A rare inherited genetic mutation can increase the risk of lung cancer by approximately 62 times for individuals who have never smoked, according to a study published in the journal Science. The research, which analyzed genetic data from approximately 3.37 million people of European ancestry, identified the EGFR T790M germline mutation as a significant driver of the disease regardless of tobacco use.
Rare Inherited Genetic Mutation Increases Lung Cancer Risk for Non-Smokers
While smoking remains a primary risk factor—associated with roughly four times the risk of lung cancer in the studied population—the effect of the T790M mutation is markedly more potent. Across the entire study group, carriers of the mutation faced about 25 times the risk of lung cancer compared to non-carriers. However, this association grew significantly stronger among non-smokers, where the risk increased 62-fold.
The Role of the EGFR Gene
The mutation occurs in the epidermal growth factor receptor (EGFR), a gene responsible for controlling how cells divide and grow. When this protein is mutated, it can cause cancer cells to expand and spread. Unlike many EGFR mutations that appear only after a tumor has developed, the T790M germline variant is present in the inherited DNA a person is born with, meaning it exists in cells throughout the body.
Researchers noted that while they evaluated 17 different cancers and nonpulmonary conditions, the T790M mutation only showed a significant association with lung cancer. This finding helps explain why the disease develops in some people who have no history of tobacco use, though other factors such as air pollution, radon, occupational exposures, and secondhand smoke also contribute to non-smoking lung cancer cases.
Geographic Origins and Prevalence
The mutation is extremely rare, appearing in approximately one out of every 15,850 individuals. Because of its rarity, previous research struggled to accurately quantify the specific risk it carried until a larger dataset from the genetic testing company 23andMe was utilized.
The study traced the origins of the variant to a “founder effect” in the Southern Appalachian region of the United States about 200 to 225 years ago. In this specific region, the carrier frequency is significantly higher, at 1 in 2,078. The variant arrived in the U.S. around 1803 during westward expansion and is particularly enriched among people of Southern Colonial ancestry compared to those of British or Irish descent. The mutation did not appear to spread to non-European populations until the early 1900s.
Implications for Cancer Screening
Current lung cancer screening is driven almost entirely by a patient’s smoking history. However, these findings suggest that genetic risk could eventually play a role in medical diagnostics.
Jaclyn LoPiccolo, MD, PhD, a lung cancer researcher at Dana-Farber Cancer Institute and co-study lead, stated that the findings raise the possibility that future screening could be dictated by inherited genetic risk. If further studies confirm the benefits, individuals with the EGFR T790M mutation could be identified via genetic testing and provided with personalized computed tomography (CT) screening to catch cancers at a more curable stage.
Pasi A. Jänne, MD, PhD, a lung cancer specialist at Dana-Farber and corresponding author, noted that the study does not provide a complete picture of lifetime risk, as environmental factors and other genetic nuances may still modify the risk for these individuals.
Existing and Emerging Treatments
The American Lung Association reports that lung cancers positive for EGFR mutations account for roughly 10% to 15% of cases in the U.S., with higher occurrences in Asian populations. Several therapies already target EGFR-mutated lung cancer, including Rybrevant from Johnson & Johnson and Tagrisso from AstraZeneca. BlossomHill also announced a macrocyclic molecule called BH-30643 in August to compete with Tagrisso.
Separate reports from September 2026 indicate that the drug daraxonrasib, which recently received US approval for advanced pancreatic cancer, is also showing promise against lung cancer, the world’s leading cause of cancer deaths.