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

By Hannah R. Parker, Stephany Orjuela, Andreia Martinho Oliveira, Fabrizio Cereatti, Matthias Sauter, Henriette Heinrich, Giulia Tanzi, Achim Weber, Paul Komminoth, Stephan Vavricka, Luca Albanese, Federico Buffoli, Mark D Robinson, Giancarlo Marra

Posted 27 Jun 2018
bioRxiv DOI: 10.1101/357178 (published 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), but their molecular features are poorly understood. We used high-throughput analysis of DNA methylation and gene expression to investigate the epigenetic phenotype of SSA/Ps. Fresh-tissue samples of 17 SSA/Ps and (for comparison purposes) 15 conventional adenomas (cADNs) - each with a matched sample of normal mucosa - were prospectively collected during colonoscopy (total no. samples analyzed: 64). DNA and RNA were extracted from each sample. DNA was subjected to bisulfite next-generation sequencing to assess methylation levels at ~2.7 million CpG sites located predominantly in gene regulatory regions and spanning 80.5Mb (~2.5% of the genome); RNA was sequenced to define the samples' transcriptomes. An independent series of 61 archival lesions was used for targeted verification of DNA methylation findings. Compared with normal mucosa samples, 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 (3 SSA/P-specific and 3 common) demonstrated the high potential of DNA methylation markers for predicting the diagnosis of SSA/Ps and cADNs. Surprisingly, proto-CIMP in SSA/Ps was associated with upregulated gene expression (n=618 genes vs 349 that were downregulated); downregulation was more common in cADNs (n=712 vs 516 upregulated genes). 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 that can add precision to the clinical management of the two most frequent colon-cancer precursors.

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