title: Genomic models of short-term exposure accurately predict long-term chemical carcinogenicity and identify putative mechanisms of action.
abstract: BACKGROUND
  Despite an overall decrease in incidence of and mortality from cancer, about 40% of Americans will be diagnosed with the disease in their lifetime, and around 20% will die of it. Current approaches to test carcinogenic chemicals adopt the 2-year rodent bioassay, which is costly and time-consuming. As a result, fewer than 2% of the chemicals on the market have actually been tested. However, evidence accumulated to date suggests that gene expression profiles from model organisms exposed to chemical compounds reflect underlying mechanisms of action, and that these toxicogenomic models could be used in the prediction of chemical carcinogenicity.
  
  
  RESULTS
  In this study, we used a rat-based microarray dataset from the NTP DrugMatrix Database to test the ability of toxicogenomics to model carcinogenicity. We analyzed 1,221 gene-expression profiles obtained from rats treated with 127 well-characterized compounds, including genotoxic and non-genotoxic carcinogens. We built a classifier that predicts a chemical's carcinogenic potential with an AUC of 0.78, and validated it on an independent dataset from the Japanese Toxicogenomics Project consisting of 2,065 profiles from 72 compounds. Finally, we identified differentially expressed genes associated with chemical carcinogenesis, and developed novel data-driven approaches for the molecular characterization of the response to chemical stressors.
  
  
  CONCLUSIONS
  Here, we validate a toxicogenomic approach to predict carcinogenicity and provide strong evidence that, with a larger set of compounds, we should be able to improve the sensitivity and specificity of the predictions. We found that the prediction of carcinogenicity is tissue-dependent and that the results also confirm and expand upon previous studies implicating DNA damage, the peroxisome proliferator-activated receptor, the aryl hydrocarbon receptor, and regenerative pathology in the response to carcinogen exposure.
authors: Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America; Department of Computational Biomedicine, Boston University Medical Campus, Boston, Massachusetts, United States of America.
authors: Daniel
authors: D
authors: Gusenleitner
authors: Biomolecular Screening Branch, Division of the National Toxicology Program at the National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina, United States of America.
authors: Scott S
authors: SS
authors: Auerbach
authors: Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America.
authors: Tisha
authors: T
authors: Melia
authors: Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America.
authors: Harold F
authors: HF
authors: Gómez
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors: David H
authors: DH
authors: Sherr
authors: Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America; Department of Computational Biomedicine, Boston University Medical Campus, Boston, Massachusetts, United States of America.
authors: Stefano
authors: S
authors: Monti
mesh_terms: D000818:Animals; D019540:Area Under Curve; D015197:Carcinogenicity Tests / Q000379:methods; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage; D004260:DNA Repair; D016208:Databases, Factual; D015507:Drugs, Investigational / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D008297:Male; D008957:Models, Genetic; D009928:Organ Specificity; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D012680:Sensitivity and Specificity; D043922:Toxicogenetics
chemical_list: D002273:Carcinogens; D015507:Drugs, Investigational; D047492:Peroxisome Proliferator-Activated Receptors; D018336:Receptors, Aryl Hydrocarbon