Researchers discover why many smokers will never develop lung cancer
[May 26, 2023: Staff Writer, The Brighter Side of News]
Study suggests that some smokers may have robust mechanisms that protect them from lung cancer. (CREDIT: iStock Photos)
Although cigarette smoking is the primary culprit behind lung cancer, not all smokers develop this disease. In a recent study published in Nature Genetics, researchers from Albert Einstein College of Medicine propose that certain smokers may have resilient protective mechanisms that limit mutations and, thus, safeguard them against lung cancer.
This discovery could aid in the identification of smokers who are more susceptible to lung cancer and require close surveillance.
“This may prove to be an important step toward the prevention and early detection of lung cancer risk and away from the current herculean efforts needed to battle late-stage disease, where the majority of health expenditures and misery occur,” said Simon Spivack, M.D., M.P.H., a co-senior author of the study, professor of medicine, of epidemiology & population health, and of genetics at Einstein, and a pulmonologist at Montefiore Health System.
Overcoming Obstacles to Study Cell Mutations
For a long time, it has been widely believed that smoking causes lung cancer by inducing DNA mutations in healthy lung cells. The lack of an accurate method to quantify mutations in normal cells has prevented the verification of this theory until recently. According to Jan Vijg, Ph.D., a co-senior author of the study and a professor and chair of genetics, ophthalmology and visual sciences, and the Lola and Saul Kramer Chair in Molecular Genetics at Einstein, this study was the first to provide evidence for the theory due to the limitations of the existing methods.
Dr. Vijg, who is also affiliated with the Center for Single-Cell Omics at Jiaotong University School of Medicine in Shanghai, China, developed an improved approach to sequence the entire genomes of individual cells a few years ago, overcoming this obstacle.
Sequencing errors can be a serious issue when analyzing cells with rare and random mutations using single-cell whole-genome sequencing methods. These errors can be difficult to distinguish from true mutations.
In 2017, Dr. Vijg developed a new sequencing technique called single-cell multiple displacement amplification (SCMDA) to address this problem. According to a report published in Nature Methods, this method reduces sequencing errors and takes them into account.
The researchers at Einstein utilized SCMDA to compare the mutational landscape of normal lung epithelial cells from two groups: 14 never-smokers, aged 11 to 86, and 19 smokers, aged 44 to 81, with a maximum smoking history of 116 pack years. The cells were collected from patients undergoing bronchoscopy for diagnostic tests unrelated to cancer.
Dr. Spivack, one of the researchers involved in the study, noted that these lung cells can accumulate mutations over time due to both aging and smoking, and are among the most likely cell types in the lung to become cancerous. The cells can survive for years or even decades.
Mutations Caused by Smoking
In a study, researchers observed that non-smokers and smokers accumulate mutations (single-nucleotide variants and small insertions and deletions) in their lung cells as they age. However, the lung cells of smokers had a significantly higher number of mutations than those of non-smokers. This observation supports the hypothesis that smoking increases the risk of lung cancer by elevating the frequency of mutations. Dr. Spivack highlighted that this could be one reason why lung cancer is uncommon among non-smokers while 10% to 20% of lifelong smokers develop lung cancer.
Effects of smoking cessation on mutation frequency: Median number of SNV and INDEL frequency among former smokers (n = 7) and current smokers (n = 12). a, each data point indicates the median value and the minimal and maximal range of SNV frequency of 3-8 nuclei per subject. b, each data point indicates the median value and the minimal and maximal range of INDEL frequency of 3-8 nuclei per subject. P values were obtained by likelihood ratio tests using negative binomial mixed-effect model. (CREDIT: Nature Methods)
Furthermore, the number of mutations detected in lung cells increased proportionally with the number of pack years of smoking, implying an increased risk of lung cancer. Nevertheless, the researchers noted that the rise in cell mutations reached a plateau after 23 pack years of exposure, indicating a limit to the amount of mutations that can accumulate in lung cells.
According to Dr. Spivack, the individuals who smoked the most did not have the highest burden of mutations. This indicates that such individuals might have managed to suppress further accumulation of mutations, allowing them to survive for an extended period despite heavy smoking. Dr. Spivack suggests that the mutation plateau could result from their effective systems for repairing DNA damage or detoxifying cigarette smoke.
INDEL frequency and smoking dose. a, INDEL frequency versus smoking pack-years across all individuals (n = 33). Each dot indicates the median value and the minimal and maximal range of INDEL frequency of individuals. b, INDEL frequency of different group of individuals according to the smoking pack-years, with boxes indicating median number and interquartile range of the never (n = 14), light (n = 6), moderate (n = 6), and heavy (n = 7) smoking group, respectively. (CREDIT: Nature Methods)
The new research direction is a result of this finding. Dr. Vijg stated that they plan to develop novel assays capable of measuring an individual's capacity for DNA repair or detoxification. This approach may provide a new means of assessing the risk of lung cancer.
How does smoking affect your body?
According to the Cleveland Clinic, tobacco use harms every organ in your body. Smoking tobacco introduces not only nicotine but also more than 5,000 chemicals, including numerous carcinogens (cancer-causing chemicals), into your lungs, blood and organs.
The damage caused by smoking can shorten your lifespan significantly. In fact, smoking is the number one cause of preventable death in the United States.
Pregnant women who smoke put their unborn babies at risk, too. Possible effects on pregnancy include:
Ectopic pregnancy, a life-threatening condition when the embryo implants outside the uterus.
Birth defects, such as cleft palate.
Low birth weight.
What other conditions may be caused or worsened by tobacco?
In addition to its known cancer risks, the Cleveland Clinic states that smoking causes many other chronic (long-term) health problems that need ongoing care. Specific smoking-related problems that need treatment include:
Decreased HDL (good) cholesterol and increased blood pressure (increasing risks for heart attack and stroke).
Lower oxygen to the heart and other tissues in the body (increasing risks for coronary artery disease, peripheral artery disease, and diabetes).
More frequent routine illnesses like colds, especially in children living with smokers.
Poorer lung function (ability to get enough oxygen) leading to COPD, asthma, bronchitis, or emphysema.
The study is titled, “Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking.”
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