Fig. 6
Functional correlation of CC-subtype specific methylation. a Enriched KEGG pathways (P < 0.01) within CCN-CpGs and CIMP-CpG-associated genes. Shown are only those pathways that were enriched exclusively. b Correlation between methylation and expression at CCN-CpGs and CIMP-CpG-associated genes in nonCIMP-CC or CIMP-CCs. Number of samples are shown as n. P values are calculated as Pearson correlation.c Overlap of CIMP-CpG-associated genes with genes acquiring mutations during colon tumorigenesis (left) and differential gene expression of these overlapped genes (74) in CIMP-CCs versus paired normal mucosa. Shown are log2 fold changes (x-axis) versus −log10 false discovery rate (FDR)-adjusted P value (y-axis). Colored dots represent significant (FDR-adjusted P < 0.05) upregulated (red) or downregulated (blue) genes and number of samples are shown as n. d Model depicting changes in methylation at CCN-CpGs and CIMP-CpGs from healthy normal mucosa through precursor lesions to cancer as described in text. TA Tubular adenoma, SSA/P sessile serrated adenoma/polyp. (
), downregulated gene expression; m, methylated; (
), inhibition; (
), feedback inhibition. e Epigenetic progression model for subtype-specific colon carcinogenesis. Illustration depicting identical (solid rectangle) or functionally equivalent (dotted rectangle) genes affected by genetic mutation in nonCIMP (blue) or by epigenetic deregulation in CIMP (red) carcinogenesis. Normal epithelium to carcinoma progression is depicted by rectangles with arrowheads. Genomic instability (CIN or MSI) associated with specific tumor subtypes is indicated