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

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

doi:10.1080/15592294.2018.1543504

Cited by 23 publications

(72 citation statements)

References 85 publications

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“…RNA-based gene expression pro les obtained in previous studies by our group have revealed numerous RNA markers that are differentially expressed in SSA/Ps and cADNs [28]. Here, using ISH, we veri ed the accuracy of 9 of the 12 markers putatively capable of distinguishing between these two major premalignant tumor types.…”

Section: Discussionmentioning

confidence: 57%

“…In each section, staining of the normal mucosal crypts at the border of each lesion was assessed as an internal normal-tissue control. The choice of the RNA targets to be veri ed was based on RNA-sequencing data on precancerous colorectal lesions previously published by our group [28] (Supplementary Fig. 2) and others [45] ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The VSIG1 protein, a member of the junctional adhesion molecule family, is normally expressed in the gastric mucosa and testis [49] [50]. Its ectopic expression in serrated colorectal lesions, which has been documented at both the transcript and protein levels [44][51] [28], is thought to re ect aberrant differentiation toward a gastric-cell phenotype during the development of these tumors. SSA/Ps and HPs also acquire expression of other molecules typically found in the gastric mucosa, e.g., ANXA10 (Annexin 10), a known marker of the normal mucosa of the stomach [52][53] [54].…”

Section: Discussionmentioning

confidence: 99%

“…Three-quarters of the CRCs arising in SSA/Ps (10-15% of all CRCs) have a well-de ned phenotype characterized by location in the proximal colon, the BRAFV600E gain-of-function mutation, and methylation of cytosines in CpG islands that are generally unmethylated in the DNA of the normal colorectal mucosa (a feature referred to as the CpG island methylator phenotype (CIMP) [18][27] [28].…”

Section: Introductionmentioning

confidence: 99%

“…Attempts have recently been made to differentiate CRC precursor lesions based on high-throughput transcriptome pro ling data. RNA sequencing studies of serrated lesions and cADNs by our group [28] and that of Delker [44] [45] have identi ed a large number of putative gene expression markers that could be used for this purpose, following their veri cation and validation with in situ hybridization (ISH) and immunohistochemistry. In the study described below, we used ISH to verify the expression pro les of 21 transcriptome-based RNA molecules that appeared to be promising differentiation markers among CRC precursors.…”

Section: Introductionmentioning

confidence: 99%

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An “Expressionistic” Look at Serrated Precancerous Colorectal Lesions

Marra¹

2020

Preprint

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Background: Approximately 60% of colorectal cancer (CRC) precursor lesions are the genuinely-dysplastic conventional adenomas (cADNs). The others include hyperplastic polyps (HPs), sessile serrated adenoma/polyps (SSA/Ps), and traditional serrated adenomas (TSAs), subtypes of a class of lesions collectively referred to as “serrated.” Endoscopic and histologic differentiation between cADNs and serrated lesions, and between serrated lesion subtypes can be difficult. Methods: We used in situ hybridization to verify the expression patterns in CRC precursors of 21 RNA molecules that appear to be promising differentiation markers on the basis of previous RNA sequencing studies.Results: SSA/Ps could be clearly differentiated from cADNs by the expression patterns of 9 of the 12 RNAs tested for this purpose (VSIG1, ANXA10, ACHE, SEMG1, AQP5, LINC00520, ZIC5/2, FOXD1, NKD1). Expression patterns of all 9 in HPs were similar to those in SSA/Ps. Nine putatively HP-specific RNAs were also investigated, but none could be confirmed as such: most (e.g., HOXD13 and HOXB13), proved instead to be markers of the normal mucosa in the distal colon and rectum, where most HPs arise. TSAs displayed mixed staining patterns reflecting the presence of serrated and dysplastic glands in the same lesion. Conclusions: Using a robust in situ hybridization protocol, we identified promising tissue-staining markers that, if validated in larger series of lesions, could facilitate more precise histologic classification of CRC precursors and, consequently, more tailored clinical follow-up of their carriers. Our findings should also fuel functional studies on the pathogenic significance of specific gene expression alterations in the initiation and evolution of CRC precursor subtypes.

