CHFR and cancer: The mechanism underlying the association between CHFR inactivation and MSI is unknown but might be due to an underlying DNA methylation defect that causes promoter CpG island methylation of both CHFR and MLH1. Murine studies, however, demonstrated that simultaneous loss of Chfr and Mlh1 synergistically increased predisposition to cancer development, which implicates a more functional interaction [38].