Dietary, lifestyle and clinicopathological factors associated with BRAF and K-ras mutations arising in distinct subsets of colorectal cancers in the EPIC Norfolk study

186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for BRAF and K-ras mutations. Diet and lifestyle data were collected prospectively using seven day food diaries.BRAF V600E mutation was found in 15.6% of colorectal cancers but at higher frequencies in cancers with proximal location, poor differentiation and microsatellite instability (MSI) (all p < 0.001). K-ras mutation (mostly in codons 12 and 13) was found in 22.0% of colorectal cancers but at higher frequencies in cancers of more advanced Dukes' stage (p = 0.001), microsatellite stable (MSS) status (p = 0.002) and in individuals with lower blood high-density lipoprotein concentrations (p = 0.04). Analysis of dietary factors demonstrated no link between BRAF mutation and any specific dietary constituent, however, K-ras mutation was found at higher frequencies in individuals with higher white meat consumption (p < 0.001). Further analysis of specific mutation type demonstrated that G to A transitions in K-ras were observed at higher frequencies in individuals consuming lower amounts of fruit (p = 0.02).These data support the model of BRAF and K-ras mutations arising in distinct colorectal cancer subsets associated with different clinicopathological and dietary factors, acting as mutually exclusive mechanisms of activation of the same signalling pathway.BRAF and K-ras genes both encode proteins that act in the ERK signalling pathway, which mediates cellular responses to growth factors and regulates elements of the cell cycle, apoptosis and differentiation [1]. Activating mutations in both genes have been found in colorectal cancer with mutation frequencies of 4-13% for BRAF [2-9] and of 20-50% for K-ras [10-17] having been reported. BRAF and K-ras mutations are frequently found to be mutually exclusive in colorectal cancer [5,18] and both genes harbour the majority of mutations in distinct hotspots: BRAF at codons 463-468 [19] and 600 [18,19] and K-ras at codons 12 and 13 [20] and also, bu