Genome widespread CpG island promoter methylation is a molecular feature of RCT pathogenesis. (A) The table reports the promoter methylation analysis carried out on 14 genes; six are the canonical, representative CIMP loci (MLH1, CDKN2A, IGF2, SOX2, NEUROG1, RUNX3); the others are either involved in cell cycle control as CDKN1B and CDKN1C; or in cell-cell adhesion as CDH1 and CTNNB1 or in DNA repair as XPD, XPA. The differential promoter methylation level in rhabdoid colorectal and adjacent lesions is shown. (B) Representative methylation specific PCR analysis at three CIMP loci (MLH1, RUNX3, CDKN2A) and CTNNB1 (β-catenin) in case I; (PC) indicates positive unmethylated (U) or methylated (M) control, respectively. (C) Progressive accumulation of promoter methylation at six specific CIMP loci from normal mucosa, tubular adenomas and finally to composite RCT. (D) The schematic drawing illustrates the possible CRC pathogenetic mechanisms; rhabdoid CRC originates through an alternative pathway resembling the serrated pathway. Abbreviations: glandular (GC) and rhabdoid (RC) component of rhabdoid colorectal tumor case II (RCTII). NM: normal mucosa; TA: tubular adenoma; CTA: cancerized tubular adenoma.