Major mutational pattern in cancer may appear in bursts

Written by Natalie Morton, Future Science Group

Researchers have created a new resource for studying mutational signatures in cell lines, which has already revealed that a key mutational fingerprint occurs in bursts.

A new resource which catalogues mutational signatures in over 1000 cell lines has been compiled by researchers as an aid to investigating the causes of mutations in cancer cells. The resource has already helped the team to discover that a key mutational signature occurs in bursts, dubbed ‘episodic mutagenesis’.

The DNA mutations that cause all cancers, can be identified within cells as unique mutational signatures, of which there are over 50. The nature of these signatures makes them difficult to study yet understanding their causes could be extremely important for oncologists.

Researchers from the Wellcome–Sanger Institute (UK), along with collaborators, recorded the genome sequences of 577 human cancer cell grafts and 1001 human cancer cell lines. They included the models most widely used in oncology research and created a catalogue of which signature could be found in which cell line. The findings were recently published in Cell.

“By annotating over a thousand publicly available cancer cell lines with information on mutational signatures, we have provided the largest ever resource for experimentally investigating the biological mechanisms underlying these signatures,” explained author Peter Campbell. “Now, researchers will be able to choose the right cell line to work with and systematically knock-out individual genes to study how this affects the generation of any mutational signature over time.”

The team then picked specific cell lines to study, and, possibly unsurprisingly, found that mutational signatures from external factors, such as UV light and smoking, stopped being created over time, whereas those signatures caused by internal cellular factors continued to be created at a steady rate. However, two very common mutational signatures appeared to switch on and off throughout the course of the experiment. The researchers called this ‘episodic mutagenesis’.

APOBEC, a gene-editing immune system protein, which causes mutations in viruses such as HIV, is the cause of mutational signatures found in more than 70% of cancers. It is as of yet unknown what activates APOBEC to attack the human genome instead of harmful viruses, but the new catalog could help researchers to investigate these mutations further.

First author Mia Petjak concluded: “We found that the signatures previously associated with APOBEC enzymes were the only mutations that came in bursts of activity.  Cell lines that continue to generate APOBEC-associated, and other, signatures over time now provide us and other groups with a set of powerful tools to study root causes of human cancer – the origins of mutations.”

Sources: Petljak M et al. Characterizing mutational signatures in human cancer cell lines reveals episodic APOBEC mutagenesis. Cell (2019); www.sanger.ac.uk/news/view/major-mutation-pattern-cancer-occurs-bursts

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