Individuals who have never smoked can still possess a much higher risk of developing lung cancer due to a rare genetic mutation. A new study indicates that carriers of the rare EGFR T790M mutation may face a 62-fold increased risk of developing lung cancer, compared to people who have never smoked. Those with the mutation, regardless of smoking status, may still encounter a 25-fold increased risk of lung cancer.
Researcher Jaclyn LoPiccolo, MD, PhD, told Newsweek: “We often associate lung cancer risk with smoking and environmental exposures. However, this study highlights the significant role of inherited genetics in lung cancer risk.” She added that, generally, inherited risk for common diseases is distributed across many genetic variants with modest effects. Yet, this single mutation is connected with a large increase in lung cancer risk.
Lung cancer ranks among the most prevalent cancers in both men and women in the United States. The American Cancer Society projects about 229,410 new lung cancer cases in 2026. It is also the leading cause of cancer mortality in the U.S., responsible for roughly one out of every five cancer deaths.
Tobacco smoking remains the primary risk factor for lung cancer. Approximately 80 percent of lung cancer deaths are attributed to smoking. Other risk factors beyond lifestyle changes include air pollution and a family history of lung cancer. Inherited genetic factors, known to elevate lung cancer risk, are not well understood.
Published in Science, a study examined the EGFR T790M mutation, analyzing data from over 3 million individuals. Researchers discovered a strong association between this gene variant and lung cancer risk. The mutation likely entered the United States via the Southern Appalachian region around 200 years ago.
LoPiccolo noted, “Carriers of the inherited EGFR T790M mutation showed approximately 25-fold higher odds of developing lung cancer compared to non-carriers. Among never-smokers, genetic carriers had more than 60-fold higher odds.”
Linking EGFR T790M to increased lung cancer risk could help identify patients who need genetic testing and lung cancer screening. Previously, the mutation’s rarity limited studies. However, access to over 3.3 million genotyped research samples allowed accurate risk calculations based on smoking status and geographic distribution.
The variant appeared in about 1 in 15,850 participants and was “significantly enriched” in the U.S., with a carrier frequency of 1 in 8,920 among those of British, Irish, African, and Indigenous American descent. This suggests the mutation originated in Europe and came to the Southern Appalachian region with British and Irish settlers during the colonial era.
LoPiccolo stated further research is needed on the mutation and its implications for carriers. “We aim to understand how lung cancer risk varies with age, carrier lifetime risk, and why only some carriers develop lung cancer, considering potential genetic and environmental factors.” Ultimately, this data could improve CT screening and identify at-risk individuals.
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Reference: Jaclyn LoPiccolo et al., Germline EGFR T790M mutation and lung cancer risk. Science 393, eaec0473 (2026) .DOI:10.1126/science.aec0473
Contact Newsweek editors for this story: Kara Dolman and Emma Lee-Sang.
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