A rare genetic mutation could put people at a dramatically higher risk of developing lung cancer even if they’ve never smoked.

A rare mutation in the gene EGFR T790M was found to increase lung cancer risk by 25 times compared with people who did not have the mutation, according to a new study published in the journal Science.

Among people who had never smoked, carriers of the mutation had about 62 times the odds of lung cancer compared with never-smokers who did not have it.

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The study, led by investigators at Dana-Farber Cancer Institute and 23andMe Research Institute, analyzed data from more than 3.3 million people.

The gene variant showed no increased risk across 17 other cancers studied.

“Today, lung cancer screening is driven almost entirely by smoking history,” study co-author Jaclyn LoPiccolo, attending physician and lung cancer researcher at Dana-Farber Cancer Institute, said in a press release.

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“Our findings raise the possibility that, in the future, screening could also be dictated by inherited genetic risk. If further studies confirm the benefit, people with EGFR T790M could be identified through genetic testing and offered personalized CT screening to identify lung cancers when they are at their most curable stage.”

Most U.S. carriers of the mutation were traced to a shared ancestry linked to British and Irish settlers in Southern Appalachia about 200–225 years ago, the researchers found.

The mutation remains rare nationwide, affecting roughly one in 15,000–16,000 people. It is more common in some parts of Southern Appalachia, where researchers estimate as many as one in 2,000 people may carry it.

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“We found that the vast majority of carriers inherited the mutation from the same ancestral lineage,” said LoPiccolo. “We could trace that lineage to British and Irish settlers in the United States and show that the mutation became enriched after a founder event and genetic bottleneck in Southern Appalachia about 200 years ago.

“It’s a fascinating example of how human migration and genealogy can shape disease risk, generations later.”

One of the “remarkable” findings of the study was the fact that a single mutation could have such a strong effect, according to Alexander Gusev, a quantitative geneticist at Dana-Farber.

“To my knowledge, it’s one of the strongest, if not the strongest, cancer risk-increasing mutations that has ever been found,” he said in the release.

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“Smoking is bad for lung cancer. This mutation is bad for lung cancer. When you do both, your risk is the sum of those two risks,” he added. “So, you definitely don’t want to smoke.”

The researchers suggest that people with a strong family history of lung cancer, multiple lung nodules or tumors or family roots in parts of the southeastern U.S. should consider speaking with a genetic counselor about whether genetic testing or lung cancer screening makes sense for them.

There were some limitations to the study.

Because the mutation is so rare, researchers identified relatively few carriers even among the millions of participants, meaning the exact size of the increased risk remains uncertain.

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The analysis also relied heavily on 23andMe research participants, who may not represent the broader population.

Because the mutation is much more common in certain parts of the U.S., the risk estimates may not apply equally to everyone, the researchers noted.

While the study establishes a strong association with lung cancer risk, it does not demonstrate that genetic testing improves mortality or other health outcomes.

The study was funded in part by the National Institutes of Health and the American Cancer Society.

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