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Analyses of Transcriptomics Cell Signalling for Pre-Screening Applications in the Integrated Approach for Testing and
Yusuke Oku1, Federica Madia2, Pierre Lau3
1The Organisation for Economic Cooperation and Development (OECD), 2 Rue Andre Pascal, 75016 Paris, France.
Abstract:
With recent rapid advancement of methodological tools, mechanistic understanding of biological processes leading to carcinogenesis is expanding. New approach methodologies such as transcriptomics can inform on non-genotoxic mechanisms of chemical carcinogens and can be developed for regulatory applications. The Organisation for the Economic Cooperation and Development (OECD) expert group developing an Integrated Approach to the Testing and Assessment (IATA) of Non-Genotoxic Carcinogens (NGTxC) is reviewing the possible assays to be integrated therein. In this context, we review the application of transcriptomics approaches suitable for pre-screening gene expression changes associated with phenotypic alterations that underlie the carcinogenic processes for subsequent prioritisation of downstream test methods appropriate to specific key events of non-genotoxic carcinogenesis. Using case studies, we evaluate the potential of gene expression analyses especially in relation to breast cancer, to identify the most relevant approaches that could be utilised as (pre-) screening tools, for example Gene Set Enrichment Analysis (GSEA). We also consider how to address the challenges to integrate gene panels and transcriptomic assays into the IATA, highlighting the pivotal omics markers identified for assay measurement in the IATA key events of inflammation, immune response, mitogenic signalling and cell injury.
Insights
Transcriptomics can help understand non-genotoxic carcinogen mechanisms and inform regulatory testing. This review evaluates gene expression analysis for screening carcinogenic processes, particularly for breast cancer, within integrated approaches.
Area of Science:
- Toxicology and Carcinogenesis
- Molecular Biology
- Regulatory Science
Background:
- Mechanistic understanding of carcinogenesis is advancing with new tools like transcriptomics.
- Transcriptomics offers insights into non-genotoxic mechanisms of chemical carcinogens for regulatory use.
- The Organisation for the Economic Cooperation and Development (OECD) is developing an Integrated Approach to the Testing and Assessment (IATA) for Non-Genotoxic Carcinogens (NGTxC).
Purpose of the Study:
- To review transcriptomics applications for pre-screening gene expression changes in carcinogenesis.
- To evaluate gene expression analysis for prioritizing downstream testing methods in non-genotoxic carcinogenesis.
- To assess the potential of transcriptomics, including Gene Set Enrichment Analysis (GSEA), for regulatory applications, with a focus on breast cancer.
Main Methods:
- Review of transcriptomics approaches for identifying gene expression alterations linked to phenotypic changes in carcinogenesis.
- Evaluation of case studies, specifically focusing on breast cancer.
- Consideration of challenges in integrating transcriptomic assays and gene panels into the OECD's IATA framework.
Main Results:
- Transcriptomics can identify relevant gene expression changes associated with key events in non-genotoxic carcinogenesis.
- Gene Set Enrichment Analysis (GSEA) shows potential as a pre-screening tool.
- Key omics markers for inflammation, immune response, mitogenic signaling, and cell injury in the IATA have been identified.
Conclusions:
- Transcriptomics approaches are valuable for pre-screening and prioritizing assays in the IATA for NGTxC.
- Gene expression analysis, particularly GSEA, can inform on non-genotoxic carcinogenesis mechanisms.
- Integration of transcriptomics into regulatory frameworks like the IATA is feasible and crucial for advancing NGTxC assessment.
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