<i>BRAF</i> <i>V600E</i> Mutant Colorectal Cancer Subtypes Based on Gene Expression
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- David Barras
- 1Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland.
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- Edoardo Missiaglia
- 1Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland.
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- Pratyaksha Wirapati
- 1Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland.
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- Oliver M. Sieber
- 2Systems Biology and Personalized Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
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- Robert N. Jorissen
- 2Systems Biology and Personalized Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
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- Chris Love
- 2Systems Biology and Personalized Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
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- Peter L. Molloy
- 5CSIRO Preventative Health Flagship, Animal, Food & Health Sciences Division, North Ryde, NSW, Australia.
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- Ian T. Jones
- 6Department of Surgery, University of Melbourne and Colorectal Surgery Unit, Royal Melbourne Hospital, Parkville, Victoria, Australia.
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- Stephen McLaughlin
- 7Department of Colorectal Surgery, Western Hospital, Footscray, Victoria, Australia.
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- Peter Gibbs
- 2Systems Biology and Personalized Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
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- Justin Guinney
- 9Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Iris M. Simon
- 10Agendia NV, Amsterdam, the Netherlands.
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- Arnaud D. Roth
- 11Oncology, Hôpitaux Universitaires de Genève, Genève, Switzerland.
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- Fred T. Bosman
- 12Department of Pathology, Lausanne University, Lausanne, Switzerland.
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- Sabine Tejpar
- 13Laboratory of Molecular Digestive Oncology, Department of Oncology, Katholieke Universiteit Leuven.
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- Mauro Delorenzi
- 1Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland.
Description
<jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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.</jats:p>
Journal
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- Clinical Cancer Research
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Clinical Cancer Research 23 (1), 104-115, 2017-01-01
American Association for Cancer Research (AACR)
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Details 詳細情報について
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- CRID
- 1360011145774510080
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- ISSN
- 15573265
- 10780432
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- Data Source
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- Crossref