The International Agency for Research on Cancer (IARC) aims to identify preventable cancer causes; to this end, the ongoing research programs employ innovative experimental models and computational approaches to investigate previously unrecognized mutagenic effects of human carcinogens. Such effects of candidate substances are studied in clonally expanded cell lines and by massively parallel sequencing conducted at the genome-scale. Highly complementary <i>in vitro</i> adductomics experiments as well as sequencing of rodent tumors associated with the corresponding chemical exposures further elucidate the underlying mutagenic processes. The experimental results are matched with the sequencing data from human pan-cancer genome repositories, to identify relevant exposure fingerprints in humans. Several novel mutational signatures associated with dietary compounds, mycotoxins, therapeutic agents and industrial chemicals will be presented, alongside mechanistic insights into the possible causes of particular cancer types. Selection of the studied compounds reflects the priorities set for carcinogen evaluation by IARC, yet other sources, such as the results from independent adductomics and metabolomics studies, can also inform the design of these integrative analyses. Overall, this powerful approach has a considerable potential for improved understanding of cancer causes and for cancer prevention efforts aimed at modifiable exposures.

Integrative experimental modelling reveals novel genome-scale mutation fingerprints of carcinogens

2019 Fall National Meeting

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