The EU FP6 project carcinoGENOMICS explored the combination of toxicogenomics and in
vitro cell culture models for identifying organotypical genotoxic- and non-genotoxic carcinogen-
specific gene signatures. Here the performance of its gene classifier, derived from exposure
of metabolically competent human HepaRG cells to prototypical non-carcinogens (10
compounds) and hepatocarcinogens (20 compounds), is reported. Analysis of the data at the
gene and the pathway level by using independent biostatistical approaches showed a distinct
separation of genotoxic from non-genotoxic hepatocarcinogens and non-carcinogens (up to
88 % correct prediction). The most characteristic pathway responding to genotoxic exposure
was DNA damage. Interlaboratory reproducibility was assessed by blindly testing of three
compounds, from the set of 30 compounds, by three independent laboratories. Subsequent
classification of these compounds resulted in correct prediction of the genotoxicants. As expected,
results on the non-genotoxic carcinogens and the non-carcinogens were less predictive.
In conclusion, the combination of transcriptomics with the HepaRG in vitro cell model
provides a potential weight of evidence approach for the evaluation of the genotoxic potential
of chemical substances.JRC.I.5 - Systems Toxicolog
