title: Cancer as the Disintegration of Robustness: Population-Level Variance in Gene Expression Identifies Key Differences Between Tobacco- and HPV-Associated Oropharyngeal Carcinogenesis.
abstract: BACKGROUND
  Oropharyngeal squamous cell carcinoma is associated both with tobacco use and with human papillomavirus (HPV) infection. It is argued that carcinogen-driven tumorigenesis is a distinct disease from its virally driven counterpart. We hypothesized that tumorigenesis is the result of a loss of genotypic robustness resulting in an increase in phenotypic variation in tumors compared with adjacent histologically normal tissues, and that carcinogen-driven tumorigenesis results in greater variation than its virally driven counterpart.
  
  
  OBJECTIVE
  To examine the loss of robustness in carcinogen-driven and virally driven oropharyngeal squamous cell carcinoma samples, and to identify potential pathways involved.
  
  
  METHODS
  We used coefficients of variation for messenger RNA and microRNA expression to measure the loss of robustness in oropharyngeal squamous cell carcinoma samples. Tumors were compared with matched normal tissues, and were further categorized by HPV and patient smoking status. Weighted gene coexpression networks were constructed for genes with highly variable expression among the HPV⁻ tumors from smokers.
  
  
  RESULTS
  We observed more genes with variable messenger RNA expression in tumors compared with normal tissues, regardless of HPV and smoking status, and more microRNAs with variable expression in HPV⁻ and HPV⁺ tumors from smoking patients than from nonsmokers. For both the messenger RNA and microRNA data, we observed more variance among HPV⁻ tumors from smokers compared with HPV⁺ tumors from nonsmokers. The gene coexpression network construction highlighted pathways that have lost robustness in carcinogen-induced tumors but appear stable in virally induced tumors.
  
  
  CONCLUSIONS
  Using coefficients of variation and coexpression networks, we identified multiple altered pathways that may play a role in carcinogen-driven tumorigenesis.
authors.forename: Miriam M
authors.initials: MM
authors.lastname: Ben-Dayan
authors.forename: Thomas
authors.initials: T
authors.lastname: MacCarthy
authors.forename: Nicolas F
authors.initials: NF
authors.lastname: Schlecht
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Belbin
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Childs
authors.forename: Richard V
authors.initials: RV
authors.lastname: Smith
authors.forename: Michael B
authors.initials: MB
authors.lastname: Prystowsky
authors.affiliation: From the Departments of Pathology (Ms Ben-Dayan and Drs Belbin, Childs, and Prystowsky), Epidemiology and Population Health (Dr Schlecht), and Computational and Systems Biology (Dr Bergman), Albert Einstein College of Medicine, Bronx, New York; the Department of Applied Mathematics and Statistics, SUNY Stony Brook, Stony Brook, New York (Dr MacCarthy); and the Department of Otorhinolaryngology, Montefiore Medical Center, Bronx, New York (Dr Smith).
authors.forename: Aviv
authors.initials: A
authors.lastname: Bergman
mesh_terms: D063646:Carcinogenesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D009959:Oropharyngeal Neoplasms / Q000150:complications / Q000235:genetics; D030361:Papillomavirus Infections / Q000150:complications; D012307:Risk Factors; D012907:Smoking