Why Do Nonsmokers Get Lung Cancer? Rare Gene Raises Risk 60-Fold

“It really does significantly increase the risk of someone developing lung cancer, much more than smoking does,” says Sarah Goldberg, MD, MPH, a thoracic oncologist at Yale Medicine in New Haven, Connecticut, who wasn’t involved in the study.

“It doesn’t seem to increase the risk of any other cancer,” says Dr. Goldberg. “It really is something specific about this mutation.”

A Mutation With an Outsize Effect on Lung Cancer Risk

For the new study, researchers analyzed genetic data from more than 3.3 million people who sent off a DNA sample to the 23andMe Research Institute, which recently became a nonprofit. All participants gave consent for their data to be used in research studies.

The mutation in question, called EGFR T790M, turned up in about 1 of every 15,850 people.

“We’ve known about germline EGFR T790M [mutation] from individual patients and families for years, but the mutation is so rare that we needed to study millions of people to quantify just how strong that risk is,” says lead study author Jaclyn LoPiccolo, MD, PhD, an attending physician and lung cancer researcher at the Dana-Farber Cancer Institute in Boston.

But Dr. LoPiccolo cautions against reading the odds as a prediction for any one carrier. “It does not mean someone will definitely develop lung cancer. The study does not yet provide a precise lifetime risk,” she says.

Could This Rare Mutation Help Explain Lung Cancer Beyond These Carriers?

The mutation occurs in a gene called EGFR, short for epidermal growth factor receptor, which is already known to play a role in many lung cancers, says Goldberg.

“What makes this version unusual is that it’s inherited, or ‘germline,’ meaning it’s present in every cell in a person’s body from birth and can be passed down through a family,” she says.

That’s different from the far more common EGFR mutations found in lung tumors, which are considered “somatic” — changes that arise only within cancer cells themselves and aren’t inherited or passed to children, she says.

Germline EGFR T790M is rare by comparison, but researchers say studying it closely may reveal more about how it drives cancer. That could eventually inform how doctors detect or treat the far more common, somatic form of EGFR-mutant lung cancer, says Goldberg — though that’s a hope for future research, not something this study shows, she adds.

This Mutation Is More Common in the Southeastern U.S.

“A founder event happens when a mutation is present in a small number of individuals within a population that becomes isolated, and it becomes more common as that population grows,” LoPiccolo says. The variant then spread into other populations, including people of African American, Indigenous American, and Acadian and French Canadian descent, particularly after the Civil War.

To be clear, the mutation isn’t caused by living in the Southeast United States. What we are seeing is a footprint of ancestry, she says.

Someone living in Southern Appalachia today doesn’t necessarily carry the mutation, and someone who carries it may live anywhere, says LoPiccolo. The region’s broader lung cancer burden (which is well above the national average) shouldn’t be attributed to this rare variant either. “This remains a rare mutation,” she says.

A New Way to Study Rare Genetic Mutations

Previous reports on this inherited gene mutation were limited to small families and case series, too small to pin down how common it is or how much it raises risk. Goldberg compares it with BRCA, the well-known breast cancer gene. Because BRCA mutations are relatively common, scientists have been able to study them the traditional way. EGFR T790M, by contrast, “has been very elusive” because it’s so rare, she says.

“Until companies like 23andMe started to test people without diseases, it was very hard to know the frequency of certain mutations in the general population,” says Goldberg. Both she and LoPiccolo expect the approach to extend to other rare variants and diseases.

Could Genetic Testing Flag High-Risk People Today?

Currently, lung cancer screening recommendations are based on age and smoking history, which means someone who has never smoked, but has a very high inherited risk, may not qualify, says LoPiccolo.

“Our goal is to determine whether genetics can eventually identify additional people who would benefit from CT [computerized tomography] screening — which we are studying in the ongoing INHERIT study,” short for “Investigating Hereditary Risk in Thoracic Cancers,” she says.

Currently, 23andMe doesn’t inform users when they have the T790M mutation. But a statement from the nonprofit, shared by LoPiccolo, said that will change. “We're planning to make this available in a future release, because we think this is information people should have and be able to bring to their doctor.”

People who carry this mutation should have appropriate clinical confirmation, genetic counseling, and an individualized discussion about ongoing testing, says LoPiccolo.

What Are the Study’s Limitations?

The 25-times figure reflects how much more often lung cancer occurred in carriers versus noncarriers in this population, LoPiccolo says, “but it doesn’t tell an individual carrier their lifetime probability of developing lung cancer.” The 23andMe cohort, while enormous, also isn’t a perfect cross-section of the U.S. population, which matters for a rare, ancestry-linked mutation, she notes.

What Should You Do if You’re Worried About Your Lung Cancer Risk?

Germline EGFR T790M testing isn’t part of routine care today, and experts aren’t recommending the public seek it out based on this study alone. But people with a strong family history of lung cancer, multiple lung cancers, lung nodules, or who have Southeastern U.S. ancestry may want to raise the subject with a doctor, according to the study authors.

For anyone confirmed to carry the mutation, LoPiccolo says the single most important step is one within anyone’s control: Don’t smoke. “Beyond that, we don’t yet have evidence that there is a specific lifestyle intervention that eliminates or mitigates the inherited risk,” she says.