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Lung cancer is the tumor that kills the most in the world and also in Spain. Tobacco is the main cause of its appearance. 80% of cases are related to smoking. Experts say that without tobacco, we would be talking about a rare disease and not the epidemic we are facing today.
Nevertheless, not all smokers develop lung cancer and researchers are looking at what mechanisms protect some people from this tumor. Now a study led by scientists at the Albert Einstein College of Medicine, published Monday in Nature Genetics, suggests that some smokers may have robust mechanisms that protect them from lung cancer through limiting mutations.
The findings could help identify smokers who are at higher risk of developing the disease and therefore warrant especially close follow-up.
“This could be a important step towards prevention and early detection of lung cancer risk, far from the current Herculean efforts needed to combat late-stage disease,” said Simon Spivack, co-senior author of the study, Einstein professor of medicine, epidemiology and public health, and genetics, and pulmonologist at Montefiore Health System.
It has long been assumed that smoking leads to lung cancer by triggering DNA mutations in normal lung cells. “But that could never be proven until our study, as there was no way to precisely quantify mutations in normal cells,” said Jan Vijg, co-senior author of the study, professor and director of genetics, professor of ophthalmology and visual sciences, and Professor of Molecular Genetics at Einstein. Dr. Vijg overcame that hurdle a few years ago by developing an improved method for sequencing the entire genomes of individual cells.
Single cell whole genome sequencing methods can introduce sequencing errors that are difficult to distinguish from true mutations, a serious flaw when analyzing cells containing rare and random mutations. Dr. Vijg solved this problem by developing a new sequencing technique called Single Cell Multiple Displacement Amplification (SCMDA). As reported in “Nature Methods” in 2017, this method accounts for and reduces sequencing errors.
The Einstein researchers used SCMDA to compare the mutational landscape of normal lung epithelial cells (ie, the cells that line the lung) from two types of people: 14 never smokers, ages 11 to 86; and 19 smokers, ages 44 to 81, who had smoked a maximum of 116 pack-years. The cells were collected from patients who underwent bronchoscopy for diagnostic tests unrelated to cancer. “These lung cells survive for years, even decades, and therefore can accumulate mutations both with age and with smoking. Of all the cell types in the lung, these are among the most likely to become cancerous,” says Dr. Spivack.
The researchers found that the mutations accumulated in the lung cells of non-smokers as they aged, and that they were found many more mutations in the lung cells of smokers. “This experimentally confirms that smoking increases the risk of lung cancer by increasing the frequency of mutations, as previously suggested,” says Dr. Spivack. “This is probably one of the reasons why so few nonsmokers get lung cancer, whereas 10% to 20% of lifelong smokers do,” he says.
Another finding of the study is that the number of cellular mutations detected in lung cells increased in a straight line with the number of packs smoked per year and presumably also increased the risk of lung cancer. But, curiously, increase in cell mutations stopped after 23 years of exposition.
“The heaviest smokers did not have the highest mutation load. Our data suggest that these individuals may have survived for so long despite heavy smoking because they managed to suppress a greater accumulation of mutations. This leveling of mutations could be due to the fact that these people have highly competent systems to repair DNA damage or detoxify it from cigarette smoke,” says Dr. Spivack.
The finding has led to a new research direction: “We now want to develop new assays that can measure a person’s ability to repair or detoxify DNA, which could offer a new way to assess lung cancer risk,” he says. Dr. Vijg.
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