title: A colorectal cancer classification system that associates cellular phenotype and responses to therapy.
abstract: Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise, individualized treatment strategies are needed. To that end, we analyzed gene expression profiles from 1,290 CRC tumors using consensus-based unsupervised clustering. The resultant clusters were then associated with therapeutic response data to the epidermal growth factor receptor-targeted drug cetuximab in 80 patients. The results of these studies define six clinically relevant CRC subtypes. Each subtype shares similarities to distinct cell types within the normal colon crypt and shows differing degrees of 'stemness' and Wnt signaling. Subtype-specific gene signatures are proposed to identify these subtypes. Three subtypes have markedly better disease-free survival (DFS) after surgical resection, suggesting these patients might be spared from the adverse effects of chemotherapy when they have localized disease. One of these three subtypes, identified by filamin A expression, does not respond to cetuximab but may respond to cMET receptor tyrosine kinase inhibitors in the metastatic setting. Two other subtypes, with poor and intermediate DFS, associate with improved response to the chemotherapy regimen FOLFIRI in adjuvant or metastatic settings. Development of clinically deployable assays for these subtypes and of subtype-specific therapies may contribute to more effective management of this challenging disease.
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Anguraj
authors.initials: A
authors.lastname: Sadanandam
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.forename: Krisztian
authors.initials: K
authors.lastname: Homicsko
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.forename: William J
authors.initials: WJ
authors.lastname: Gibb
authors.forename: Stephan
authors.initials: S
authors.lastname: Wullschleger
authors.forename: Liliane C Gonzalez
authors.initials: LC
authors.lastname: Ostos
authors.forename: William A
authors.initials: WA
authors.lastname: Lannon
authors.forename: Carsten
authors.initials: C
authors.lastname: Grotzinger
authors.forename: Maguy
authors.initials: M
authors.lastname: Del Rio
authors.forename: Benoit
authors.initials: B
authors.lastname: Lhermitte
authors.forename: Adam B
authors.initials: AB
authors.lastname: Olshen
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000145:classification* / Q000175:diagnosis* / Q000628:therapy*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D005819:Genetic Markers; D000068818:Cetuximab