{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T17:18:13Z","timestamp":1769188693582,"version":"3.49.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2008,9,9]],"date-time":"2008-09-09T00:00:00Z","timestamp":1220918400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Cancer"],"published-print":{"date-parts":[[2008,12]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n BRAF<\/jats:italic>, KRAS<\/jats:italic> and PIK3CA<\/jats:italic> mutations are frequently found in sporadic colorectal cancer (CRC). In contrast to KRAS<\/jats:italic> and PIK3CA<\/jats:italic> mutations, BRAF<\/jats:italic> mutations are associated with tumours harbouring CpG Island methylation phenotype (CIMP), MLH1<\/jats:italic> methylation and microsatellite instability (MSI). We aimed at determine the frequency of KRAS<\/jats:italic>, BRAF<\/jats:italic> and PIK3CA<\/jats:italic> mutations in the process of colorectal tumourigenesis using a series of colorectal polyps and carcinomas. In the series of polyps CIMP, MLH1<\/jats:italic> methylation and MSI were also studied.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n Mutation analyses were performed by PCR\/sequencing. Bisulfite treated DNA was used to study CIMP and MLH1<\/jats:italic> 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.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n KRAS<\/jats:italic>, PIK3CA<\/jats:italic> or BRAF<\/jats:italic> occur in 71% of polyps and were mutually exclusive. KRAS<\/jats:italic> mutations occur in 35% of polyps. PIK3CA<\/jats:italic> was found in one of the polyps. V600E BRAF<\/jats:italic> 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<\/jats:italic>. MLH1<\/jats:italic> 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<\/jats:italic> and PIK3CA<\/jats:italic> are likely to precede both types of CRC. BRAF<\/jats:italic> mutations are likely to precede MSI carcinomas since the frequency found in serrated polyps is similar to what is found in MSI CRC (P<\/jats:italic> = 0.9112), but statistically different from what is found in microsatellite stable (MSS) tumours (P<\/jats:italic> = 0.0191).<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Our results show that BRAF<\/jats:italic>, KRAS<\/jats:italic> and PIK3CA<\/jats:italic> mutations occur prior to malignant transformation demonstrating that these oncogenic alterations are primary genetic events in colorectal carcinogenesis. Further, we show that BRAF<\/jats:italic> 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<\/jats:italic> mutations. These results support that BRAF<\/jats:italic> mutations harbour a mild oncogenic effect in comparison to KRAS<\/jats:italic> and suggest that BRAF<\/jats:italic> mutant colorectal cells need to accumulate extra epigenetic alterations in order to acquire full transformation and evolve to MSI CRC.<\/jats:p>\n <\/jats:sec>","DOI":"10.1186\/1471-2407-8-255","type":"journal-article","created":{"date-parts":[[2008,9,9]],"date-time":"2008-09-09T18:09:53Z","timestamp":1220983793000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: Primary or secondary genetic events in colorectal carcinogenesis?"],"prefix":"10.1186","volume":"8","author":[{"given":"S\u00e9rgia","family":"Velho","sequence":"first","affiliation":[]},{"given":"C\u00e1tia","family":"Moutinho","sequence":"additional","affiliation":[]},{"given":"Lu\u00eds","family":"Cirnes","sequence":"additional","affiliation":[]},{"given":"Cristina","family":"Albuquerque","sequence":"additional","affiliation":[]},{"given":"Richard","family":"Hamelin","sequence":"additional","affiliation":[]},{"given":"Fernando","family":"Schmitt","sequence":"additional","affiliation":[]},{"given":"F\u00e1tima","family":"Carneiro","sequence":"additional","affiliation":[]},{"given":"Carla","family":"Oliveira","sequence":"additional","affiliation":[]},{"given":"Raquel","family":"Seruca","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2008,9,9]]},"reference":[{"issue":"6429","key":"1193_CR1","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1038\/363558a0","volume":"363","author":"Y Ionov","year":"1993","unstructured":"Ionov Y, Peinado M, Malkhosyan S, Shibata D, Perucho M: Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. 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