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

• Published in: Epigenetics Vol. 13; no. 10-11; pp. 1088 - 1105
• Main Authors: Parker, Hannah R., Orjuela, Stephany, Martinho Oliveira, Andreia, Cereatti, Fabrizio, Sauter, Matthias, Heinrich, Henriette, Tanzi, Giulia, Weber, Achim, Komminoth, Paul, Vavricka, Stephan, Albanese, Luca, Buffoli, Federico, Robinson, Mark D., Marra, Giancarlo
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.11.2018; Taylor & Francis Group
• Subjects: Adenoma - genetics; Adenoma - pathology; adenomatous polyp; Aged; Aged, 80 and over; colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Colonic Polyps - genetics; Colonic Polyps - pathology; CpG Islands; DNA Methylation; Female; Humans; Male; Middle Aged; Phenotype; Research Paper; Sessile serrated adenoma/polyp; DNA methylation; Sessile serrated adenoma/polyp; colon cancer; adenomatous polyp
• ISSN: 1559-2294; 1559-2308; 1559-2308
• DOI: 10.1080/15592294.2018.1543504

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.