“…Previous literature reports showed that APC mutations and promoter hypermethylation tend to be more frequent in distal colon cancers, and less frequent in those CRCs showing MSI [35]. Indeed, with the exception of CIMP high CRCs, most of the sporadic CRCs show low or absence of CIMP, and are believed to progress following the adenoma-carcinoma pathway, with APC mutation or epigenetic silencing being one of the earliest events [7,8]. Consistently, APC hypomethylation is clustered in the central pathway characterized by hypomethylation of the other four genes and the MTR 2756AA genotype (Figure 3), and hypermethylation was linked to a cluster of variables characterized by advanced age (>70 years), certain polymorphisms of genes of the folate pathway, including the MTRR 66GG genotype and DNMT3B heterozygous genotypes, but also by MGMT hypermethylation, adenoma stage and other polymorphisms (Figure 2).…”