Rare EGFR Gene Mutation Greatly Increases Lung Cancer Risk in Nonsmokers

Scientists have identified an inherited genetic mutation that increases the risk of lung cancer by up to 62-fold in people who have never smoked, according to a study published on September 17 in the journal Science. Researchers analyzed data from more than 3.3 million participants to trace the variant, known as the EGFR T790M mutation, finding that it alters cellular growth and division while remaining exceptionally rare in the general population at a rate of roughly 1 in every 15,850 individuals.

How the EGFR T790M Mutation Amplifies Lung Cancer Risk

The study reveals that nonsmokers who carry the EGFR T790M mutation face a significantly higher likelihood of developing lung cancer than nonsmokers without the variant. By comparison, individuals who smoked but did not carry the mutation experienced a fourfold increase in risk, meaning the genetic variant alone carried a heavier statistical weight than smoking status in certain comparisons. Among study participants who both smoked and carried the mutation, T790M increased cancer risk 11-fold relative to other smokers. Overall, carriers exhibited about 25 times the odds of developing lung cancer compared to noncarriers, according to data pulled from 23andMe customer cohorts who consented to research use.

According to Chris Amos, a genetic epidemiologist at the Baylor College of Medicine who was not involved in the research, the findings address a major knowledge gap. The prevalence of the T790M variant and its impact on lung cancer risk has previously been poorly understood, Amos said, noting that the variant also influences treatment decisions for patients who already have the disease. Dr. Stephen Chanock, director of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, pointed out that because the mutation is rare, it does not account for a large percentage of overall lung cancer cases nationwide.

Geographic Distribution and Historical Spread in the U.S.

When mapping the birthplaces of study participants, researchers discovered that the T790M mutation is notably more common in the Southeastern United States, particularly across Alabama, Mississippi, and Tennessee. In those three states, the genetic variant appeared in 1 out of every 2,078 people who contributed data. Historical records suggest that British and Irish settlers brought the mutation to North America in the early 1700s. Families carrying the variant later settled in southern Appalachia, where geographic isolation allowed the gene to pass down repeatedly through generations.

According to experts, this localized concentration helps explain elevated lung cancer rates in the region, where smoking rates also run higher than the national average at approximately 20% of adults compared to 16% elsewhere in the country. However, researchers emphasize that the mutation’s presence in the Southeast is a footprint of ancestry rather than an environmental consequence of living there. To be clear, the mutation isn’t caused by living in the Southeast United States, said Dr. Christine LoPiccolo, a researcher working on related hereditary lung cancer studies.

Screening Challenges and Ongoing Clinical Research

Current medical guidelines recommend annual low-dose CT lung cancer screening primarily based on age and smoking history. Because the study found that individuals with T790M developed lung cancer roughly five years earlier than noncarriers on average, experts argue that screening criteria may need revision. Amos highlighted the need to begin screen[ing] at an earlier age and irrespective of smoking status.

To address these screening gaps, researchers have launched a clinical trial called INHERIT, short for Investigating Hereditary Risk in Thoracic Cancers, led by LoPiccolo. The trial evaluates CT-based lung cancer screening in people with inherited genetic risks, including the T790M mutation, to help establish personalized monitoring plans. While 23andMe does not currently notify users of their T790M status, company representatives have indicated plans to incorporate the finding into future customer health reports to help carriers discuss proactive care with their physicians.