Pan-cancer analysis reveals presence of pronounced DNA methylation drift in CpG island methylator phenotype clusters

Abstract

Aim: To provide characteristics of major genomic correlates in CpG island methylator phenotype-high (CIMP-H) subgroups in relation to corresponding non-CIMP-H subgroups by use of phenotypic, DNA methylation and RNAseq data.

Materials & methods: Twenty-three datasets generated by The Cancer Genome Atlas project encompassing over 7200 unique samples were analyzed. We identified 23 CIMP-H clusters by use of unsupervised clustering.

Results & conclusion: More than 90% of CIMP-H clusters were significantly associated with accelerated epigenetic mitotic clock, demethylation of enhancer sites, backbone and repetitive sequences. Pronounced epigenetic drift observed in majority of CIMP-H subgroups may be related to increased cell division rate, which leads to expansion of DNA methylation errors. This may explain pan-cancer mechanism of establishing CIMP-H in majority of tissue types.

Keywords: CpG island; DNA methylation; Illumina 450k; backbone; cancer; clustering; epigenetic drift; methylator phenotype; repetitive sequences.