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

Abstract

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). Conclusion: 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.

The Molecular Genetic Events in Colorectal Cancer and Diet

“…However, this association with PUFA has not been identifed in any other report (Bautista et al, 1997;Laso et al, 2004;Naguib et al, 2010;Slattery et al, 2000;Wark et al, 2006). Taken together, the published data describing the association of dietary fats with K-RAS mutations have failed to identify a convincing association, and have generated conflicting results.…”

“…In this same report, a reduction in pork consumption was found to be linked to reduced frequency of both colonic and rectal cancers harbouring mutated K-RAS. Another report, assessing K-RAS mutations and diet in 155 K-RAS wildtype and 41 K-RAS mutated CRC, identified an increased white meat consumption associated with higher incidence of K-RAS mutated CRC (Naguib et al, 2010). Although positive associations were identified in these two analyses, there appears to be little consistency between these independent findings.…”

“…However, contradictory findings of an increased MUFA consumption being associated with a higher prevalence of K-RAS wildtype neoplasia in a study assessing adenomas (453 wildtype, 81 mutated) (Wark et al, 2006) challenges the observation made by Bautista and co-workers. Other published reports have failed to identify any link between K-RAS mutation status and MUFA intake (Brink et al, 2004;Laso et al, 2004;Naguib et al, 2010;Slattery et al, 2000;.…”

“…However, in addition to these positive associations in relatively large cohorts, several other studies have failed to identify a link between folate intake and K-RAS mutation status in colorectal neoplasms. Reports describing the testing of 67 K-RAS wildtype and 39 K-RAS mutated CRC (Bautista et al, 1997), 68 K-RAS wildtype, 49 K-RAS mutated CRC (Laso et al, 2004), 155 K-RAS wildtype, 41 K-RAS mutated CRC (Naguib et al, 2010), 427 K-RAS wildtype, 242 K-RAS mutated CRC (Schernhammer, Giovannuccci, Fuchs & Ogino, 2008), 971 K-RAS wildtype 457 K-RAS mutated CRC (Slattery et al, 2000) and 453 K-RAS wildtype, 81 K-RAS mutated adenomas (Wark et al, 2006) failed to identify folate intake as associated with K-RAS mutation status. Increased consumption of folate offering some degree of protection against K-RAS mutation was observed in two independent studies.…”

Concurrent mutation in exons 1 and 2 of the K-ras oncogene in colorectal cancer

“…This study, published in 2002, focused attention for the first time on determining the presence of the double mutation in heterozygosity or on the same allele [8]. In a recent study performed on 186 adenocarcinomas and 16 adenomas from the EPICNorfolk study, one sample, harboring a double mutation at codons 19 (Leu to Phe) and 20 (Thr to Ala), showed these two changes based on the same allele [9] In fact, a few previous studies had exclusively described the double mutations at codon 12, consequently assuming that these concurrent mutations inevitably affected both alleles [10,11]. Sato et al, using dot blot hybridization, reported a double codon 12 mutation from wild type GGT (Gly) to GAT (Asp) and GCT (Ala), observed in a case of human endometri- www.fhc.viamedica.pl al carcinoma [10].…”