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

Q: How often do colorectal cancers arise from sessile serrated lesions (SSLs)?

Up to 30% of colorectal cancers develop from sessile serrated lesions (SSLs).

Q: What methylation changes were linked to MLH1 status in SSLs?

PRDM2 promoter methylation correlated with MLH1 expression status, being largely hypermethylated in MLH1-deficient SSL-Ds and hypomethylated in MLH1-proficient SSL-Ds.

Q: Do PRDM2 and MLH1 epigenetic alterations appear early in SSL formation?

Yes. Increased DNA methylation levels of PRDM2 and MLH1 were already visible in SSLs compared with normal mucosa, indicating early introduction of epigenetic alterations during SSL formation.

Sep 21, 2026

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Up to 30% of colorectal cancers (CRCs) develop from sessile serrated lesions (SSLs). Within the serrated neoplasia pathway, distinct oncogenetic routes generate microsatellite-stable and microsatellite-instable CRCs. Aberrant DNA methylation appears early, so a cohort of 23 SSLs with dysplasia or cancer was analyzed using genome-wide and tumor-suppressor gene–focused methylation profiling of SSL-D, SSL, and adjacent normal mucosa.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

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Abstract

Introduction

Background on colorectal cancer and serrated neoplasia pathway

BRAFV600E and CIMP as initiating and progression drivers

The Journal of Pathology: Clinical Research J Pathol Clin Res March 2024; 10: e348 Published online 21 February 2024 in Wiley Online Library (wi[leyonlinelibrary.com](leyonlinelibrary.com). DOI: 10.1002/cjp2.348)[).](leyonlinelibrary.com). DOI: 10.1002/cjp2.348)[ DOI: 10.1002/cjp2.348](leyonlinelibrary.com). DOI: 10.1002/cjp2.348) ORIGINAL ARTICLE Aberrant PRDM2 methylation as an early event in serrated lesions destined to evolve into microsatellite-instable colorectal cancers David EFWM van Toledo 1,2,3†, Arne GC Bleijenberg 1,2,3†, Andrea Venema4, Mireille J de Wit5, Susanne van Eeden5, Gerrit A Meijer6 , Beatrice Carvalho6, Evelien Dekker 1,2,3 , Peter Henneman4 , Joep EG IJspeert 1,2,3 and Carel JM van Noesel5* 1 Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands 2Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam, The Netherlands 3Cancer Center Amsterdam, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, The Netherlands 4Department of Human Genetics, Epigenetics of disease, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, The Netherlands 5Department of Pathology, Amsterdam, Amsterdam University Medical Centers, Location Academic Medical Center, The Netherlands 6Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands *Correspondence to: CarelJM van Noesel, Department of Pathology, Amsterdam University Medical Centers, Location Academic Medical Center, Meibergdreef 9 1105 AZ, Amsterdam, The Netherlands. E-mail: [c.j.vannoesel@amsterdamumc.nl](c.j.vannoesel@amsterdamumc.nl)[ ](c.j.vannoesel@amsterdamumc.nl)†Shared ﬁrst authorship. Abstract 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 handspeciﬁcally 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. Keywords: colorectal cancer; sessile serrated lesions; serrated neoplasia pathway; methylation Received 31 May 2023; Revised 17 August 2023; Accepted 15 October 2023 Conﬂict of interest statement: ED received endoscopic equi

FAQs

How often do colorectal cancers arise from sessile serrated lesions (SSLs)?

Up to 30% of colorectal cancers develop from sessile serrated lesions (SSLs).

What methylation changes were linked to MLH1 status in SSLs?

PRDM2 promoter methylation correlated with MLH1 expression status, being largely hypermethylated in MLH1-deficient SSL-Ds and hypomethylated in MLH1-proficient SSL-Ds.

Do PRDM2 and MLH1 epigenetic alterations appear early in SSL formation?

Yes. Increased DNA methylation levels of PRDM2 and MLH1 were already visible in SSLs compared with normal mucosa, indicating early introduction of epigenetic alterations during SSL formation.

Sep 21, 2026

Upload by Anda