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

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

Author information

a Institute of Molecular Cancer Research , University of Zurich , Zurich , Switzerland.
b Institute of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics , University of Zurich , Zurich , Switzerland.
c Gastroenterology and Endoscopy Unit , Hospital of Cremona , Cremona , Italy.
d Division of Gastroenterology , Triemli Hospital , Zurich , Switzerland.
e Division of Pathology , Hospital of Cremona , Cremona , Italy.
f Institute of Surgical Pathology , University of Zurich , Zurich , Switzerland.
g Division of Pathology , Triemli Hospital , Zurich , Switzerland.


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.


DNA methylation; Sessile serrated adenoma/polyp; adenomatous polyp; colon cancer

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