Tumour budding is associated with the mesenchymal colon cancer subtype and RAS/RAF mutations: a study of 1320 colorectal cancers with Consensus Molecular Subgroup (CMS) data
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BACKGROUND: Tumour budding is an important prognostic factor in colorectal cancer (CRC). Molecular profiling of tumour buds suggests (partial) epithelial-mesenchymal transition and cancer stem-cell phenotype, similarly described in the "mesenchymal" Consensus Molecular Subtype 4 (CMS4), which identifies a particularly poor prognostic subgroup. Here, we determine the association of tumour budding with CMS classification, prognosis, and response to therapy. METHODS: AMC-AJCCII-90 cohort (n = 76, stage II) was evaluated for peritumoural budding on H&E slides. LUMC (n = 270, stage I-IV), CAIRO (n = 504, metastatic CRC) and CAIRO2 (n = 472, metastatic CRC) cohorts were investigated for intratumoural budding using pan-cytokeratin-stained tissue microarrays. Budding was scored as count/area, then classified as <5 or ≥5 buds. For all cohorts, CMS classifications were available (gene-expression/immunohistochemistry-based classifiers). RESULTS: High (≥5) budding predicted a worse outcome in multivariate analysis in AMC-AJCCII-90 (p = 0.018), LUMC (p < 0.0001), and CAIRO (p = 0.03), and in CAIRO2 (continuous variable, p = 0.02). Tumour budding counts were higher in CMS4 compared to epithelial CMS2/3 cancers (p < 0.01, all), and associated with KRAS/BRAF mutations (p < 0.01, AMC-AJCCII-90, CAIRO, CAIRO2). CONCLUSION: Tumour budding is an adverse prognostic factor across all CRC stages and is associated with the mesenchymal CMS4 phenotype. KRAS/BRAF mutations are strongly correlated with tumour budding suggesting their involvement in the regulation of this process.
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The CMS4 subtype is associated with tumor budding.
“several studies have documented an association between the CMS4 subtype and tumor budding, defined as a single tumor cell or tumor cluster of up to four cells at the invasive margin (29–31)”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [31]
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- Authors
- Trinh, A., Lädrach, C., Dawson, H. E., ten Hoorn, S., Kuppen, P. J. K., Reimers, M. S., Koopman, M., Punt, C. J. A., Lugli, A., Vermeulen, L., & Zlobec, I.
- Affiliations
- Harvard University (US)
- University of Bern (CH)
- Leiden University Medical Center (NL)
- University Medical Center Utrecht (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- Amsterdam University Medical Centers (NL)
- Corresponding author
- Zlobec, Inti
- ORCID
- Venue
- British Journal of Cancer
- Published
- 2018-11
- Volume
- 119
- Issue
- 10
- Pages
- 1244-1251
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC6251036
- OpenAlex
- W2899462292
- Cited by
- 83
- References
- 31
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 9 · 2023: 15 · 2022: 12 · 2021: 13 · 2020: 13 · 2019: 7 · 2018: 1
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- British Journal of Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- BORIS (University Library Bern) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- New York Stem Cell Foundation (ERG-StG 638193, UVA2014-7245)
- Mach-Gaensslen Foundation of Canada
- ZonMw (ERG-StG 638193, 016.156.308, UVA2014-7245, Vidi 016.156.308)
- KWF Kankerbestrijding (UVA2014‐7245, ERG-StG 638193)
- Innovatiefonds Zorgverzekeraars
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- tumor budding, colorectal cancer, mesenchymal subtype, KRAS mutation, BRAF mutation, RAS/RAF mutations, epithelial-mesenchymal transition, cancer stem cells, prognostic factors, metastatic colorectal cancer, tumor microenvironment
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Mesoderm, Middle Aged, Mutation, Prognosis, Genes, ras, Biomarkers, Tumor, Colorectal Neoplasms, Cohort Studies, Randomized Controlled Trials as Topic, raf Kinases, Epithelial-Mesenchymal Transition
About these checks
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