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Your search keyword '"Joep EG IJspeert"' showing total 4 results
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4 results on '"Joep EG IJspeert"'

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

Author

David EFWM vanToledo, Arne GC Bleijenberg, Andrea Venema, Mireille J deWit, Susanne vanEeden, Gerrit A Meijer, Beatrice Carvalho, Evelien Dekker, Peter Henneman, Joep EG IJspeert, and Carel JM vanNoesel

Subjects
colorectal cancer, sessile serrated lesions, serrated neoplasia pathway, methylation, Pathology, RB1-214
Abstract

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 (

Published
2024
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2. TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype

Author

Evelyn Fessler, Jarno Drost, Sander R van Hooff, Janneke F Linnekamp, Xin Wang, Marnix Jansen, Felipe De Sousa E Melo, Pramudita R Prasetyanti, Joep EG IJspeert, Marek Franitza, Peter Nürnberg, Carel JM van Noesel, Evelien Dekker, Louis Vermeulen, Hans Clevers, and Jan Paul Medema

Subjects
cancer subtypes, colorectal cancer, epithelial–mesenchymal transition, sessile serrated adenoma, transforming growth factor beta (TGFβ), Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract The heterogeneous nature of colorectal cancer (CRC) complicates prognosis and is suggested to be a determining factor in the efficacy of adjuvant therapy for individual patients. Based on gene expression profiling, CRC is currently classified into four consensus molecular subtypes (CMSs), characterized by specific biological programs, thus suggesting the existence of unifying developmental drivers for each CMS. Using human organoid cultures, we investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFβ plays an important role in the development of the mesenchymal CMS4, which is of special interest due to its association with dismal prognosis. We show that in tubular adenomas (TAs), which progress to classical CRCs, the dominating response to TGFβ is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFβ treatment prevails in a genetically engineered organoid culture carrying a BRAFV600E mutation, constituting a model system for sessile serrated adenomas (SSAs). Our data indicate that TGFβ signaling is already active in SSA precursor lesions and that TGFβ is a critical cue for directing SSAs to the mesenchymal, poor‐prognosis CMS4 of CRC.

Published
2016
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3. The earliest events in <scp> BRAF </scp> ‐mutant colorectal cancer: exome sequencing of sessile serrated lesions with a tiny focus dysplasia or cancer reveals recurring mutations in two distinct progression pathways

Author

Arne GC Bleijenberg, Joep EG IJspeert, Jos BG Mulder, Paul Drillenburg, Herbert V Stel, Elisabeth M Lodder, Beatriz Carvalho, Jade Jansen, Gerrit Meijer, Susanne Eeden, Evelien Dekker, and Carel JM Noesel

Subjects
Pathology and Forensic Medicine
Published
2022
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4. The earliest events in BRAF-mutant colorectal cancer: exome sequencing of sessile serrated lesions with a tiny focus dysplasia or cancer reveals recurring mutations in two distinct progression pathways

Author

Arne Gc, Bleijenberg, Joep Eg, IJspeert, Jos Bg, Mulder, Paul, Drillenburg, Herbert V, Stel, Elisabeth M, Lodder, Beatriz, Carvalho, Jade, Jansen, Gerrit, Meijer, Susanne, van Eeden, Evelien, Dekker, and Carel Jm, van Noesel

Subjects
Proto-Oncogene Proteins B-raf, Hyperplasia, Mutation, Exome Sequencing, Humans, Exome, Neoplasm Recurrence, Local, Colorectal Neoplasms
Abstract

Around 15-30% of colorectal cancers (CRC) develop from sessile serrated lesions (SSLs). After many years of indolent growth, SSLs can develop dysplasia and rapidly progress to CRC through events that are only partially understood. We studied molecular events at the very early stages of progression of SSLs via the MLH1-proficient and deficient pathways to CRC. We collected a cohort of rare SSLs with a small focus (10 mm) of dysplasia or cancer from the pathology archives of three hospitals. Whole-exome sequencing was performed on DNA from nonprogressed and progressed components of each SSL. Putative somatic driver mutations were identified in known cancer genes that were differentially mutated in the progressed component. All analyses were stratified by MLH1 proficiency. Forty-five lesions with a focus dysplasia or cancer were included, of which 22 (49%) were MLH1-deficient. Lesions had a median diameter of 10 mm (interquartile range [IQR] 8-15), while the progressed component had a median diameter of 3.5 mm (IQR 1.75-4.75). Tumor mutational burden (TMB) was high in MLH1-deficient lesions (23.9 mutations per MB) as compared to MLH1-proficient lesions (6.3 mutations per MB). We identified 34 recurrently mutated genes in MLH1-deficient lesions. Most prominently, ACVR2A and RNF43 were affected in 18/22 lesions, with mutations clustered in three hotspots. Most lesions with RNF43 mutations had concurrent mutations in ZNRF3. In MLH1-proficient lesions APC (10/23 lesions) and TP53 (6/23 lesions) were recurrently mutated. Our results show that the mutational burden is exceptionally high even in the earliest MLH1-deficient lesions. We demonstrate that hotspot mutations in ACVR2A and in the RNF43/ZNRF3 complex are extremely common in the early progression of SSLs along the MLH1-deficient serrated pathway, while APC and TP53 mutations are early events in the the MLH1-proficient pathway. © 2022 The Authors. The Journal of Pathology published by John WileySons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Published
2022

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