Intratumor CMS heterogeneity impacts patient prognosis in localized colon cancer
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Abstract
Purpose: The consensus molecular subtypes (CMS) represent a significant advance in the understanding of intertumor heterogeneity in colon cancer. Intratumor heterogeneity (ITH) is the new frontier for refining prognostication and understanding treatment resistance. This study aims at deciphering the transcriptomic ITH of colon cancer and understanding its potential prognostic implications. Experimental Design: We deconvoluted the transcriptomic profiles of 1,779 tumors from the PETACC8 trial and 155 colon cancer cell lines as weighted sums of the four CMSs, using the Weighted In Silico Pathology (WISP) algorithm. We assigned to each tumor and cell line a combination of up to three CMS subtypes with a threshold above 20%. Results: Over 55% of tumors corresponded to mixtures of at least two CMSs, demonstrating pervasive ITH in colon cancer. Of note, ITH was associated with shorter disease-free survival (DFS) and overall survival, [HR, 1.34; 95% confidence interval (CI; 1.12–1.59), 1.40, 95% CI (1.14–1.71), respectively]. Moreover, we uncovered specific combinations of CMS associated with dismal prognosis. In multivariate analysis, ITH represents the third parameter explaining DFS variance, after T and N stages. At a cellular level, combined WISP and single-cell transcriptomic analysis revealed that most colon cancer cell lines are a mixture of cells falling into different CMSs, indicating that ITH may correspond to distinct functional statuses of colon cancer cells. Conclusions: This study shows that CMS-based transcriptomic ITH is frequent in colon cancer and impacts its prognosis. CMS-based transcriptomic ITH may correspond to distinct functional statuses of colon cancer cells, suggesting plasticity between CMS-related cell populations. Transcriptomic ITH deserves further assessment in the context of personalized medicine.
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Mixed CMS tumors with a CMS4 component also have a poor outcome.
“This also holds for mixed CMS tumors with a CMS4 component (13).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [13]
Intratumor heterogeneity is associated with the notable dismal prognosis of CMS4-associated combinations.
“Finally, one challenging issue arising from intratumor heterogeneity pertains to the notable dismal prognosis of CMS4-associated combinations (13).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [13]
NanoString-based classifiers have been developed for CMS4 colorectal cancer.
“A number of teams, including ours, have further developed NanoString-based classifiers (13, 22, 59).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [13]
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- Authors
- Marisa, L., Blum, Y., Taieb, J., Ayadi, M., Pilati, C., Le Malicot, K., Lepage, C., Salazar, R., Aust, D., Duval, A., Blons, H., Taly, V., Gentien, D., Rapinat, A., Selves, J., Mouillet-Richard, S., Boige, V., Emile, J.-F., de Reyniès, A., & Laurent-Puig, P.
- Affiliations
- 1Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France.
- La Ligue Contre le Cancer (FR)
- 2Institut du cancer Paris CARPEM, AP-HP, European Georges Pompidou Hospital, Paris, France.
- Centre National de la Recherche Scientifique (FR)
- 4Fédération Francophone de Cancérologie Digestive, INSERM, Université de Bourgogne et Franche Comté, Dijon, France.
- Inserm (FR)
- 6Catalan Institute of Oncology (IDIBELL), Universitat de Barcelona, CIBERONC, Spanish Gastrointestinal Tumors TTD Group, Barcelona, Spain.
- University Hospital Carl Gustav Carus (DE)
- Université Paris Sciences et Lettres (FR)
- 10Centre de Recherche en Cancérologie de Toulouse, INSERM, Université Toulouse III, Department of Pathology, CHU Toulouse, Toulouse, France.
- 3Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Sorbonne Université, Université de Paris, Paris, France.
- Hôpital Ambroise-Paré (FR)
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2021-06-24
- Volume
- 27
- Issue
- 17
- Pages
- 4768-4780
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC8974433
- OpenAlex
- W3174644591
- Cited by
- 68
- References
- 37
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 17 · 2023: 9 · 2022: 12 · 2021: 1
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Clinical Cancer Research (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion, other-oa)
- Funders
- SIRIC CARPEM (INCa-DGOS-Inserm_12561)
- ITMO CANCER (COCAHEMISCLE)
- Fédération Francophone de cancerologie digestive (FFCD)
- Ligue Contre le Cancer (CIT)
- Institut National Du Cancer (HETCOLI)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- intratumoral heterogeneity, consensus molecular subtypes, colon cancer, transcriptomic heterogeneity, prognosis, disease-free survival, overall survival, colon cancer cell lines, single-cell transcriptomics, tumor plasticity, treatment resistance
- MeSH terms
- Aged, Colonic Neoplasms, Female, Humans, Male, Prognosis, Survival Rate, Gene Expression Profiling, Cell Line, Tumor, Tumor Microenvironment
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