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Clin Cancer Res. 2017 Jan 1;23(1):104-115. doi: 10.1158/1078-0432.CCR-16-0140. Epub 2016 Jun 27.

BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression.

Author information

1
Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland. david.barras@unil.ch Mauro.delorenzi@unil.ch sabine.tejpar@uzleuven.be.
2
Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland.
3
Systems Biology and Personalized Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
4
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
5
Department of Surgery - Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.
6
CSIRO Preventative Health Flagship, Animal, Food & Health Sciences Division, North Ryde, NSW, Australia.
7
Department of Surgery, University of Melbourne and Colorectal Surgery Unit, Royal Melbourne Hospital, Parkville, Victoria, Australia.
8
Department of Colorectal Surgery, Western Hospital, Footscray, Victoria, Australia.
9
Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
10
Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, Washington.
11
Agendia NV, Amsterdam, the Netherlands.
12
Oncology, Hôpitaux Universitaires de Genève, Genève, Switzerland.
13
Department of Pathology, Lausanne University, Lausanne, Switzerland.
14
Laboratory of Molecular Digestive Oncology, Department of Oncology, Katholieke Universiteit Leuven. david.barras@unil.ch Mauro.delorenzi@unil.ch sabine.tejpar@uzleuven.be.
15
University Hospital, Leuven, Belgium.
16
Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.
17
Department of Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
27354468
DOI:
10.1158/1078-0432.CCR-16-0140
[Indexed for MEDLINE]
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