A study by Xueqing Zou from Serena Nik-Zainal’s group (Medical Genetics and MRC Cancer Unit), in collaboration with David Phillips (King’s College London) systematically explored mutational signatures associated with environmental agents that are either known or suspected to be linked to cancer. Mutational signatures are mutations in cancer cells, arising through cell-intrinsic and exogenous processes that mark the genome with distinctive patterns.
 
In all, 79 agents from 13 families were used to treat human induced pluripotent stem cells (IPSCs), including agents found in everyday exposures like exhaust fumes, tobacco smoke, chemical dyes and things we ingest. Cell viability was aimed for 40-60%, functional DNA damage response assays were obtained, and metabolic activation was taken into consideration. Single-cell subclones were derived from recovered cells. In all, 324 iPSC subclones were whole genome sequenced to seek genome-wide mutation patterns. Published in Cell,computational analysis highlighted pathognomonic “fingerprints” of 41 environmental agents. The research provides new mechanistic insight into mutagenesis including the contributions of DNA repair pathways to the final mutational outcomes. Critically, these results will serve as a reference set of mutational signatures with public health and surveillance implications. In the future, when all tumours are sequenced, these reference catalogues of mutational signatures can be used to understand whether environmental mutagens are culprits in the development of a patient’s tumour.