title: The consensus molecular subtypes of colorectal cancer.
abstract: Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth factor-β activation, stromal invasion and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions.
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Guinney
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.|Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Dienstmann
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands.|Department of Biomedical Sciences, City University of Hong Kong, Hong Kong.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Ligue Nationale Contre le Cancer, Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reyniès
authors.affiliation: Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlicker
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Soneson
authors.affiliation: Ligue Nationale Contre le Cancer, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Marisa
authors.affiliation: Agendia NV, Amsterdam, the Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Roepman
authors.affiliation: Institute of Cancer Research, London, UK.
authors.forename: Gift
authors.initials: G
authors.lastname: Nyamundanda
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Angelino
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Bot
authors.affiliation: The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Morris
authors.affiliation: Agendia NV, Amsterdam, the Netherlands.
authors.forename: Iris M
authors.initials: IM
authors.lastname: Simon
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gerster
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Fessler
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Felipe
authors.initials: F
authors.lastname: De Sousa E Melo
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Missiaglia
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Hena
authors.initials: H
authors.lastname: Ramay
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Barras
authors.affiliation: École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Krisztian
authors.initials: K
authors.lastname: Homicsko
authors.affiliation: The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Dipen
authors.initials: D
authors.lastname: Maru
authors.affiliation: The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ganiraju C
authors.initials: GC
authors.lastname: Manyam
authors.affiliation: The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Bradley
authors.identifier: http://orcid.org/0000-0002-0915-3164
authors.initials: B
authors.lastname: Broom
authors.affiliation: Gustave Roussy, Villejuif, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Boige
authors.affiliation: Laboratorio de Genomica y Microarrays, Instituto de Investigación Sanitaria San Carlos, Hospital Clinico San Carlos, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Perez-Villamil
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Ted
authors.identifier: http://orcid.org/0000-0002-6207-7068
authors.initials: T
authors.lastname: Laderas
authors.affiliation: Institut Catala d'Oncologia, L'Institut d'Investigació Biomèdica de Bellvitge, Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Salazar
authors.affiliation: Biomedical Engineering, Oregon Health Sciences University, Portland, Oregon, USA.
authors.forename: Joe W
authors.identifier: http://orcid.org/0000-0001-9225-6756
authors.initials: JW
authors.lastname: Gray
authors.affiliation: École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands.
authors.forename: Rene
authors.identifier: http://orcid.org/0000-0001-8677-3423
authors.initials: R
authors.lastname: Bernards
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Friend
authors.affiliation: Université Paris Descartes, Paris, France.|Department of Biology, Hôpital Européen Georges-Pompidou, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.affiliation: Institute of Cancer Research, London, UK.
authors.forename: Anguraj
authors.initials: A
authors.lastname: Sadanandam
authors.affiliation: Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands.
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.|Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.|Department of Oncology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Mauro
authors.identifier: http://orcid.org/0000-0001-7631-3263
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Louis
authors.identifier: http://orcid.org/0000-0002-6066-789X
authors.initials: L
authors.lastname: Vermeulen
authors.affiliation: Universitair ziekenhuis Leuven, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
mesh_terms: D002277:Carcinoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D032921:Consensus; D018899:CpG Islands; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D033181:Information Dissemination; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016212:Transforming Growth Factor beta / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins