Fig. 3

Oncogenic BRAFV600E mutation in colorectal cancer allows MLH1 methylation after TFAP4 disruption. a Colorectal cancer: A BRAFV600E mutation activates the MEK/ERK pathway to phosphorylate MAFG, allowing DNMT3B recruitment. TFAP4 binding sterically hinders MAFG on the protective (G) rs1800734 allele, preventing DNMT3B recruitment and subsequent MLH1 methylation. TFAP4 binding is disrupted on the rs1800734 risk (A) allele leading to DNMT3B mediated MLH1 promoter methylation and transcriptional repression. b Endometrial cancer: BRAF is rarely mutated and MLH1 methylation does not occur via the MAFG pathway. TFAP4 is still able to bind the protective allele but this has no significant effect on methylation accumulation