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ToxSci Advance Access originally published online on June 8, 2007
Toxicological Sciences 2007 99(1):90-100; doi:10.1093/toxsci/kfm156
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A Gene Expression Biomarker Provides Early Prediction and Mechanistic Assessment of Hepatic Tumor Induction by Nongenotoxic Chemicals

Mark R. Fielden1, Richard Brennan and Jeremy Gollub

Iconix Biosciences, Inc., Mountain View, California 94043

1 To whom correspondence should be addressed at Investigative Toxicology, Non-Clinical Drug Safety, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304. Fax: (650) 855-5588. E-mail: mark.fielden{at}roche.com.

Received April 13, 2007; accepted June 4, 2007


  Abstract

There are currently no accurate and well-validated short-term tests to identify nongenotoxic hepatic tumorigens, thus necessitating an expensive 2-year rodent bioassay before a risk assessment can begin. Using hepatic gene expression data from rats treated for 5 days with one of 100 structurally and mechanistically diverse nongenotoxic hepatocarcinogens and nonhepatocarcinogens, a novel multigenebiomarker (i.e., signature) was derived to predict the likelihood of nongenotoxic chemicals to induce liver tumors in longer term studies. Independent validation of the signature on 47 test chemicals indicates an assay sensitivity and specificity of 86% and 81%, respectively. Alternate short-term in vivo pathological and genomic biomarkers were evaluated in parallel for comparison, including liver weight, hepatocellular hypertrophy, hepatic necrosis, serum alanine aminotransferase activity, induction of cytochrome P450 genes, and repression of Tsc-22 or alpha2-macroglobulin messenger RNA. In contrast to these biomarkers, the gene expression–based signature was more accurate. Unlike existing tests, an understanding of potential modes of action for hepatic tumorigenicity can be derived by comparison of the signature profile of test chemicals to hepatic tumorigens of known mechanism, including regenerative proliferation, proliferation associated with xenobiotic receptor activation, peroxisome proliferation, and steroid hormone–mediated mechanisms. This signature is not only more accurate than current methods, but also facilitates the identification of mode of action to aid in the early assessment of human cancer risk.

Key Words: biomarker; carcinogenicity; nongenotoxic; toxicogenomics; microarray.


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