Lung cancer is the leading cause of cancer death in the world, 80%-90% of lung cancers are caused by smoking, and the risk of lung cancer in smokers is 20 times that of non-smokers as much. Tobacco contains more than 60 carcinogens, which enter the lungs with the smoke when ignited, causing DNA damage in lung cells and even causing cancer-causing mutations. Studies show that there are thousands of somatic mutations in lung cancer cells of smokers, of which less than 20 mutations can drive tumor formation . It stands to reason that the more you smoke and the longer you are exposed to these carcinogens, the greater the risk of lung cancer for smokers. However, in reality, a pack of cigarettes a day, There are many people who are happy like gods and live to 80 years old without lung cancer. How can this be explained? A recent study from the Albert Einstein College of Medicine in the United States may answer this question by comparing the proximal bronchioles of smokers and non-smokers of all ages. The mutation status of basal cells, it was found that those who smoked the most did not necessarily have the most somatic mutations. The reason why old smokers smoked for many years without getting cancer is because they have a powerful mechanism to limit somatic mutations. Protect yourself from lung cancer. The study was published in Nature Genetics on April 11, 2022. 
Aging and smoking are known to lead to the accumulation of somatic mutations. 14 non-smokers aged 11-86 years and 19 smokers aged 44-81 years, bronchoscopy for lung sampling and single-cell whole-genome sequencing for bronchial basal cell mutation . 
In this study, the types of somatic mutations mainly involved single-nucleotide variants (SNVs) and small insertions and deletions (SNVs). insertions and deletions, INDELs). By comparing the mutation frequencies in bronchial basal cells of non-smokers of different ages, the researchers found that,with age, the number of intracellular single nucleotide variants Also increasing, with a median of 464 ± 108 intracellular SNVs in 11-year-old participants and 2,739 ± 778 in 86-year-old participants. Each cell adds 28 SNVs each year. In contrast, the frequency of small insertion and deletion mutations in bronchial basal cells was lower, ranging from 59 ± 18 (11 years old) to 304 ± 94 (86 years old), a similar Only 2 INDELs are added per cell per year. 
Legend: Non-smokers, with age, the number of SNVs and INDELs in bronchial basal cells changes with age , and analyzed the mutation frequency of bronchial basal cells in smokers of different ages, and obtained similar conclusions-With age, the number of somatic mutations increases, the difference is that , the cells of smokers were mutating at a higher frequency, with 91 single-nucleotide variants per cell per year, 63 more than those of non-smokers. The frequency of small insertions and deletions in cells of smokers was also higher than that of non-smokers, but did not reach statistical significance. 
The relationship between aging and the number of somatic mutations was explored. The next step is to study the relationship between smoking and somatic mutations. “Pack-year” is used as the unit of smoking volume, and 1 pack-year is defined as smoking 20 cigarettes per day (equivalent to one pack of cigarettes)/year. The 19 smokers ranged from 5.6-116 pack-years. Unexpectedly, the researchers found thatsomatic mutations did not rise with the increase in smoking, but took “23 pack years” as an inflection point, After “23 pack years”, the number of somatic mutationsThe volume stops rising and tends to stabilize or even decline. It can also be seen from the figure below that the number of somatic mutations in heavy smokers (smoking >60 pack-years) is even lower than that in moderate smokers (smoking 20.1-60 pack-years) ). 
Heavy smokers do not have the highest mutational burden, and the researchers suggest two possible reasons for this phenomenon: Heavy smokers have a strong ability to repair DNA damage, which of course has yet to be proven. Second, they can quickly metabolize harmful substances in cigarettes and reduce the risk of cancer. In the study, C>A/G>T occurred in two participants who had AKR1C2 gene polymorphisms, which led to a decrease in their ability to detoxify polycyclic aromatic hydrocarbons (PAHs) in cigarettes The frequency of base substitutions (common in lung adenocarcinomas in smokers) was more than twice that of others, suggesting that the AKR1C2 gene polymorphism partly determines the effects of cigarette carcinogens on smokers. The researchers believe the discovery will lead to a new direction of research, such as the development of new assays to measure someone’s DNA repair or detoxification ability of cigarette carcinogens to assess a smoker’s Lung cancer risk. Rather than investing a lot of effort into fighting lung cancer, it is better to identify smokers who are at higher risk of developing cancer early and get regular testing. It is worth noting thatthis study does not suggest that smoking is associated with a lower risk of cancer—all smokers have a lower risk of cancer than non-smokers The higher the number of cell mutations, the higher the risk of lung cancer. In this study, the person with the highest number of somatic mutations turned out to be a light smoker who smoked for 6 pack-years. Therefore, smoking is risky, and the best advice is not to smoke until you find out whether you are a “super-strong DNA repairer” or a “little expert in detoxification of cigarette carcinogens”. References
[1]Huang Z, Sun S, Lee M, et al. Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking. Nat Genet. 2022;54(4):492-498. doi:10.1038/s41588-022-01035-w
[ 2] Alberg AJ, Brock MV, Ford JG, Samet JM, Spivack SD. Epidemiology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143( 5 Suppl):e1S-e29S. doi:10.1378/chest.12-2345
[3]Yoshida K, Gowers KHC, Lee-Six H, et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature. 2020;578(7794):266-272. doi:10.1038/s41586-020-1961-1
Writing|457 span>Edit | Swagpp
![]()
Click “read the original text” below Download Metz Medical APP