RT Journal Article SR Electronic T1 Braf mutation induces rapid neoplastic transformation in the aged and aberrantly methylated intestinal epithelium JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 1127 OP 1140 DO 10.1136/gutjnl-2020-322166 VO 71 IS 6 A1 Fennell, Lochlan A1 Kane, Alexandra A1 Liu, Cheng A1 McKeone, Diane A1 Hartel, Gunter A1 Su, Chang A1 Bond, Catherine A1 Bettington, Mark A1 Leggett, Barbara A1 Whitehall, Vicki YR 2022 UL http://gut.bmj.com/content/71/6/1127.abstract AB Objective Sessile serrated lesions (SSLs) are common across the age spectrum, but the BRAF mutant cancers arising occur predominantly in the elderly. Aberrant DNA methylation is uncommon in SSL from young patients. Here, we interrogate the role of ageing and DNA methylation in SSL initiation and progression.Design We used an inducible model of Braf mutation to direct recombination of the oncogenic Braf V637E allele to the murine intestine. BRAF mutation was activated after periods of ageing, and tissue was assessed for histological, DNA methylation and gene expression changes thereafter. We also investigated DNA methylation alterations in human SSLs.Results Inducing Braf mutation in aged mice was associated with a 10-fold relative risk of serrated lesions compared with young mice. There were extensive differences in age-associated DNA methylation between animals induced at 9 months versus wean, with relatively little differential Braf-specific methylation. DNA methylation at WNT pathway genes scales with age and Braf mutation accelerated age-associated DNA methylation. In human SSLs, increased epigenetic age was associated with high-risk serrated colorectal neoplasia.Conclusions SSLs arising in the aged intestine are at a significantly higher risk of spontaneous neoplastic progression. These findings provide support for a new conceptual model for serrated colorectal carcinogenesis, whereby risk of Braf-induced neoplastic transformation is dependent on age and may be related to age-associated molecular alterations that accumulate in the ageing intestine, including DNA methylation. This may have implications for surveillance and chemopreventive strategies targeting the epigenome.Data are available on reasonable request.