Concomitant KRAS and BRAF mutations in colorectal cancer

Somatic mutations involving the GTP-ase RAS protein family and its downstream serine-threonine kinase BRAF lead to loss of cell cycle regulation at key checkpoints and are the main driver mutations for colorectal carcinogenesis (1). The reported incidence of RAS (including KRAS and NRAS) mutations in colorectal cancer (CRC) is about 53% (2), while BRAF is mutated less frequently at a rate of 10% (3). The most common point mutation in KRAS involves an amino acid substitution at codons 12 or 13 (G12D, G12V and G13D) in exon 2, but codons 59 and 61 in exon 3 and codons 117 and 146 in exon 4 may also be affected. Approximately 80% of mutation in BRAF has been identified as gain-of-function mutation in exon 15 leading to the substitution of glutamine for valine at codon 600 (V600E), which is more likely to be found in older women and associated with poorly differentiated tumors in the proximal (right-sided) colon (4). In addition, BRAF V600E mutation has been identified in ‘mismatch repair deficient tumor cells’ that are more prone to microsatellite instability due to epigenetic changes of the MLH1 gene (5)