Genetic Mutation Linked to Increased Lung Cancer Risk in Nonsmokers

A rare genetic mutation, T790M in the EGFR gene, has been identified as a significant factor that may explain why some individuals who have never smoked develop lung cancer. Researchers found that people carrying this mutation have a 25-fold increased risk of developing lung cancer compared to those without it, a risk that escalates to 60-fold for nonsmokers who carry the mutation.

The findings, published in the journal Science, add crucial insights into the drivers of lung cancer among the nonsmoking population. While several genetic mutations have been associated with lung cancer in nonsmokers, including some more prevalent in certain ethnic groups and inherited mutations like BRCA2, the specific role of the EGFR T790M mutation was not well understood until now. The mutation was first identified in 2005 in a European family with a history of lung cancer, but its population-level impact remained unclear.

Scientists, co-led by Dr. Jaclyn LoPiccolo of Dana Farber Cancer Institute, utilized a large dataset from the genetics company 23andMe to assess the mutation's prevalence and impact. "This mutation is so rare that we weren’t able to get population-level risk estimates without the size of a database like that from 23andMe," LoPiccolo stated. Approximately one in 15,000 individuals in the U.S. carry the T790M mutation, but its prevalence is higher in regions like Southern Appalachia, where it is believed to have been introduced over 200 years ago.

These discoveries could influence future lung cancer screening strategies. Current recommendations for low-dose CT scans are primarily for individuals with a significant smoking history. Nadia Litterman, executive director of the Susan Wojcicki Foundation, which supported the research, highlighted the potential for genetic testing to become a part of risk assessment. "I do think that understanding your risk of lung cancer, especially from a genetic perspective, along with your exposures to things like radon and other environmental factors, would be really valuable," Litterman said. She drew a parallel to BRCA genetic testing for breast cancer, suggesting that individuals identified as carriers of the EGFR T790M mutation could undergo more frequent screenings.

The research offers a glimmer of hope for individuals like Frank McKenna, a personal trainer diagnosed with Stage IV lung cancer in 2016, despite never smoking. McKenna discovered he carried the EGFR T790M mutation after his diagnosis. He was able to begin targeted therapy, a daily pill designed to neutralize his specific mutation, which he credits with significantly improving his condition. "When I started that targeted therapy, which is a pill I take once a day, within a couple of days, I could feel a difference," McKenna shared.

McKenna's experience extends to his daughter, who also carries the T790M mutation but currently has no specific screening guidelines. This situation underscores the need for personalized screening approaches. "That’s why I’m pushing for how we can screen younger people, knowing that she has a genetic risk, and what low-dose screening she should get," McKenna stated, advocating for early detection to improve outcomes.

Dr. LoPiccolo is currently leading the INHERIT study, which aims to personalize lung cancer screening for individuals with inherited genetic risks, including the EGFR T790M mutation. The study involves assessing family history, smoking habits, genetic profiles, and environmental exposures to develop tailored screening schedules using low-dose CT scans. "The goal is to use CT screening to detect lung cancer at the earliest, most curable stage when it can be removed or cured," LoPiccolo explained. The data generated from such studies is considered vital for revising lung cancer screening guidelines and providing greater peace of mind to families managing genetic predispositions to the disease.