Why do some smokers get lung cancer while others do not ? The genetics behind risk

Naorem Loya Mangang
Smoking is widely recognized as the leading cause of lung cancer. Cigarette smoke contains thousands of chemicals, including dozens known to damage DNA and trigger cancer. Yet a puzzling question often arises: why do some lifelong smokers never develop lung cancer, while others develop the disease even with relatively lower exposure to tobacco smoke ? For decades, this question has intrigued scientists, clinicians, and public health researchers. While smoking dramatically increases the risk of lung cancer, the answer to this paradox lies in a complex interaction between environmental exposure and human genetics.
 In other words, the chemicals we are exposed to and the genes we inherit together shape our vulnerability to the disease.
India is currently facing a growing burden of lung cancer. According to data from the Global Cancer Observatory (GLOBOCAN 2022), the country records more than 81,000 new lung cancer cases each year, and the disease causes over 70,000 deaths annually. Although lung cancer represents roughly 5–6% of all cancer cases in India, it remains one of the leading causes of cancer-related mortality. Tobacco smoking continues to be the most significant risk factor, but other environmental exposures such as air pollution, indoor biomass fuel smoke, and occupational hazards also contribute to the rising cases. To understand why risk varies among individuals, it is important to look at how the body responds to toxic chemicals in cigarette smoke. When smoke enters the lungs, the body activates a series of biological defense mechanisms designed to neutralize harmful substances. Specialized enzymes break down carcinogens into less harmful compounds so that they can be safely eliminated from the body.
However, these detoxification systems do not function identically in every individual. Small differences in our DNA can influence how efficiently these protective pathways operate. These differences often arise from single nucleotide polymorphisms (SNPs) tiny variations in the genetic code where a single building block of DNA is altered. Although such changes may appear minor, they can affect how certain genes function and how proteins involved in detoxification are produced. Some SNPs occur in genes that regulate the metabolism of toxic substances found in tobacco smoke. When these genes function less efficiently due to inherited genetic variation, harmful chemicals may remain in the body longer.
This prolonged exposure can increase the likelihood of DNA damage, which may eventually lead to cancer. One important group of detoxification genes involved in this process is the glutathione S-transferase (GST) family. These enzymes are part of what scientists call Phase II detoxification pathways. Their primary function is to neutralize reactive chemicals generated during the metabolism of carcinogens. But some individuals carry variations or deletions in GST genes that reduce their ability to detoxify these harmful compounds. In such cases, carcinogens may accumulate more easily in lung tissue, potentially increasing cancer risk. In contrast, individuals with more efficient detoxification systems may be able to process and eliminate carcinogens more effectively. This does not mean that smoking becomes harmless for them. Rather, it suggests that genetic factors can influence how severely the body is affected by environmental exposures.
Another crucial layer of protection comes from the body’s DNA repair mechanisms. Every day, our cells experience numerous instances of DNA damage caused by environmental factors such as radiation, pollutants, and tobacco smoke. Fortunately, cells possess sophisticated repair systems that continuously monitor and correct these errors. When these repair mechanisms function properly, they can prevent damaged DNA from leading to permanent mutations. However, genetic variations in DNA repair genes can influence how effectively these systems work. If DNA damage caused by tobacco smoke is not properly repaired, mutations may accumulate over time. These mutations can disrupt normal cell growth and eventually contribute to the development of cancer.
Genetics alone does not determine whether a person will develop lung cancer. Smoking remains the most powerful and well-established risk factor. The majority of lung cancer cases worldwide are directly linked to tobacco use. Genetics simply helps explain why individuals exposed to the same environmental risks may experience very different health outcomes. This emerging understanding of gene environment interaction is also shaping the future of medical research. Scientists are increasingly exploring the field of precision medicine, which aims to tailor prevention strategies, screening programs, and treatments based on an individual’s genetic profile. In the future, genetic testing may help identify individuals who are particularly vulnerable to lung cancer due to inherited susceptibility. Such knowledge could enable more targeted prevention strategies, including earlier screening and closer monitoring of high-risk individuals. It may also help guide the development of new therapies that take genetic differences into account. These advances should never be interpreted as suggesting that some people are naturally protected from the harmful effects of smoking.
The central message from modern cancer research remains clear: no level of smoking is safe. While genetic factors may influence susceptibility, the most effective way to reduce lung cancer risk is to avoid tobacco use altogether and minimize exposure to harmful environmental pollutants. Public awareness also plays an important role in prevention. Understanding that cancer risk is shaped by both lifestyle and biology can help individuals make more informed health decisions. Ultimately, the relationship between smoking and lung cancer illustrates a broader lesson about human health. We cannot change the genes we inherit, but we can make choices that reduce our exposure to harmful environ- mental risks. In doing so, we significantly improve our chances of living healthier and longer lives.

The writer is a PhD Scholar in the Department of Life Sciences (Zoology), Manipur University