The dynamics of gene expression changes in a mouse model of oral tumorigenesis may help refine prevention and treatment strategies in patients with oral cancer

// Jean-Philippe Foy 1, 2, 3 , Antonin Tortereau 4 , Carlos Caulin 5 , Vincent Le Texier 6 , Emilie Lavergne 7 , Emilie Thomas 6 , Sylvie Chabaud 7 , David Perol 7 , Joël Lachuer 1, 2, 8 , 9 , Wenhua Lang 10 , Waun Ki Hong 11 , Patrick Goudot 3 , Scott M Lippman 12 , Chloé Bertolus 3 , Pierre Saintigny 1, 2, 13, 14 1 INSERM U1052, Cancer Research Center of Lyon, Lyon, France 2 CNRS UMR 5286, Cancer Research Center of Lyon, Lyon, France 3 Department of Oral and Maxillofacial Surgery, University of Pierre Marie Curie-Paris 6, Pitié-Salpêtrière Hospital, Paris, France 4 Université de Lyon, VetAgro Sup, UPSP 2011-03-101, ICE, Marcy-l’Étoile, France 5 Head and Neck Surgery at The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Department of Bioinformatics, Centre Léon Bérard, Lyon, France 7 Department of Biostatistics, Centre Léon Bérard, Lyon, France 8 Université Lyon 1, Université de Lyon, Lyon, France 9 ProfileXpert, SFR-Est, CNRS UMR-S3453, INSERM US7, Lyon, France 10 Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, TX, USA 11 Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston, TX, USA 12 UC San Diego Moores Cancer Center, La Jolla, CA, USA 13 Departments of Medicine and Translational Research and Innovation, Centre Leon Berard, Lyon, France 14 Centre Léon Bérard, Lyon, France Correspondence to: Pierre Saintigny, email: pierre.saintigny@lyon.unicancer.fr Keywords: oral preneoplasia, tumorigenesis, prevention, oral cancer, genome-wide expression profiles Received: December 03, 2015      Accepted: March 06, 2016      Published: March 24, 2016 ABSTRACT A better understanding of the dynamics of molecular changes occurring during the early stages of oral tumorigenesis may help refine prevention and treatment strategies. We generated genome-wide expression profiles of microdissected normal mucosa, hyperplasia, dysplasia and tumors derived from the 4-NQO mouse model of oral tumorigenesis. Genes differentially expressed between tumor and normal mucosa defined the “tumor gene set” (TGS), including 4 non-overlapping gene subsets that characterize the dynamics of gene expression changes through different stages of disease progression. The majority of gene expression changes occurred early or progressively. The relevance of these mouse gene sets to human disease was tested in multiple datasets including the TCGA and the Genomics of Drug Sensitivity in Cancer project. The TGS was able to discriminate oral squamous cell carcinoma (OSCC) from normal oral mucosa in 3 independent datasets. The OSCC samples enriched in the mouse TGS displayed high frequency of CASP8 mutations, 11q13.3 amplifications and low frequency of PIK3CA mutations. Early changes observed in the 4-NQO model were associated with a trend toward a shorter oral cancer-free survival in patients with oral preneoplasia that was not seen in multivariate analysis. Progressive changes observed in the 4-NQO model were associated with an increased sensitivity to 4 different MEK inhibitors in a panel of 51 squamous cell carcinoma cell lines of the aerodigestive tract. In conclusion, the dynamics of molecular changes in the 4-NQO model reveal that MEK inhibition may be relevant to prevention and treatment of a specific molecularly-defined subgroup of OSCC.