Now a reference library of DNA mutation ‘fingerprints’

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3D render of a medical background with DNA strandScientists from King College London and Cambridge University have developed a comprehensive catalogue of DNA mutation ‘fingerprints’ that could help doctors pinpoint the environmental culprit responsible for a patient’s tumour – including showing some of the fingerprints left in lung tumours by specific chemicals found in tobacco smoke.

Our DNA, the human genome, comprises of a string of molecules known as nucleotides. These are represented by the letters A, C, G and T. Sometimes, changes occur in the ‘spelling’ of our DNA – an A becomes a G, for example. These changes, known as mutations, can be caused by a number of factors, some environmental, such as exposure to tobacco smoke or to ultraviolet light.

As cells divide and multiply, they make copies of their DNA, so any spelling mistakes will be reproduced. Over time, the number of errors accumulates leading to uncontrolled cell growth – the development of tumours.

Previously, scientists have had only a limited number of tools for working out the cause of an individual’s tumour. As it is now possible to study the entire human genome very rapidly, scientists have been able to find all the mutations in a patient’s cancer, and see patterns – or ‘mutational signatures’ – in these tumours.

Now, a team of researchers from King’s and Cambridge have developed a comprehensive catalogue of the mutational signatures caused by 41 environmental agents linked to cancer. In future they hope to expand it further, using similar experimental techniques, to produce an encyclopaedia of mutation patterns caused by environmental agents.

“We’ve used this technique to create the most comprehensive catalogue to date of the patterns of DNA damage produced by environmental agents across the whole human genome,” said Professor David Phillips, who led the King’s team. “It should allow us to examine a patient’s tumour and identify some of the carcinogens they have been exposed to that may have caused the cancer.”

“Mutational signatures are the fingerprints that carcinogens leave behind on our DNA, and just like fingerprints, each one is unique,” said Dr Serena Nik-Zainal from the University of Cambridge. “They allow us to treat tumours as a crime scene and, like forensic scientists, allow us to identify the culprit – and their accomplices – responsible for the tumour.”

The researchers exposed induced pluripotent stem cells – skin cells that have been reprogrammed to return to their original, ‘master’ state – to 79 known or suspected environmental carcinogens. The team then used whole genome sequencing to look at the patterns of changes caused by the agents and found that 41 of the suspects left a characteristic fingerprint on the stem cells’ DNA.

Some of the environmental agents studied are known carcinogens, such as polycyclic hydrocarbons and sunlight. For the first time, the researchers also studied some of the individual chemicals found in tobacco smoke and identified which ones cause signatures similar to those found in smokers’ lung cancer.

They also identified the fingerprints left behind by common chemotherapy drugs, some dietary chemicals and some present in diesel exhaust fumes. This study shows how human DNA is vulnerable to many agents in our surroundings.

Nik-Zainal illustrates potential uses of the catalogue by referring to the case of Balkan endemic nephropathy (BEN), which is linked to dietary exposure to a plant chemical called aristolochic acid. The mutational signature of this chemical was verified in this study to be virtually identical to the signature found in the tumours of BEN patients. So, although this connection was first made prior to the current study, Nik-Zainal says it is an example of how one might use their catalogue in future.

“Our reference library will allow doctors in future to identify those culprits responsible for causing cancer,” adds Nik-Zainal. “Such information could be invaluable in helping inform measures to reduce people’s exposure to potentially dangerous carcinogens.”

The research was funded by a Wellcome Strategic Award, with additional support from Cancer Research UK and the Medical Research Council.

Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures. Some were similar to signatures found in human tumors. Additionally, six agents produced double-substitution signatures and eight produced indel signatures. Investigating mutation asymmetries across genome topography revealed fully functional mismatch and transcription-coupled repair pathways. DNA damage induced by environmental mutagens can be resolved by disparate repair and/or replicative pathways, resulting in an assortment of signature outcomes even for a single agent. This compendium of experimentally induced mutational signatures permits further exploration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA is directly vulnerable to environmental agents.

Jill E Kucab, Xueqing Zou, Sandro Morganella, Madeleine Joel, A Scott Nanda, Eszter Nagy, Celine Gomez, Andrea Degasperi, Rebecca Harris, Stephen P Jackson, Volker M Arlt, David H Phillips, Serena Nik-Zainal

Kings College London material
Cell abstract

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