Study sheds light on why some smokers stay cancer-free

According to its recent article, The Brighter Side features that in recent years, significant progress has been made in understanding the complex relationship between smoking and lung cancer. 

Lung cancer continues to be the leading cause of cancer-related deaths worldwide, primarily driven by cigarette smoking. The chemicals in tobacco smoke, such as polycyclic aromatic hydrocarbons (PAHs), damage DNA, resulting in mutations that contribute to the development of cancer.

Despite the well-established link between smoking and lung cancer, most smokers do not develop the disease. Recent research indicates that some smokers have protective mechanisms that reduce DNA mutations, providing new perspectives on cancer prevention and early detection.

Epidemiological studies have long linked lung cancer risk to factors such as total smoking exposure, duration, and the timing of smoking cessation. However, 80-90 per cent of lifelong smokers never develop lung cancer, and most smoking-related deaths occur in older populations. To address this paradox, researchers have shifted their attention to molecular and genetic factors in an effort to uncover specific mechanisms that may protect certain individuals from developing cancer.

Tumor cells in the lungs of smokers often carry tens of thousands of somatic mutations. However, there is limited understanding of the mutation landscape in normal bronchial basal cells, which are thought to be the precursors to squamous cell carcinoma. These cells, found in the proximal airway, accumulate distinct mutations over a person’s lifetime.

To fully understand these patterns, single-cell whole-genome sequencing (WGS) is essential. This advanced technique enables precise identification of mutations without introducing errors that could occur during cell expansion.

Recent advancements have enabled researchers to systematically assess mutational burdens in lung cells from both smokers and non-smokers. By sequencing individual cells from a varied group, scientists can now measure the impact of age and smoking on mutation buildup. This method has shed light on the interaction between smoking and aging in promoting carcinogenesis.

For many years, researchers faced challenges in proving the theory that smoking causes lung cancer by inducing DNA mutations. Earlier sequencing methods often introduced errors, making it hard to differentiate genuine mutations from background noise, which slowed progress. However, recent advances in single-cell genomics have addressed these issues.

Jan Vijg, Ph.D., a prominent molecular genetics expert, developed a groundbreaking sequencing method known as single-cell multiple displacement amplification (SCMDA). Introduced in Nature Methods in 2017, this technique reduces errors and enhances the accuracy of mutation detection.

Researchers from the Albert Einstein College of Medicine recently employed SCMDA to analyze lung cells from 14 non-smokers aged 11 to 86 and 19 smokers aged 44 to 81, with smokers in the study having a maximum smoking history of 116 pack-years.

The team gathered bronchial epithelial cells during diagnostic bronchoscopies. These cells, which are highly susceptible to developing into cancer, accumulate mutations from both aging and smoking. By comparing the mutation rates between these groups, researchers have started to unravel the molecular signature of smoking and its contribution to lung cancer risk.

The study, published in Nature Genetics, showed that lung cells accumulate mutations as people age, with smokers experiencing significantly higher mutation rates compared to non-smokers. These mutations include single-nucleotide variants and small insertions or deletions. The results support the theory that smoking accelerates mutation accumulation, thereby increasing cancer risk. This is consistent with broader epidemiological data indicating that lung cancer is rare among non-smokers, while 10-20 per cent of lifelong smokers develop the disease.

By Naila Huseynova