The scientists ofOntario Institute for Cancer Research (OICR) have discovered a way in which tobacco smoking causes cancer and makes it more difficult to treat, undermining the body’s anti-tumor defenses.
The results of the study were published in the magazine Science Advances.
Tobacco smoking: Here’s why it makes cancer harder to treat
Their new study connects the tobacco smoke to harmful changes in the DNA called “stop-gain mutations” that tell the body to stop making certain proteins before they are fully formed.
They found that these stop-gain mutations They were particularly prevalent in genes known as “tumor suppressors,” which produce proteins that would normally prevent the growth of abnormal cells.
“Our study showed that smoking is associated with changes in DNA that disrupt the formation of smoking suppressants. cancer“, he claims Nina Adler, PhD candidate at the University of Toronto. student who conducted the study during her postgraduate research in Dr. Jüri’s laboratory Remand at the OICR. “Without them, abnormal cells can continue to grow unchecked by cellular defenses, and cancer can develop more easily.”
Adler, Reimand and colleagues used powerful computational tools to analyze DNA from more than 12,000 tumor samples across 18 different cancer types. Their analysis showed a strong link between the stop-gain mutations in lung cancer and the telltale “footprint” that smoking leaves in DNA.
The researchers then examined whether how much someone smoked had an impact. Surely, their analysis demonstrated that a more smoking leads to more of these harmful mutationswhich can ultimately make cancer more complex and more difficult to treat.
“Tobacco causes a lot of damage to our DNA and this can have a major impact on the function of our cells,” says Reimand, OICR researcher and associate professor at theUniversity of Toronto. “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.”
The study also identified other factors and processes responsible for creating large numbers of stop-gain mutations, also called “nonsense” mutations.
Some, like a group of enzymes called APOBEC which is strongly linked to stop-gain mutations in breast cancer and other cancers, occur naturally in the body. Other factors, such as an unhealthy diet and alcohol consumption, could also have similar damaging effects on DNA, but Reimand says more information is needed to fully understand how this works.
As for smoking, Adler says the results of this study are an important piece of the puzzle which is behind one of the leading causes of cancer in the world.
“Everyone knows that smoking can cause cancerbut being able to explain one of the ways it works at the molecular level is an important step in understanding how our lifestyle affects cancer risk,” says Adler.
The president and scientific director of the OICR, Dr. Laszlo Radvanyisays this new knowledge should reinforce the fact that tobacco smoking is one of the biggest threats to our health.
“This is further proof of the immense damage smoking has on our bodies, and further proof that quitting smoking is always the right choice”says Radvanyi.
Scientists have measured the catastrophic genetic damage caused by smoking in different organs of the body and identified different mechanisms by which tobacco smoke causes mutations in DNA.
The researchers of Wellcome Trust Sanger Institute, Los Alamos National Laboratory and their collaborators found that smokers accumulated an average of 150 extra mutations in each lung cell for every year they spent smoking a pack of cigarettes a day.
Reported in the magazine Science , the study provides a direct link between the number of cigarettes smoked over a lifetime and the number of mutations in tumor DNA. The highest mutation rates were seen in lung tumors, but tumors elsewhere in the body also contained these smoking-associated mutations, explaining how smoking causes many types of human cancer.
Tobacco smoking claims the lives of at least six million people every year and, if current trends continue, theWorld Health Organization predicts more than 1 billion tobacco-related deaths this century. Smoking has been epidemiologically associated with at least 17 types of human cancer, but until now no one had seen the mechanisms by which smoking causes many of these cancers.
Cancer is caused by mutations in a cell’s DNA. In the first comprehensive DNA analysis of smoking-related cancers, researchers looked further 5,000 tumors, comparing the tumors of smokers with the tumors of people who had never smoked. They found particular molecular signatures of DNA damage – called mutational signatures – in the DNA of smokers, and counted how many of these particular mutations were found in different tumors.
The authors found that, on average, smoking a pack of cigarettes a day leads to 150 mutations in each lung cell every year. These mutations represent potential individual starting points for a cascade of genetic damage that can ultimately lead to cancer. The number of mutations within any cancer cell varies between individuals, but this study shows the additional mutational burden caused by tobacco.
Doctor Ludmil Alexandrovfirst author of Los Alamos National Laboratorysaid: “Before now we had a large body of epidemiological evidence linking smoking to cancer, but now we can actually observe and quantify molecular changes in DNA due to cigarette smoking.
With this study, we found that people who smoke a pack a day develop an average of 150 extra mutations in their lungs every year, which explains why smokers have such a high risk of developing lung cancer.”
Other organs were also affected and the study showed that one pack a day led to an estimated average of 97 mutations in each cell of the larynx, 39 mutations for the pharynx, 23 mutations for the mouth, 18 mutations for the bladder and 6 mutations in each cell. liver cell every year.
Until now, it was not fully understood how smoking increases the risk of developing cancer in parts of the body that do not come into direct contact with smoke. However, the study revealed different mechanisms by which tobacco smoking causes these mutationsdepending on the area of the body affected.
The professor David Phillips, study author and professor of environmental carcinogenesis at King’s College London, said: “The findings are a mix of the expected and the unexpected and reveal a picture of direct and indirect effects. Mutations caused by direct DNA damage from The carcinogens contained in tobacco have been found mainly in organs that come into direct contact with inhaled smoke.
On the contrary, others body cells have suffered only indirect damage, as tobacco smoke appears to affect key mechanisms in these cells which in turn mutate DNA.”
The study revealed at least five distinct DNA damage processes due to cigarette smoking. The most widespread of these is a mutational signature already found in all tumors. In this case, Tobacco smoking appears to speed up the speed of a cellular clock that mutates DNA prematurely.
Professor Sir Mike Stratton, co-lead author from the Wellcome Trust Sanger Institute, said: “The genome of each cancer provides a kind of ‘archaeological record’, written in the DNA code itself, of the exposures that caused the mutations that led to the cancer. cancer. Our research indicates that how tobacco smoking causes cancer is more complex than we thought.
In fact, we do not fully understand the underlying causes of many types of cancer, and there are other known causes, such as obesity, where we understand little of the underlying mechanism. This study on smoking tells us that the analysis of Tumor DNA It may provide exciting new clues about how tumors develop and therefore, potentially, how they can be prevented.”
In Italy, according to the ISS: “In 2022, in Italy, they are estimated 390,700 new cancer diagnoses (in 2020 they were 376,600), 205,000 in men and 185,700 in women. In two years, the increase was 14,100 cases. The most frequently diagnosed tumorin 2022, is the carcinoma of breast (55,700 cases, +0.5% compared to 2020), followed by colorectal (48,100, +1.5% in men and +1.6% in women), lung (43,900, +1.6% in men and +3.6% in women), prostate (40,500, +1.5%) e bladder (29,200, +1.7% in men and +1.0% in women)”.
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