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'Fingerprint database' could help to identify new cancer culprits

last modified Jul 09, 2019 02:28 PM

Somatic mutations in cancer cells, arising through cell-intrinsic and exogenous processes, mark the genome with distinctive  patterns termed mutational signatures. In a collaboration with David Phillips, King’s College London, Serena Nik Zainal’s group systematically explored mutational signatures associated with environmental agents that are either known or suspected to be linked to cancer.

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. A highly standardised set-up was used to ensure that all results were comparable to one another. 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. Computational analysis highlighted pathognomonic “fingerprints” of 41 environmental agents including 41 substitution patterns, 6 double-substitution and 8 indel signatures. New mechanistic insights was gained into mutagenesis and learned about contributions of DNA repair pathways to the final mutational outcome. 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.

 79agents

The study entitled A Compendium of Mutational Signatures of Environmental Agents has been published in Cell  on 02 May, 2019.

It has received wide press coverage including in newspapers like the Guardian and the Telegraph and has also been widely discussed across social media channels and highlighted on various scientific and University websites. A video summary of the article released by Cell Press is available here: https://www.youtube.com/watch?v=kzorkO2rsm8