Rare EGFR mutation sharply raises lung cancer risk in large genetic study

A rare inherited mutation in the epidermal growth factor receptor gene, known as EGFR T790M, was associated with a 25-fold higher risk of lung cancer in a large observational study led by investigators at Dana-Farber Cancer Institute and 23andMe Research Institute. The analysis included de-identified, aggregated genetic and health data from 3.3 million 23andMe research participants. Among people who had never smoked, carriers were more than 60 times as likely to develop lung cancer as noncarriers, according to the peer-reviewed study published in Science in September 2026.

Researchers first identified EGFR T790M in a European family in 2005 after documenting multiple cases of lung cancer. The variant was subsequently reported in other families with unusually high rates of the disease, but its rarity had made accurate measurement of the associated risk difficult. The new study used the scale of the 23andMe research database to compare people with and without lung cancer and determine whether the mutation was more common among affected participants.

The investigators also analyzed people who had never smoked separately to examine the association in the absence of tobacco use. The study combined several sources of evidence, including additional data from the INHERIT Study, which was led at Dana-Farber by Jaclyn LoPiccolo and Pasi A. Jänne in partnership with GO2 for Lung Cancer and the Addario Lung Cancer Medical Institute. The 23andMe research database included more than 10 million people who had consented to participate in research, but the investigators focused on 3.3 million participants for whom both genetic and lung cancer data were available.

This combination allowed them to examine the frequency of the rare variant, estimate its association with lung cancer, and investigate the ancestry and population history of many carriers. Risk estimates differed markedly according to smoking status. Among people who had smoked, EGFR T790M carriers were about 10 times as likely to develop lung cancer as noncarriers.

Among people who had never smoked, carriers were more than 60 times as likely to develop lung cancer. The researchers stressed that the lower relative estimate among people who had smoked does not mean smoking is protective. Tobacco use already greatly increases lung cancer risk, so the additional effect associated with the mutation appears smaller by comparison.

Co-senior author Alexander Gusev described the findings as evidence of the unusually strong effect that a single inherited mutation can have on cancer risk. EGFR T790M is uncommon, with LoPiccolo estimating that it occurs in about 1 in 15,000 people in the United States. In some areas of the Southeastern United States, however, its frequency reaches approximately 1 in 2,000.

The researchers traced the vast majority of carriers to the same ancestral lineage and connected it to British and Irish settlers in the United States. According to their analysis, the mutation became more common after a founder event and genetic bottleneck in Southern Appalachia about 200 years ago. The distribution therefore reflects a combination of inherited ancestry, migration and population history.

The analysis found no association between EGFR T790M and any of 17 other common cancers studied, suggesting that its effects may be largely limited to lung cancer. That result does not explain why the variant is associated with lung cancer or why some carriers develop the disease while others do not. The investigators identified several questions for future research, including the influence of environmental exposures and additional genetic changes, the basis of the lung-cancer specificity, and the factors that distinguish carriers who remain healthy from those who develop lung cancer.

Future work will also examine more diverse populations and other inherited EGFR mutations that may predispose people to lung cancer. The findings also address a limitation in the way lung cancer screening is currently approached. Although most lung cancers are associated with tobacco use or exposure, the proportion diagnosed in people who have never smoked has been rising, while the genetic factors underlying these cancers remain incompletely understood.

Screening is driven almost entirely by smoking history. LoPiccolo said the results raise the possibility that inherited genetic risk could eventually also influence screening decisions, but further studies would need to confirm whether identifying carriers and offering personalized computed-tomography screening would be beneficial. Because the mutation is rare and geographically concentrated in some communities, the researchers advised people with several family members who have had lung cancer, multiple lung nodules, multifocal lung cancers, or ancestral roots in parts of the Southeastern United States to consult a genetic counselor.

A counselor can help determine whether genetic testing and regular lung cancer screening may be appropriate. The study did not establish that broad screening of every EGFR T790M carrier is warranted. Instead, its results identify a group for which targeted genetic counseling and further research on testing and surveillance may be useful.

The scale of the cohort provides an unusually detailed view of a mutation that had previously been studied mainly in a small number of families, although the number of carriers remains limited by the variant’s rarity. Data from the INHERIT Study provided additional support for the association. Continued recruitment for INHERIT and the separate Lung Cancer Genetics Study is intended to expand knowledge of inherited susceptibility, genetic and environmental influences, and disease progression.

Until further evidence establishes the benefits of carrier screening, the central finding remains that germline EGFR T790M is strongly associated with elevated lung cancer risk, particularly among people who have never smoked.

Subject of Research: Inherited EGFR T790M mutations and lung cancer risk in a large genetics cohort.

Article Title: Rare inherited EGFR mutation linked to dramatically increased lung cancer risk

Article References: Rare inherited EGFR mutation linked to dramatically increased lung cancer risk. Original publication (Bibliographic details unavailable.)

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Keywords: EGFR T790M, lung cancer, inherited risk, germline mutation, never-smokers, genetic testing, cancer screening, 23andMe, Dana-Farber, population genetics, Rare, inherited