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Background  Recent work led to recognize sessile serrated adenomas (SSA) as precursor to many of the sporadic colorectal cancers with microsatellite instability (MSI). However, comprehensive analyses of DNA methylation in SSA and MSI cancer have not been conducted.    Methods  With an array-based methylation sensitive amplified fragment length polymorphism (MS-AFLP) method we analyzed 8 tubular (TA) and 19 serrated (SSA) adenomas, and 14 carcinomas with (MSI) and 12 without (MSS) microsatellite instability. MS-AFLP array can survey relative differences in methylation between normal and tumor tissues of 9,654 DNA fragments containing all  NotI  sequences in the human genome.    Results  Unsupervised clustering analysis of the genome-wide hypermethylation alterations revealed no major differences between or within these groups of benign and malignant tumors regardless of their location in intergenic, intragenic, promoter, or 3′ end regions. Hypomethylation was less frequent in SSAs compared with MSI or MSS carcinomas. Analysis of variance of DNA methylation between these four subgroups identified 56 probes differentially altered. The hierarchical tree of this subset of probes revealed two distinct clusters: Group 1, mostly composed by TAs and MSS cancers with  KRAS  mutations; and Group 2 with  BRAF  mutations, which consisted of cancers with MSI and  MLH1  methylation (Group 2A), and SSAs without  MLH1  methylation (Group 2B).  AXIN2 , which cooperates with APC and β-catenin in Wnt signaling, had more methylation alterations in Group 2, and its expression levels negatively correlated with methylation determined by bisulfite sequencing. Within group 2B, low and high  AXIN2  expression levels correlated significantly with differences in size (P = 0.01) location (P = 0.05) and crypt architecture (P = 0.01).    Conclusions  Somatic methylation alterations of  AXIN2 , associated with changes in its expression, stratify SSAs according to some clinico-pathological differences. We conclude that hypermethylation of  MLH1 , when occurs in an adenoma cell with  BRAF  oncogenic mutational activation, drives the pathway for MSI cancer by providing the cells with a mutator phenotype.  AXIN2  inactivation may contribute to this tumorigenic pathway either by mutator phenotype driven frameshift mutations or by epigenetic deregulation contemporary with the unfolding of the mutator phenotype.

DNA methylation alterations of AXIN2 in serrated adenomas and colon carcinomas with microsatellite instability