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DNA mutation fingerprints that help explain cancer causes catalogued by Cambridge researchers


By Paul Brackley


The most comprehensive catalogue yet of DNA mutation ‘fingerprints’ across the whole human genome could help medics detect what has led to a patient’s tumour.

Mutations present in whole genome cancers as seen in patients. three have environmental exposures: smoking, UV-damage and aristolochic acidtwo have internal sources of DNA damage: BRCA1 and Lynch Syndrome (MLH1)one has pink pattern but the source is unknown. Picture: University of Cambridge (9279114)
Mutations present in whole genome cancers as seen in patients. three have environmental exposures: smoking, UV-damage and aristolochic acidtwo have internal sources of DNA damage: BRCA1 and Lynch Syndrome (MLH1)one has pink pattern but the source is unknown. Picture: University of Cambridge (9279114)

The research, by scientists at the University of Cambridge and King’s College London, uncovered the patterns of DNA damage caused by 41 environmental agents, such as ultraviolet light, tobacco smoke and polycyclic hydrocarbons.

The human genome is made up of nucleotides represented by the letters A, C, G and T. Mutations in the sequence of these letters - such as when an A becomes a G, for example - can be caused by multiple factors, including environmental ones. These are copied when cells divide and reproduce, and over time the number of errors accumulates, leading to uncontrolled cell growth - the development of tumours.

Researchers can now detect the patterns, or mutational signatures, in these tumours.

Dr Serena Nik-Zainal from the Department of Medical Genetics and MRC Cancer Unit, who led the Cambridge team, said: “Mutational signatures are the fingerprints that carcinogens leave behind on our DNA, and just like fingerprints, each one is unique.

“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.”

To study this, the researchers used induced pluripotent stem cells, which are skin cells that have been reprogrammed to return to their original, master cell state.

Exposing them to 79 known or suspected environmental carcinogens, they examined them using whole genome sequencing and found 41 had left a characteristic fingerprint on the DNA.

The sequence of nucleotides in DNA (8944836)
The sequence of nucleotides in DNA (8944836)

Professor David Phillips, who led the King’s College London team, said: “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.

“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.”

Exploring individual chemicals found in tobacco smoke, they identified, for the first time, which ones caused signatures like those found in the lung cancer of patients who smoked.

They also identified fingerprints left by common chemotherapy drugs, some dietary chemicals and some present in diesel exhaust fumes.

The teams hope to expand the research to develop an encyclopedia of signatures.

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

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

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