DNA methylation analysisof KRAS mutated colorectal tumors and adjacent tissues from cancer patinets and KRAS mutated Aberrant Crypt Foci and matching normal crypts from healthy individuals by using RRBS

ABSTRACT: Colorectal cancer (CRC) is characterized by genome-wide alterations to DNA methylation that influence gene expression and genomic stability. Less is known about the extent to which methylation is disrupted in the earliest stages of CRC development. In this study we have combined laser-capture microdissection (LCM) with reduced representation bisulfite sequencing (RRBS) to identify cancer associated DNA methylation changes in human aberrant crypt foci (ACF), the earliest putative precursor to CRC. Using this approach, methylation profiles have been generated for 10 KRAS-mutant ACF and 10 CRCs harboring a KRAS mutation, as well as matched samples of normal mucosa. Of 811 differentially methylated regions (DMRs) identified in ACF, 537 (66%) were hypermethylated and 274 (34%) were hypomethylated. DMRs located within intergenic regions were heavily enriched for AP-1 transcription factor binding sites and were frequently hypomethylated. Furthermore, gene ontology (GO) analysis demonstrated that DMRs associated with promoters were enriched for genes involved in intestinal development, including homeobox genes and targets of the Polycomb repressive complex 2 (PRC2).Consistent with their role in the earliest stages of colonic neoplasia, 75% of the methylation changes identified in ACF were also present in the CRC samples. Together, these data demonstrate that DNA methylation changes, including significant hypomethylation, occur more frequently in early colonic neoplasia than previously believed, and identify epigenomic features of ACF that may provide new targets for cancer chemoprevention or lead to the development of new biomarkers for CRC risk.

ORGANISM(S): Homo sapiens

PROVIDER: GSE95654 | GEO | 2018/01/23

REPOSITORIES: GEO