The proto CpG island methylator phenotype of sessile serrated adenomas/polyps

Epigenetics. 2018;13(10-11):1088-1105. doi: 10.1080/15592294.2018.1543504. Epub 2018 Nov 22.

Abstract

Sessile serrated adenomas/polyps (SSA/Ps) are the putative precursors of the ~20% of colon cancers with the CpG island methylator phenotype (CIMP). To investigate the epigenetic phenotype of these precancers, we prospectively collected fresh-tissue samples of 17 SSA/Ps and 15 conventional adenomas (cADNs), each with a matched sample of normal mucosa. Their DNA was subjected to bisulfite next-generation sequencing to assess methylation levels at ~2.7 million CpGs located predominantly in gene regulatory regions and spanning 80.5Mb; RNA was sequenced to define the samples' transcriptomes. Compared with normal mucosa, SSA/Ps and cADNs exhibited markedly remodeled methylomes. In cADNs, hypomethylated regions were far more numerous (18,417 vs 4288 in SSA/Ps) and rarely affected CpG islands/shores. SSA/Ps seemed to have escaped this wave of demethylation. Cytosine hypermethylation in SSA/Ps was more pervasive (hypermethylated regions: 22,147 vs 15,965 in cADNs; hypermethylated genes: 4938 vs 3443 in cADNs) and more extensive (region for region), and it occurred mainly within CpG islands and shores. Given its resemblance to the CIMP typical of SSA/Ps' putative descendant colon cancers, we refer to the SSA/P methylation phenotype as proto-CIMP. Verification studies of six hypermethylated regions in an independent series of precancers demonstrated DNA methylation markers' high potential for predicting the diagnosis of SSA/Ps and cADNs. Surprisingly, proto-CIMP in SSA/Ps was associated with upregulated gene expression; downregulation was more common in cADNs. In conclusion, the epigenetic landscape of SSA/Ps differs markedly from that of cADNs. These differences are a potentially rich source of novel tissue-based and noninvasive biomarkers.

Keywords: DNA methylation; Sessile serrated adenoma/polyp; adenomatous polyp; colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics*
  • Adenoma / pathology
  • Aged
  • Aged, 80 and over
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology
  • Colonic Polyps / genetics*
  • Colonic Polyps / pathology
  • CpG Islands
  • DNA Methylation*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Phenotype*

Grant support

Schweizerischer Nationalfonds zur Förderung der wissenschaftlichen Forschung [310030-160163/1].