Rare Genetic Mutation Dramatically Increases Lung Cancer Risk, Even in Non-Smokers

A rare genetic mutation known as EGFR T790M could significantly increase an individual's risk of developing lung cancer, even if they have no history of smoking, according to a new study published in the journal Science. The research, which analyzed data from over 3.3 million people, found that carriers of this mutation had approximately 25 times the risk of developing lung cancer compared to those without it. For individuals who have never smoked, the odds of developing lung cancer were about 62 times higher if they carried the mutation.

The study, led by researchers at the Dana-Farber Cancer Institute and 23andMe Research Institute, indicated that the EGFR T790M gene variant did not appear to increase the risk for 17 other types of cancer examined. This finding suggests a specific link between the mutation and lung cancer development.

"Today, lung cancer screening is driven almost entirely by smoking history," said Jaclyn LoPiccolo, M.D., Ph.D., a study co-author and lung cancer researcher at Dana-Farber Cancer Institute, in a press release. "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."

Researchers traced the majority of U.S. carriers of the mutation to a shared ancestry linked to British and Irish settlers in the Southern Appalachian region approximately 200 to 225 years ago. While the mutation remains rare nationwide, affecting an estimated one in 15,000 to 16,000 people, it is more prevalent in certain parts of Southern Appalachia, where as many as one in 2,000 individuals may carry it.

"We found that the vast majority of carriers inherited the mutation from the same ancestral lineage," LoPiccolo stated. "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."

Alexander Gusev, Ph.D., a quantitative geneticist at Dana-Farber, described the mutation's strong effect as "remarkable," noting, "To my knowledge it's one of the strongest, if not the strongest, cancer risk increasing mutations that has ever been found."

He emphasized that while smoking is a significant risk factor for lung cancer, this mutation independently increases risk. "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," Gusev added. "So, you definitely don't want to smoke."

The study's authors suggest that individuals with a significant family history of lung cancer, multiple lung nodules or tumors, or those with family roots in specific southeastern U.S. regions should consider discussing genetic counseling to determine if genetic testing or lung cancer screening is appropriate for them.

However, the researchers acknowledged certain limitations. Due to the mutation's rarity, the sample size of carriers was relatively small, making precise risk estimates subject to some uncertainty. The analysis also relied heavily on participants from 23andMe, who may not be representative of the general population. The study establishes a strong association between the mutation and lung cancer risk but does not yet demonstrate that genetic testing improves mortality or other health outcomes.

The research received partial funding from the National Institutes of Health and the American Cancer Society.