BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression.

Details

Serval ID
serval:BIB_38D193B4AD19
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression.
Journal
Clinical cancer research
Author(s)
Barras D., Missiaglia E., Wirapati P., Sieber O.M., Jorissen R.N., Love C., Molloy P.L., Jones I.T., McLaughlin S., Gibbs P., Guinney J., Simon I.M., Roth A.D., Bosman F.T., Tejpar S., Delorenzi M.
ISSN
1078-0432 (Print)
ISSN-L
1078-0432
Publication state
Published
Issued date
01/01/2017
Peer-reviewed
Oui
Volume
23
Number
1
Pages
104-115
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Mutation of BRAF at the valine 600 residue occurs in approximately 10% of colorectal cancers, a group with particularly poor prognosis. The response of BRAF mutant colorectal cancer to recent targeted strategies such as anti-BRAF or combinations with MEK and EGFR inhibitors remains limited and highly heterogeneous within BRAF V600E cohorts. There is clearly an unmet need in understanding the biology of BRAF V600E colorectal cancers and potential subgroups within this population.
In the biggest yet reported cohort of 218 BRAF V600E with gene expression data, we performed unsupervised clustering using non-negative matrix factorization to identify gene expression-based subgroups and characterized pathway activation.
We found strong support for a split into two distinct groups, called BM1 and BM2. These subtypes are independent of MSI status, PI3K mutation, gender, and sidedness. Pathway analyses revealed that BM1 is characterized by KRAS/AKT pathway activation, mTOR/4EBP deregulation, and EMT whereas BM2 displays important deregulation of the cell cycle. Proteomics data validated these observations as BM1 is characterized by high phosphorylation levels of AKT and 4EBP1, and BM2 patients display high CDK1 and low cyclin D1 levels. We provide a global assessment of gene expression motifs that differentiate BRAF V600E subtypes from other colorectal cancers.
We suggest that BRAF mutant patients should not be considered as having a unique biology and provide an in depth characterization of heterogeneous motifs that may be exploited for drug targeting. Clin Cancer Res; 23(1); 104-15. ©2016 AACR.

Keywords
Amino Acid Substitution, Biomarkers, Tumor, Cluster Analysis, Codon, Cohort Studies, Colorectal Neoplasms/diagnosis, Colorectal Neoplasms/genetics, Colorectal Neoplasms/metabolism, Colorectal Neoplasms/mortality, Computational Biology/methods, DNA Methylation, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Models, Biological, Mutation, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Proteomics/methods, Proto-Oncogene Proteins B-raf/genetics, Proto-Oncogene Proteins B-raf/metabolism, Signal Transduction, Workflow
Pubmed
Web of science
Open Access
Yes
Create date
01/07/2016 9:13
Last modification date
20/08/2019 13:28
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