Dietary, lifestyle and clinicopathological factors associated with BRAF and K-ras mutations arising in distinct subsets of colorectal cancers in the EPIC Norfolk study.
BACKGROUND
BRAF and K-ras proto-oncogenes encode components of the ERK signalling pathway and are frequently mutated in colorectal cancer. This study investigates the associations between BRAF and K-ras mutations and clinicopathological, lifestyle and dietary factors in colorectal cancers.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Naguib
Adam
A
Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB22QQ, UK.
Mitrou
Panagiota N
PN
Gay
Laura J
LJ
Cooke
James C
JC
Luben
Robert N
RN
Ball
Richard Y
RY
McTaggart
Alison
A
Arends
Mark J
MJ
Rodwell
Sheila A
SA
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000368:Aged; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D004032:Diet; D004739:England / Q000453:epidemiology; D005260:Female; D011905:Genes, ras; D006801:Humans; D008019:Life Style; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf