title: A 12-gene signature to distinguish colon cancer patients with better clinical outcome following treatment with 5-fluorouracil or FOLFIRI.
abstract: Currently, there is no marker in use in the clinical management of colon cancer to predict which patients will respond efficiently to 5-fluorouracil (5-FU), a common component of all cytotoxic therapies. Our aim was to develop and validate a multigene signature associated with clinical outcome from 5-FU therapy and to determine if it could be used to identify patients who might respond better to alternate treatments. Using a panel of 5-FU resistant and sensitive colon cancer cell lines, we identified 103 differentially expressed genes providing us with a 5-FU response signature. We refined this signature using a clinically relevant DNA microarray-based dataset of 359 formalin-fixed and paraffin-embedded (FFPE) colon cancer samples. We then validated the final signature in an external independent DNA microarray-based dataset of 316 stage III FFPE samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial. Finally, using a drug sensitivity database of 658 cell lines, we generated a list of drugs that could sensitize 5-FU resistant patients using our signature. We confirmed using the PETACC-3 dataset that the overall survival of subjects responding well to 5-FU did not improve with the addition of irinotecan (FOLFIRI; two-sided log-rank test p = 0.795). Conversely, patients who responded poorly to 5-FU based on our 12-gene signature were associated with better survival on FOLFIRI therapy (one-sided log-rank test p = 0.039). This new multigene signature is readily applicable to FFPE samples and provides a new tool to help manage treatment in stage III colon cancer. It also provides the first evidence that a subgroup of colon cancer patients can respond better to FOLFIRI than 5-FU treatment alone.
authors: Molecular and Cellular Biology division, Centre de Recherche sur le Cancer de l'Université LavalQuebec City, QuébecCanada; Department of BiochemistryCentre for BioinformaticsMcGill UniversityThe Rosalind and Morris Goodman Cancer Research CentreMontrealQuebec, Canada.
authors: Eric R
authors: ER
authors: Paquet
authors: Swiss Institute of Bioinformatics, Bioinformatics Core Facility Lausanne Switzerland.
authors: Jing
authors: J
authors: Cui
authors: Division of Experimental Medicine & Department of Oncology McGill University Segal Cancer Centre Jewish General Hospital Montreal, Quebec Canada.
authors: David
authors: D
authors: Davidson
authors: Swiss Institute of Bioinformatics, Bioinformatics Core Facility Lausanne Switzerland.
authors: Natalia
authors: N
authors: Pietrosemoli
authors: Biological Sciences Department School of Arts and Sciences Lebanese International University Beirut Lebanon.
authors: Houssein Hajj
authors: HH
authors: Hassan
authors: Molecular and Cellular Biology division, Centre de Recherche sur le Cancer de l'Université Laval Quebec City, Québec Canada.
authors: Serges P
authors: SP
authors: Tsofack
authors: Molecular and Cellular Biology division, Centre de Recherche sur le Cancer de l'Université Laval Quebec City, Québec Canada.
authors: Annie
authors: A
authors: Maltais
authors: Department of Biochemistry Centre for Bioinformatics McGill University The Rosalind and Morris Goodman Cancer Research Centre Montreal Quebec, Canada.
authors: Michael T
authors: MT
authors: Hallett
authors: Swiss Institute of Bioinformatics, Bioinformatics Core FacilityLausanneSwitzerland; Department of OncologyUniversity of LausanneLudwig Center for Cancer ResearchLausanneSwitzerland.
authors: Mauro
authors: M
authors: Delorenzi
authors: Division of Experimental Medicine & Department of Oncology McGill University Segal Cancer Centre Jewish General Hospital Montreal, Quebec Canada.
authors: Gerald
authors: G
authors: Batist
authors: Division of Experimental Medicine & Department of Oncology McGill University Segal Cancer Centre Jewish General Hospital Montreal, Quebec Canada.
authors: Raquel
authors: R
authors: Aloyz
authors: Department of molecular biology medical biochemistry and pathology Laval University Centre de Recherche du CHU de Québec, Centre Hospitalier de l'Université Laval Québec Canada.
authors: Michel
authors: M
authors: Lebel
keywords: adjuvant; chemotherapy; colon neoplasms/drug therapy; colon neoplasms/genetics; colon neoplasms/mortality; gene expression profiling; gene expression regulation; neoplastic/genetics; prognosis; treatment outcome