At a glance
Carriers of the EGFR T790M gene variant face roughly 25 times the lung cancer risk of noncarriers, according to the largest-yet study of the variant.
People with ancestry from certain areas of Appalachia and the Southeastern United States were more likely to carry the mutation.
The findings could help shape targeted genetic testing and expand future lung cancer screening guidelines beyond age and smoking history.
A rare inherited mutation in a gene known as the Epidermal Growth Factor Receptor, or EGFR, is associated with a 25-fold increased risk of lung cancer, making it one of the strongest inherited risk factors for lung cancer discovered to date, according to a study by investigators at Harvard Medical School, Dana-Farber Cancer Institute, and 23andMe Research Institute.
Analysis of the risk conveyed by the variant EGFR T790M could help shape targeted genetic testing and expand future lung cancer screening guidelines beyond age and smoking history.
The findings, based on genetic and health data from more than 3.3 million research-consented participants, were published Sept. 17 in Science.
“Today, lung cancer screening is driven almost entirely by smoking history,” said Jaclyn LoPiccolo, HMS instructor in medicine at Dana-Farber and first author of the study. “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,” she said.
The researchers further found that in the United States, the variant is more common among people with ancestry from certain areas of the Southeast.
A strong genetic signal
Although most lung cancers are associated with tobacco use or exposure, the proportion diagnosed in people who have never smoked has been rising. Yet the genetic factors underlying these cancers, particularly the role of inherited risk, are poorly understood.
In 2005, researchers identified the rare inherited EGFR T790M mutation in a European family with multiple cases of lung cancer. Since then, the mutation has been reported in other families with unusually high rates of the disease. However, previous studies have been too small to reliably estimate the associated cancer risk.
“For years we’ve known that some families inherit a markedly increased risk of lung cancer, but because this variant is so rare, we’ve never been able to accurately measure that risk,” said co-senior author Pasi Antero Jänne, HMS professor of medicine and senior vice president for translational research at Dana-Farber. “By studying more than three million people, we were able to demonstrate just how strongly this inherited mutation is associated with lung cancer.”
The researchers initially considered genetic data from more than 10 million 23andMe research-consented participants. They narrowed down the sample to the more than 3.3 million participants for whom both genetic information and lung cancer data were available. They also examined data from the Dana-Farber-led INHERIT study (Investigating Hereditary Risk in Thoracic Cancers), conducted in partnership with GO2 for Lung Cancer and the Addario Lung Cancer Medical Institute.
Comparing people with lung cancer to those without the disease, the team examined whether EGFR T790M was more common among those who had developed lung cancer. They also separately analyzed people who had never smoked.
The researchers expected EGFR T790M to increase lung cancer risk, but they had not anticipated the magnitude of the association.
“One of the remarkable findings here is just how strong an effect a single mutation can have,” said co-senior author Alexander Gusev, HMS associate professor of medicine at Dana-Farber. “To my knowledge it’s one of the strongest cancer risk-increasing mutations that has ever been found.”
Among people who smoked, carriers of the mutation were about 10 times as likely to develop lung cancer as noncarriers. Among people who never smoked, carriers were more than 60 times as likely to develop lung cancer.
This relative risk does not mean smoking is protective, the researchers explained. Because smoking already greatly increases lung cancer risk, the mutation’s effect appears smaller by comparison.
“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 said. “So, you definitely don’t want to smoke.”
The mutation was not linked to any of 17 other common cancers studied, suggesting that its effects may be largely limited to lung cancer.
Appalachian origins
The study also examined how the variant’s frequency varied across geographic and ancestral groups. The prevalence of the mutation in the U.S. population was about 1 in 15,000 people. But in certain areas of the Southeastern United States, the carrier frequency was approximately 1 in 2,000 people.
Most carriers shared a genetic signature suggesting that they inherited the mutation from the same ancestral lineage. The researchers traced that lineage to British and Irish settlers in the United States and showed that the mutation became enriched through a founder effect in Southern Appalachia about 200 to 225 years ago. The variant later spread to additional populations, including people with African American and Indigenous American ancestry.
“It’s a fascinating example of how human migration and genealogy can shape disease risk generations later,” LoPiccolo said.
The researchers say that people with a strong family history of lung cancer, multiple lung nodules, multifocal lung cancers, or ancestral roots in areas of the U.S. Southeast where the variant is more common may wish to discuss their personal and family history with a genetic counselor, who can help determine whether genetic testing and regular lung cancer screening may be appropriate.
As next steps, the researchers hope to learn why some EGFR T790M carriers develop lung cancer while others do not, why the mutation appears to increase the risk of lung cancer but not other common cancers, and how environmental exposures and additional genetic changes influence risk. They said future studies will include more diverse populations and investigate other inherited EGFR mutations that may predispose people to lung cancer.
Adapted from a Dana-Farber news release.
Authorship, funding, disclosures
Additional authors on the paper include Steven Micheletti, Jing Shi, Wei Wang, Shubham Saini, Keng-Han Lin, Wanwan Xu, Pierre Fontanillas, the 23andMe Research Team, Diane R. Koeller, Helen Yatzus, Victoria G. Williamson, Jose A. Avila, Raphael B. Liautaud, Courtney A. Granville, Ryan L. Collins, Judy E. Garber, David C. Christiani, Stella Aslibekyan, and Julia M. Granka.
Funding for this study was provided by a LUNGevity Foundation Career Development Award; the Elaine & Gerald Schuster Fund for Lung Cancer Research; the National Institutes of Health (grants R01 HG012133, U01 CA209414, and R35 CA220497); the American Cancer Society; the Chen-Huang Center for EGFR-Mutant Lung Cancers; GO2 for Lung Cancer (INHERIT study); the Addario family; Sam and Janet Bain; the Burns family; the Jain and Patkar family; David Lefkowitz and Julie Persily; the Smita and Pankaj Patel family; SITA Foundation; the Van Auken Private Foundation; the Ray Marglous Family Foundation in memory of Lindsey Rae Marglous; the Michele Simeone Abrecht Memorial Fund, established by Charlotte and Clifford Abrecht; the Cammarata Family Foundation Research Fund; the Zhen-Quan Xu and Lin Yuan Fund for Lung Cancer Research; and the Gohl Family Lung Cancer Research Fund.
A full list of disclosures can be found in the paper.
