title: BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland. david.barras@unil.ch Mauro.delorenzi@unil.ch sabine.tejpar@uzleuven.be.
authors.forename: David
authors.initials: D
authors.lastname: Barras
authors.affiliation: Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Missiaglia
authors.affiliation: Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland.
authors.forename: Pratyaksha
authors.initials: P
authors.lastname: Wirapati
authors.affiliation: Systems Biology and Personalized Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.|Department of Surgery - Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Sieber
authors.affiliation: Systems Biology and Personalized Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Jorissen
authors.affiliation: Systems Biology and Personalized Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Chris
authors.initials: C
authors.lastname: Love
authors.affiliation: CSIRO Preventative Health Flagship, Animal, Food & Health Sciences Division, North Ryde, NSW, Australia.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Molloy
authors.affiliation: Department of Surgery, University of Melbourne and Colorectal Surgery Unit, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Jones
authors.affiliation: Department of Colorectal Surgery, Western Hospital, Footscray, Victoria, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: McLaughlin
authors.affiliation: Systems Biology and Personalized Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.|Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbs
authors.affiliation: Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Justin
authors.initials: J
authors.lastname: Guinney
authors.affiliation: Agendia NV, Amsterdam, the Netherlands.
authors.forename: Iris M
authors.initials: IM
authors.lastname: Simon
authors.affiliation: Oncology, Hôpitaux Universitaires de Genève, Genève, Switzerland.
authors.forename: Arnaud D
authors.initials: AD
authors.lastname: Roth
authors.affiliation: Department of Pathology, Lausanne University, Lausanne, Switzerland.
authors.forename: Fred T
authors.initials: FT
authors.lastname: Bosman
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology, Katholieke Universiteit Leuven. david.barras@unil.ch Mauro.delorenzi@unil.ch sabine.tejpar@uzleuven.be.|University Hospital, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland. david.barras@unil.ch Mauro.delorenzi@unil.ch sabine.tejpar@uzleuven.be.|Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.|Department of Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
mesh_terms: D019943:Amino Acid Substitution; D014408:Biomarkers, Tumor; D016000:Cluster Analysis; D003062:Codon; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D019295:Computational Biology / Q000379:methods; D019175:DNA Methylation; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008954:Models, Biological; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D040901:Proteomics / Q000379:methods; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D057188:Workflow
chemical_list: D014408:Biomarkers, Tumor; D003062:Codon; D048493:Proto-Oncogene Proteins B-raf