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Background   BRAF ,  KRAS  and  PIK3CA  mutations are frequently found in sporadic colorectal cancer (CRC). In contrast to  KRAS  and  PIK3CA  mutations,  BRAF  mutations are associated with tumours harbouring CpG Island methylation phenotype (CIMP),  MLH1  methylation and microsatellite instability (MSI). We aimed at determine the frequency of  KRAS ,  BRAF  and  PIK3CA  mutations in the process of colorectal tumourigenesis using a series of colorectal polyps and carcinomas. In the series of polyps CIMP,  MLH1  methylation and MSI were also studied.    Methods  Mutation analyses were performed by PCR/sequencing. Bisulfite treated DNA was used to study CIMP and  MLH1  methylation. MSI was detected by pentaplex PCR and Genescan analysis of quasimonomorphic mononucleotide repeats. Chi Square test and Fisher's Exact test were used to perform association studies.    Results   KRAS ,  PIK3CA  or  BRAF  occur in 71% of polyps and were mutually exclusive.  KRAS  mutations occur in 35% of polyps.  PIK3CA  was found in one of the polyps. V600E  BRAF  mutations occur in 29% of cases, all of them classified as serrated adenoma. CIMP phenotype occurred in 25% of the polyps and all were mutated for  BRAF .  MLH1  methylation was not detected and all the polyps were microsatellite stable. The comparison between the frequency of oncogenic mutations in polyps and CRC (MSI and MSS) lead us to demonstrate that  KRAS  and  PIK3CA  are likely to precede both types of CRC.  BRAF  mutations are likely to precede MSI carcinomas since the frequency found in serrated polyps is similar to what is found in MSI CRC ( P  = 0.9112), but statistically different from what is found in microsatellite stable (MSS) tumours ( P  = 0.0191).    Conclusion  Our results show that  BRAF ,  KRAS  and  PIK3CA  mutations occur prior to malignant transformation demonstrating that these oncogenic alterations are primary genetic events in colorectal carcinogenesis. Further, we show that  BRAF  mutations occur in association with CIMP phenotype in colorectal serrated polyps and verified that colorectal serrated polyps and MSI CRC show a similar frequency of  BRAF  mutations. These results support that  BRAF  mutations harbour a mild oncogenic effect in comparison to  KRAS  and suggest that  BRAF  mutant colorectal cells need to accumulate extra epigenetic alterations in order to acquire full transformation and evolve to MSI CRC.

BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: Primary or secondary genetic events in colorectal carcinogenesis?