Tobacco smoking undermines anti-cancer safeguards by causing harmful DNA mutations

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Scientists at the Ontario Institute for Cancer Research (OICR) have discovered a way tobacco smoking causes cancer and weakens the body’s anti-cancer defenses, making it harder to treat.

Their new study, published today Science advancesTobacco smoking is linked to harmful changes in DNA known as ‘stop-gain mutations’ that tell the body to stop making certain proteins.

They found that these stop-gene mutations were particularly prevalent in genes known as ‘tumour-suppressors’, which make proteins that normally prevent the growth of abnormal cells.

“Our research shows that smoking is associated with changes in DNA that disrupt the formation of suppressors,” said University of Toronto PhD student Nina Adler, who led the study during her post-graduate tumor research. Jury Remand Lab at OICR. “Without them, abnormal cells are allowed to grow unchecked by the cell’s immune system and cancer can develop more easily.”

Adler, Remand and colleagues used powerful computational tools to analyze DNA from more than 12,000 tumor samples across 18 different cancer types. Their analysis shows a strong link between stop-gain mutations in lung cancer and the ‘footprint’ that smoking leaves on DNA.

The researchers then looked at whether there was an effect of how much someone smoked. Sure enough, their analysis showed that more smoking leads to these harmful mutations, which can ultimately make cancer more complex and harder to treat.

Tobacco does a lot of damage to our DNA and this can have a major impact on how our cells function. Our study highlights how tobacco smoking actually inactivates critical proteins, which can affect the building blocks of our cells and our long-term health.”

Dr. Juri Remand, an OICR investigator and associate professor at the University of Toronto

Research has also identified other factors and mechanisms responsible for the generation of large numbers of stop-gain mutations, also known as ‘nonsense’ mutations. Some, like a group of enzymes called APOBECs that are strongly associated with stop-gain mutations in breast cancer and other cancer types, occur naturally in the body. Other factors, such as an unhealthy diet and alcohol consumption, can have similar damaging effects on DNA, but Remand says more information is needed to fully understand how it works.

As for smoking, Adler says the findings are an important piece of the puzzle behind one of the world’s leading causes of cancer.

“Everyone knows that smoking can cause cancer, but being able to explain how it works at the molecular level is an important step in understanding how our lifestyle affects our risk of cancer,” Adler said.

OICR president and scientific director Dr. Laszlo Radvanyi says these new insights should reinforce that tobacco smoking is one of the biggest threats to our health.

“More proof of the enormous damage smoking does to our bodies, and more proof that quitting smoking is always the right choice,” Radvani said.


Journal Reference:

Adler, N., etc. (2023). Mutational mechanisms of tobacco smoking and APOBEC activity induce protein-truncating mutations in cancer genomes. Science advances.

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