inhibitors,research,lifescience,medical (26). During uncontrolled division in tumor cells, their demand for nutrients and oxygen increases, and to adapt to hypoxic environment, cells switch to anaerobic glycolysis and induction of survival factors and angiogenic growth over factors such as; vascular endothelial growth factor (VEGF) (27). In hypoxia, Hypoxia-inducible factors (HIFs) are thought to play a major role in controlling the transcriptional responses (28). Mutated BRAF induces and regulates both Hypoxia-inducible Factor-1α (HIF-1α) and Hypoxia inducible Factor -2α (HIF-2α) in hypoxia (29). KRAS induces only HIF-1α. HIF-1α is thought to promote the growth of colon cancer cells, whereas; HIF-2α may restrain growth. The differential effects of KARS and BRAF mutations on the HIFs presents the unique interaction between the oncogenes and the tumor microenvironment, which may provide the phenotypic differences in mutant BRAF and KRAS CRC (29).