Consensus molecular subtype transition during progression of colorectal cancer
Open accessAbstract
The consensus molecular subtype (CMS) classification divides colorectal cancer (CRC) into four distinct subtypes based on RNA expression profiles. The biological differences between CMSs are already present in CRC precursor lesions, but not all CMSs pose the same risk of malignant transformation. To fully understand the path to malignant transformation and to determine whether CMS is a fixed entity during progression, genomic and transcriptomic data from two regions of the same CRC lesion were compared: the precursor region and the carcinoma region. In total, 24 patients who underwent endoscopic removal of T1–2 CRC were included. Regions were subtyped for CMS and DNA mutation analysis was performed. Additionally, a set of 85 benign adenomas was CMS‐subtyped. This analysis revealed that almost all benign adenomas were classified as CMS3 (91.8%). In contrast, CMS2 was the most prevalent subtype in precursor regions (66.7%), followed by CMS3 (29.2%). CMS4 was absent in precursor lesions and originated at the carcinoma stage. Importantly, CMS switching occurred in a substantial number of cases and almost all (six out of seven) CMS3 precursor regions showed a shift to a different subtype in the carcinoma part of the lesion, which in four cases was classified as CMS4. In conclusion, our data indicate that CMS3 is related to a more indolent type of precursor lesion that less likely progresses to CRC and when this occurs, it is often associated with a subtype change that includes the more aggressive mesenchymal CMS4. In contrast, an acquired CMS2 signature appeared to be rather fixed during early CRC development. Combined, our data show that subtype changes occur during progression and that CMS3 switching is related to changes in the genomic background through acquisition of a novel driver mutation (TP53) or selective expansion of a clone, but also occurred independently of such genetic changes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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The CMS4 tumor state arises from the progression of a less aggressive state, rather than originating from a distinct carcinogenesis pathway, perhaps with the exception of inflammation-induced colorectal cancer.
“Altogether, several works based on paired tumor regions (11, 19, 30) support the notion that the CMS4 tumor state arises from the progression of a less aggressive state, rather than originating from a distinct carcinogenesis pathway, perhaps with the exception of inflammation-induced colorectal cancer (25).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [19]
CMS4 colorectal cancer may alternatively originate from CMS3 tubular adenomas.
“CMS4 colorectal cancer may alternatively originate from CMS3 tubular adenomas (TA; Fig. 1).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [19]
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- Authors
- van de Weerd, S., Torang, A., Zwager, L. W., Koelink, P. J., Koster, J., Bastiaansen, B. A., Lammers, V., Longobardi, C., Roodhart, J. M., van Krieken, J. H., Farina Sarasqueta, A., Dekker, E., & Medema, J. P.
- Affiliations
- Amsterdam UMC University of Amsterdam, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam Amsterdam The Netherlands
- Amsterdam UMC Location University of Amsterdam (NL)
- Utrecht University (NL)
- Department of Pathology Radboud University Medical Centre Nijmegen The Netherlands
- Department of Pathology, Amsterdam UMC University of Amsterdam Amsterdam The Netherlands
- Corresponding author
- Medema, Jan Paul
- ORCID
- Venue
- The Journal of Pathology
- Publisher
- Wiley
- Published
- 2023-09-08
- Volume
- 261
- Issue
- 3
- Pages
- 298-308
- ISSN
- 0022-3417 (ISSN-L)
- 1096-9896
- OpenAlex
- W4386529866
- Cited by
- 6
- References
- 36
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3
- FWCI
- 0.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Pathology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- KWF Kankerbestrijding (UvA2013‐6331)
- Oncode Institute
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- colorectal cancer, tumor progression, precursor lesions, colorectal adenoma, subtype switching, CMS4, mesenchymal subtype, TP53 mutation, clonal expansion, driver mutations, endoscopic resection
- MeSH terms
- Adenoma, Aged, Aged, 80 and over, Cell Transformation, Neoplastic, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Mutation, Biomarkers, Tumor, Colorectal Neoplasms, Disease Progression, Gene Expression Profiling, Consensus, Transcriptome
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