RT Journal Article SR Electronic T1 BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 1137 OP 1144 DO 10.1136/gut.2003.037671 VO 53 IS 8 A1 T Kambara A1 L A Simms A1 V L J Whitehall A1 K J Spring A1 C V A Wynter A1 M D Walsh A1 M A Barker A1 S Arnold A1 A McGivern A1 N Matsubara A1 N Tanaka A1 T Higuchi A1 J Young A1 J R Jass A1 B A Leggett YR 2004 UL http://gut.bmj.com/content/53/8/1137.abstract AB Background and aims: Mutations in BRAF have been linked with colorectal cancers (CRC) showing high level microsatellite instability (MSI-H). However, the distribution of BRAF mutations in MSI-H cancers remains to be clarified with respect to precursor lesions and the CpG island methylator phenotype (CIMP). Methods: Forty three hyperplastic polyps (HP), nine mixed polyps (MP), five serrated adenomas (SA), 28 conventional adenomas (AD), 18 hereditary non-polyposis colorectal cancers (HNPCC), and 127 sporadic CRC (46 MSI-H and 81 non-MSI-H) were collected from patients undergoing colectomy for either CRC or hyperplastic polyposis. Twenty five of 57 serrated lesions were derived from four patients with hyperplastic polyposis. HP were further subdivided according to recently documented morphological criteria into 27 classical HP and 16 variant lesions described as “sessile serrated adenoma” (SSA). All tumours were screened for BRAF activating mutations. Results: The BRAF mutation was more frequent in SSA (75%) and MP (89%) than in classical HP (19%), SA (20%), and AD (0%) (p<0.0001), and also in sporadic MSI-H cancers (76%) compared with HNPCC (0%) and sporadic non-MSI-H cancers (9%) (p<0.0001). The BRAF mutation was identified more often in CIMP-high serrated polyps (72%) and CIMP-high CRC (77%) than in CIMP-low (30%) and CIMP-negative (13%) polyps (p = 0.002) as well as CIMP-low (18%) and CIMP-negative (0%) CRC (p<0.0001). Conclusions: The BRAF mutation was frequently seen in SSA and in sporadic MSI-H CRC, both of which were associated with DNA methylation. Sporadic MSI-H cancers may originate in SSA and not adenomas, and BRAF mutation and DNA methylation are early events in this “serrated” pathway.