Genetic Mutation Significantly Increases Lung Cancer Risk
Individuals who have never smoked may still face a significantly higher risk of developing lung cancer due to a rare genetic mutation. A recent study suggests that carriers of the rare EGFR T790M mutation have a risk 62 times greater than non-smokers without the mutation. When both smokers and non-smokers are considered, those with the mutation encounter about 25 times the risk of lung cancer.
Dr. Jaclyn LoPiccolo, MD, PhD, explained to Newsweek that while smoking and environmental exposures are commonly thought of as primary lung cancer risks, this study highlights the influence of inherited genetics. In many common diseases, inherited risk is spread across numerous genetic variants with small effects. Here, one inherited mutation was linked with a substantial increase in lung cancer risk.
Lung cancer ranks among the most common cancers in the United States for both men and women. The American Cancer Society projects approximately 229,410 new diagnoses by 2026. It remains the leading cause of cancer-related death, contributing to about one in five cancer deaths. While tobacco smoking is the top risk factor, responsible for roughly 80 percent of lung cancer deaths, factors such as air pollution and family history also play a role.
Though a family history of cancer is known to elevate lung cancer risk, the role of inherited genetic factors is not fully understood. A study in Science examined the EGFR T790M mutation by analyzing genetic and health data from over 3 million individuals. This mutation is strongly linked to increased lung cancer risk.
The research traced the mutation’s history, indicating its arrival in the U.S. via the Southern Appalachian region approximately 200 years ago. According to LoPiccolo, carriers of the EGFR T790M mutation experience a 25-fold increase in lung cancer odds compared to non-carriers. The risk is even more pronounced in never-smokers, with a 60-fold increase in lung cancer odds.
The hope is that linking EGFR T790M to lung cancer risk will guide genetic testing and screening efforts. Despite the rarity of the gene, access to over 3.3 million genotyped samples allowed for calculation of cancer risk, accounting for smoking status and geographic distribution of the variant.
This variant appears in about 1 in 15,850 participants. It is significantly prevalent in the U.S., with a carrier frequency of 1 in 8,920 among descendants of British, Irish, African, and Indigenous American ancestry. This suggests its European origin and introduction to the Southern Appalachian region by British and Irish settlers in the colonial era.
LoPiccolo points out that there is much more to learn about the mutation’s implications for carriers. The ongoing goal is to understand how lung cancer risk changes with age, the lifetime risk for carriers, and why some develop cancer while others do not. Environmental and genetic factors affecting risk are under investigation.
Ultimately, this knowledge aims to inform CT screening processes to identify those at risk effectively.
Reference: Jaclyn LoPiccolo et al., Germline EGFR T790M mutation and lung cancer risk. Science 393, eaec0473 (2026). DOI:10.1126/science.aec0473.