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Tobacco Smoke Linked to Mutations That “Stop” Cancer-Fighting Proteins

A person holding a cigarette.
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A new study has revealed that tobacco smoke can cause specific DNA changes that can prevent anti-cancer proteins from being fully constructed, representing one way that tobacco smoking causes cancer. The research is published in Science Advances.

More understanding of the effects of smoking

Stop-gain mutations, also known as nonsense mutations, are changes in the DNA sequence that encodes a protein. They result in the cell terminating the production of the protein earlier than it should, producing a shortened or non-functional protein.

The researchers used powerful computational tools to analyze DNA from more than 12,000 tumor samples across 18 cancer types, finding a strong link between these stop-gain mutations in lung cancer and the signature “footprint” left in DNA by tobacco smoking.

Stop-gain mutations were widespread in a class of genes called tumor suppressor genes, the researchers discovered. Tumor suppressor genes effectively put the brakes on cell growth and division, helping to prevent cancers from developing. When these genes are faulty or inactive, cell division can go unchecked, possibly leading to cancer.

“Our study showed that smoking is associated with changes to DNA that disrupt the formation of tumor suppressors,” said Nina Adler, lead author of the study and a PhD student at the University of Toronto. “Without them, abnormal cells are allowed to keep growing unchecked by the cell’s defenses and cancer can develop more easily.”

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Next, they investigated whether the amount that someone smoked could exert any influence over these mutations, finding that more smoking led to more of these harmful mutations. This can lead to worse patient outcomes, as these mutations can result in a more complex cancer that is harder to treat.

“Tobacco does a lot of damage to our DNA, and that can have a major impact on the function of our cells,” said Dr. Jüri Reimand, an associate professor at the University of Toronto and the study’s senior author. “Our study highlights how tobacco smoking actually deactivates critical proteins, which are the building blocks of our cells, and the impact that can have on our long-term health.”

Another piece of the puzzle

These findings are an important piece of the puzzle underlying one of the world’s leading causes of cancer, explains Adler: “Everyone knows that smoking can cause cancer, but being able to explain one of the ways this works at a molecular level is an important step in understanding how our lifestyle affects our risk of cancer.”

“This is further proof of the immense damage smoking has on our bodies, and further evidence that stopping smoking is always the right choice,” said Dr. Laszlo Radvanyi, president of the Ontario Institute for Cancer Research.

The study also helped to identify other factors involved in acquiring stop-gain mutations. For example, a group of naturally occurring enzymes called APOBEC has a strong association with stop-gain mutations in breast cancers. Additionally, lifestyle factors such as unhealthy diet and alcohol consumption are likely to lead to similar effects, but further research is needed to understand more, says Reimand.

Reference: Adler N, Bahcheli AT, Cheng KCL, et al. Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes. Sci Adv. 2023;9(44):eadh3083. doi: 10.1126/sciadv.adh3083

This article is a rework of a press release issued by the Ontario Institute for Cancer Research. Material has been edited for length and content.