title: 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.
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 areodigestive 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.
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon, Lyon, France.|CNRS UMR 5286, Cancer Research Center of Lyon, Lyon, France.|Department of Oral and Maxillofacial Surgery, University of Pierre Marie Curie-Paris 6, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Foy
authors.affiliation: Université de Lyon, VetAgro Sup, UPSP 2011-03-101, ICE, Marcy-l'Étoile, France.
authors.forename: Antonin
authors.initials: A
authors.lastname: Tortereau
authors.affiliation: Head and Neck Surgery at The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caulin
authors.affiliation: Department of Bioinformatics, Centre Léon Bérard, Lyon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Le Texier
authors.affiliation: Department of Biostatistics, Centre Léon Bérard, Lyon, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Lavergne
authors.affiliation: Department of Bioinformatics, Centre Léon Bérard, Lyon, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Thomas
authors.affiliation: Department of Biostatistics, Centre Léon Bérard, Lyon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chabaud
authors.affiliation: Department of Biostatistics, Centre Léon Bérard, Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Perol
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon, Lyon, France.|CNRS UMR 5286, Cancer Research Center of Lyon, Lyon, France.|Université Lyon 1, Université de Lyon, Lyon, France.|ProfileXpert, SFR-Est, CNRS UMR-S3453, INSERM US7, Lyon, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Lachuer
authors.affiliation: Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Lang
authors.affiliation: Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Pierre Marie Curie-Paris 6, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Goudot
authors.affiliation: UC San Diego Moores Cancer Center, La Jolla, CA, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Pierre Marie Curie-Paris 6, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Bertolus
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon, Lyon, France.|CNRS UMR 5286, Cancer Research Center of Lyon, Lyon, France.|Departments of Medicine and Translational Research and Innovation, Centre Leon Berard, Lyon, France.|Centre Léon Bérard, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Saintigny
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008808:Mice, Inbred CBA; D009061:Mouth Mucosa / Q000187:drug effects / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics*; D015363:Quinolones / Q000633:toxicity
chemical_list: C120195:4-nitroquinolone-1-oxide; D000970:Antineoplastic Agents; D002273:Carcinogens; D015363:Quinolones; D015112:4-Nitroquinoline-1-oxide
keywords: genome-wide expression profiles; oral cancer; oral preneoplasia; prevention; tumorigenesis