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Section: Discussionmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An “Expressionistic” Look at Serrated Precancerous Colorectal Lesions

Marra¹

2020

Preprint

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Serum DNA methylome of the colorectal cancer serrated pathway enables non‐invasive detection

Gallardo‐Gómez,

Costas‐Ríos,

Garcia‐Prieto

et al. 2024

Molecular Oncology

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The clinical relevance of the colorectal cancer serrated pathway is evident, but the screening of serrated lesions remains challenging. We aimed to characterize the serum methylome of the serrated pathway, and to evaluate circulating cell‐free DNA (cfDNA) methylomes as a potential source of biomarkers for the non‐invasive detection of serrated lesions. We collected serum samples from individuals with serrated adenocarcinoma (SAC), traditional serrated adenomas, sessile serrated lesions, hyperplastic polyps and individuals with no colorectal findings. First, we quantified cfDNA methylation with the MethylationEPIC array. Then, we compared the methylation profiles with tissue and serum datasets. Finally, we evaluated the utility of serum cfDNA methylation biomarkers. We identified a differential methylation profile able to distinguish high‐risk serrated lesions from no serrated neoplasia, showing concordance with tissue methylation from SAC and sessile serrated lesions. Serum methylation profiles are pathway‐specific, clearly separating serrated lesions from conventional adenomas. The combination of ninjurin 2 (NINJ2) and glutamate rich 1 (ERICH1) methylation discriminated high‐risk serrated lesions and SAC with 91.4% sensitivity (64.4% specificity), while zinc finger protein 718 (ZNF718) methylation reported 100% sensitivity for the detection of SAC (96% specificity). This is the first study exploring the serum methylome of serrated lesions. Differential methylation of cfDNA can be used for the non‐invasive detection of colorectal serrated lesions.

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Aberrant PRDM2 methylation as an early event in serrated lesions destined to evolve into microsatellite‐instable colorectal cancers

van Toledo,

Bleijenberg,

Venema

et al. 2024

The Journal of Pathology CR

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Up to 30% of colorectal cancers (CRCs) develop from sessile serrated lesions (SSLs). Within the serrated neoplasia pathway, at least two principally distinct oncogenetic routes exist generating microsatellite‐stable and microsatellite‐instable CRCs, respectively. Aberrant DNA methylation (DNAm) is found early in the serrated pathway and might play a role in both oncogenetic routes. We studied a cohort of 23 SSLs with a small focus (<10 mm) of dysplasia or cancer, 10 of which were MLH1 deficient and 13 MLH1 proficient. By comparing, for each SSL, the methylation status of (1) the region of dysplasia or cancer (SSL‐D), (2) the nondysplastic SSL (SSL), and (3) adjacent normal mucosa, differentially methylated probes (DMPs) and regions (DMRs) were assessed both genome‐wide as well as in a tumor‐suppressor gene‐focused approach. By comparing DNAm of MLH1‐deficient SSL‐Ds with their corresponding SSLs, we identified five DMRs, including those annotating for PRDM2 and, not unexpectedly, MLH1. PRDM2 gene promotor methylation was associated with MLH1 expression status, as it was largely hypermethylated in MLH1‐deficient SSL‐Ds and hypomethylated in MLH1‐proficient SSL‐Ds. Significantly increased DNAm levels of PRDM2 and MLH1, in particular at ‘critical’ MLH1 probe sites, were to some extent already visible in SSLs as compared to normal mucosa (p = 0.02, p = 0.01, p < 0.0001, respectively). No DMRs, nor DMPs, were identified for SSLs destined to evolve into MLH1‐proficient SSL‐Ds. Our data indicate that, within both arms of the serrated CRC pathway, the majority of the epigenetic alterations are introduced early during SSL formation. Promoter hypermethylation of PRDM2 and MLH1 on the other hand specifically initiates in SSLs destined to transform into MLH1‐deficient CRCs suggesting that the fate of SSLs may not necessarily result from a stochastic process but possibly is already imprinted and predisposed.

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

Cited by 23 publications

References 85 publications

An “Expressionistic” Look at Serrated Precancerous Colorectal Lesions

An “Expressionistic” Look at Serrated Precancerous Colorectal Lesions

Serum DNA methylome of the colorectal cancer serrated pathway enables non‐invasive detection

Aberrant PRDM2 methylation as an early event in serrated lesions destined to evolve into microsatellite‐instable colorectal cancers

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