title: Integrative miRNA-Gene Expression Analysis Enables Refinement of Associated Biology and Prediction of Response to Cetuximab in Head and Neck Squamous Cell Cancer.
abstract: This paper documents the process by which we, through gene and miRNA expression profiling of the same samples of head and neck squamous cell carcinomas (HNSCC) and an integrative miRNA-mRNA expression analysis, were able to identify candidate biomarkers of progression-free survival (PFS) in patients treated with cetuximab-based approaches. Through sparse partial least square-discriminant analysis (sPLS-DA) and supervised analysis, 36 miRNAs were identified in two components that clearly separated long- and short-PFS patients. Gene set enrichment analysis identified a significant correlation between the miRNA first-component and EGFR signaling, keratinocyte differentiation, and p53. Another significant correlation was identified between the second component and RAS, NOTCH, immune/inflammatory response, epithelial-mesenchymal transition (EMT), and angiogenesis pathways. Regularized canonical correlation analysis of sPLS-DA miRNA and gene data combined with the MAGIA2 web-tool highlighted 16 miRNAs and 84 genes that were interconnected in a total of 245 interactions. After feature selection by a smoothed t-statistic support vector machine, we identified three miRNAs and five genes in the miRNA-gene network whose expression result was the most relevant in predicting PFS (Area Under the Curve, AUC = 0.992). Overall, using a well-defined clinical setting and up-to-date bioinformatics tools, we are able to give the proof of principle that an integrative miRNA-mRNA expression could greatly contribute to the refinement of the biology behind a predictive model.
authors.affiliation: Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy. loris.dececco@istitutotumori.mi.it.
authors.forename: Loris
authors.initials: L
authors.lastname: De Cecco
authors.affiliation: Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy. marco.giannoccaro@istitutotumori.mi.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Giannoccaro
authors.affiliation: Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy. edoardo.marchesi@istitutotumori.mi.it.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Marchesi
authors.affiliation: Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy. paolo.bossi@istitutotumori.mi.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bossi
authors.affiliation: Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy. federica.favales@istitutotumori.mi.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Favales
authors.affiliation: Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy. laura.locati@istitutotumori.mi.it.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Locati
authors.affiliation: Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy. lisa.licitra@istitutotumori.mi.it.
authors.forename: Lisa
authors.initials: L
authors.lastname: Licitra
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy. silvana.pilotti@istitutotumori.mi.it.
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.affiliation: Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy. silvana.canevari@istitutotumori.mi.it.
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
keywords: cetuximab; drug sensitivity; head and neck squamous cell carcinomas (HNSCC); miRNA; microarray