Braf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16

2010 EMBO Molecular Medicine The majority of human colorectal cancers (CRCs) are initiated by mutations arising in the adenomatous polyposis coli (APC) tumour suppressor gene. However, a new class of non-APCmutated CRCs has been defined that have a serrated histopathology and carry the BRAF oncogene. Herewe have investigated the pathogenesis of serrated CRCs by expressing Braf in the proliferative cells of the mouse gastrointestinal tract. We show that the oncogene drives an initial burst of Mekdependent proliferation, leading to the formation of hyperplastic crypts. This is associatedwithb-catenin nuclear localization by amechanism involvingMapk/Erk kinase (Mek)-dependent, Akt-independent phosphorylation of Gsk3b. However, hyperplastic crypts remain dormant for prolonged periods due to the induction of crypt senescence accompanied by upregulation of senescence-associated b-galactosidase and p16. We show that tumour progression is associated with downregulation of p16 through enhanced CpG methylation of exon 1 and knockout of Cdkn2a confirms this gene is a barrier to tumour progression. Our studies identify BRAF as an early genetic driver mutation in serrated CRCs and indicate that, unlike APC-mutated cancers, this subtype arises by the bypassing of a Braf driven oncogene-induced senescence programme.