Scientists at the Ontario Institute for Cancer Research (OICR) have uncovered one way tobacco smoking causes cancer and makes it harder to treat by undermining the body's anti-cancer safeguards.
The new study, published in the journal Science Advances, links tobacco smoking to harmful changes in DNA called "stop-gain mutations" that tell the body to stop making certain proteins before they are fully formed.
Mohammed Shaaban, PhD researcher at the Imperial College London and Francis Crick Institute, described the mutations as “defective incomplete proteins”, adding that “the findings are highly important because they provide a deeper understanding of the molecular mechanisms through which smoking contributes to the development of cancer and its resistance to treatment.”
The study found that these stop-gain mutations were especially prevalent in genes known as 'tumor-suppressors', which make proteins that would normally prevent abnormal cells from growing.
"Our study showed that smoking is associated with changes to DNA that disrupt the formation of tumor suppressors," says Nina Adler, a University of Toronto PhD student who led the study during her postgraduate research in Dr. Jüri Reimand's lab at OICR.
"Without them, abnormal cells are allowed to keep growing unchecked by the cell's defenses and cancer can develop more easily," she added.
Adler, Reimand and colleagues used powerful computational tools to analyze DNA from more than 12,000 tumor samples across 18 different types of cancer. Their analysis showed a strong link between stop-gain mutations in lung cancer and the telltale 'footprint' that smoking leaves in DNA.
The researchers then looked at whether how much someone smoked had an impact. Sure enough, their analysis showed that more smoking led to more of these harmful mutations, which can ultimately make cancer more complex and harder to treat.
“Excessive smoking can make cancer more complex and harder to treat by promoting the accumulation of these mutations in cancer genomes. The more a person smokes, the more these harmful mutations increase, which can lead to cellular dysfunction and often affect essential tumor suppressor pathways, making the disease difficult to control,” Shaaban explains.
This means that individuals who smoke excessively are not only more likely to develop cancer, but also face greater complexity in their tumors, which affects treatment outcomes, he adds.
"Tobacco does a lot of damage to our DNA and that can have a major impact on the function of our cells. 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," Reimand said.
The study also identified other factors and processes responsible for creating large numbers of stop-gain mutations that are strongly linked to breast cancer and other cancer types, like unhealthy diet and alcohol consumption that are also likely to have similar damaging effects on DNA, but Reimand says more information is needed to fully understand how that works.
As for smoking, Adler says the findings from this study are an important piece of the puzzle behind a leading cause cancer in the world. "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," Adler says.
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.
"This research can lead to developing new treatment strategies and can be used to develop more effective anti-smoking campaigns. By better understanding how smoking inactivates tumor suppressors, we can explore targeted therapies to mitigate the effects of these mutations," Shaaban notes.
"This research paper opens the door to a new era of personalized cancer treatment, tailoring interventions based on an individual's smoking history and genetic profile, ultimately leading to more effective and precise cancer care, " he concludes.
