A Collaborative Initiative to Establish Genomic Biomarkers for Assessing Tumorigenic Potential to Reduce Reliance on Conventional Rodent Carcinogenicity Studies

• Published in: Toxicological sciences Vol. 188; no. 1; pp. 4 - 16
• Main Authors: Corton, J Christopher, Mitchell, Constance A, Auerbach, Scott, Bushel, Pierre, Ellinger-Ziegelbauer, Heidrun, Escobar, Patricia A, Froetschl, Roland, Harrill, Alison H, Johnson, Kamin, Klaunig, James E, Pandiri, Arun R, Podtelezhnikov, Alexei A, Rager, Julia E, Tanis, Keith Q, van der Laan, Jan Willem, Vespa, Alisa, Yauk, Carole L, Pettit, Syril D, Sistare, Frank D
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 28-06-2022
• Subjects: Animals; Biomarkers, Tumor - genetics; Carcinogenesis; Carcinogenicity Tests; Carcinogens - toxicity; Forum; Genomics; Neoplasms - chemically induced; Neoplasms - genetics; Rodentia; risk assessment; adverse outcome pathways; cancer; error-corrected sequencing; toxicogenomics; biomarkers
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfac041

Abstract
There is growing recognition across broad sectors of the scientific community that use of genomic biomarkers has the potential to reduce the need for conventional rodent carcinogenicity studies of industrial chemicals, agrochemicals, and pharmaceuticals through a weight-of-evidence approach. These biomarkers fall into 2 major categories: (1) sets of gene transcripts that can identify distinct tumorigenic mechanisms of action; and (2) cancer driver gene mutations indicative of rapidly expanding growth-advantaged clonal cell populations. This call-to-action article describes a collaborative approach launched to develop and qualify biomarker gene expression panels that measure widely accepted molecular pathways linked to tumorigenesis and their activation levels to predict tumorigenic doses of chemicals from short-term exposures. Growing evidence suggests that application of such biomarker panels in short-term exposure rodent studies can identify both tumorigenic hazard and tumorigenic activation levels for chemical-induced carcinogenicity. In the future, this approach will be expanded to include methodologies examining mutations in key cancer driver gene mutation hotspots as biomarkers of both genotoxic and nongenotoxic chemical tumor risk. Analytical, technical, and biological validation studies of these complementary genomic tools are being undertaken by multisector and multidisciplinary collaborative teams within the Health and Environmental Sciences Institute. Success from these efforts will facilitate the transition from current heavy reliance on conventional 2-year rodent carcinogenicity studies to more rapid animal- and resource-sparing approaches for mechanism-based carcinogenicity evaluation supporting internal and regulatory decision-making.