Cigarette smoking is undeniably a primary contributor to lung cancer, yet only a minority of smokers experience the disease. A 2022 study by the Albert Einstein College of Medicine, published in Nature Genetics, proposes that certain smokers possess robust protective mechanisms that restrict mutations and lower their risk of developing lung cancer.1 These findings can potentially identify high-risk individuals who require vigilant monitoring to prevent the disease.
Simon Spivack, M.D., M.P.H., a co-senior author of the study, emphasized the significance of these findings, stating, “This could be a crucial step towards preventing and detecting lung cancer at an early stage, reducing the immense efforts currently needed to combat advanced disease, which accounts for the majority of healthcare expenditures and suffering.“
Addressing Challenges in Cell Mutation Research
The prevailing belief has been that smoking induces lung cancer by triggering DNA mutations in healthy lung cells. However, until this study, there was no effective method for accurately quantifying mutations in normal cells, making this claim unverifiable. Dr. Jan Vijg, Ph.D., a co-senior author of the study, professor and chair of genetics, and professor of ophthalmology and visual sciences, developed a better sequencing technique for whole-genome analysis of individual cells a few years ago, overcoming this obstacle.
Methods for single-cell whole-genome sequencing may introduce sequencing errors that are hard to distinguish from genuine mutations, especially when analyzing cells with rare and random mutations. Dr. Vijg addressed this issue by devising a new sequencing approach called single-cell multiple displacement amplification (SCMDA). A publication in Nature Methods in 2017 reported that this method successfully accounted for and minimized sequencing errors.
The Einstein researchers employed SCMDA to compare the mutational profiles of normal lung epithelial cells (cells lining the lungs) from two groups: 14 individuals who had never smoked, aged 11 to 86, and 19 smokers, aged 44 to 81, who had smoked a maximum of 116 pack years (equivalent to smoking one pack of cigarettes per day for one year). The cells were collected from patients undergoing bronchoscopy for unrelated diagnostic tests, and according to Dr. Spivack, these lung cells can accumulate mutations over the course of years or even decades, making them more prone to becoming cancerous.
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The research team discovered that mutations (single-nucleotide variants and small insertions and deletions) increased with age in the lung cells of non-smokers, while the lung cells of smokers exhibited a significantly higher number of mutations. Dr. Spivack confirmed, “This experimentally confirms that smoking increases the risk of lung cancer by elevating the frequency of mutations, as previously theorized. This likely explains why lung cancer is rare among non-smokers but affects 10% to 20% of lifelong smokers.”
Another intriguing finding emerged from the study: the number of cell mutations detected in lung cells displayed a linear correlation with the number of pack years of smoking, indicating an increased risk of lung cancer. However, beyond 23 pack years of exposure, the accumulation of cell mutations ceased.2
Dr. Spivack elaborated, “The heaviest smokers did not exhibit the highest mutation burden. Our data suggest that these individuals may have survived despite heavy smoking because they possessed mechanisms that effectively suppressed further mutation accumulation. This plateauing of mutations could be attributed to their highly proficient DNA repair systems or enhanced ability to detoxify cigarette smoke.”
These findings have opened up new avenues for research. Dr. Vijg explained, “Our next objective is to develop novel assays that can assess an individual’s capacity for DNA repair or detoxification, providing a new means of evaluating their risk for lung cancer.”
Although the risk of lung cancer in smokers is dependent on the amount they smoke, it remains uncertain whether this increased risk correlates with a higher rate of somatic mutation accumulation in normal lung cells. To address this question, the researchers employed single-cell whole-genome sequencing on proximal bronchial basal cells from 33 participants aged 11 to 86, with smoking histories ranging from never-smoking to 116 pack-years. The study revealed an age-related increase in the frequency of single-nucleotide variants and small insertions and deletions in never-smokers, with significantly higher mutation frequencies observed in smokers.
“Mutations exhibit a linear relationship with smoking pack-years, which aligns with the increase in cancer risk until around 23 pack-years. Going beyond this shows no further rise in mutation frequency , indicating a selective mechanism that avoids mutations. The identified mutation signatures associated with lung cancer were consistent with both age and smoking, but no significant enrichment of somatic mutations was detected in lung cancer driver genes.”
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- “Study suggests why most smokers don’t get lung cancer.” Eurekalert. Albert Einstein College of Medicine. April 2022.
- “Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking.” Nature. Zhenqiu Huang, et al. April 2022.