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.

Trinh, Anne; Lädrach, Claudia; Dawson, Heather E.; Ten Hoorn, Sanne; Kuppen, Peter J K; Reimers, Marlies S; Koopman, Miriam; Punt, Cornelis J A; Lugli, Alessandro; Vermeulen, Louis; Zlobec, Inti (2018). 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. British journal of cancer, 119(10), pp. 1244-1251. Nature Publishing Group 10.1038/s41416-018-0230-7

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Dawson, Heather; Lugli, Alessandro and Zlobec, Inti

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0007-0920

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Alessandro Lugli

Date Deposited:

28 Nov 2018 15:24

Last Modified:

23 Oct 2019 03:57

Publisher DOI:

10.1038/s41416-018-0230-7

PubMed ID:

30385823

BORIS DOI:

10.7892/boris.121735

URI:

https://boris.unibe.ch/id/eprint/121735

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