Smoking is one of the biggest contributors to lung cancer, but anywhere from 10-20% of cases in the U.S. each year are diagnosed in people who never smoked. In a new study published in Science, researchers report that for some of those cases, an inherited genetic mutation might be involved.
Scientists co-led by Dr. Jaclyn LoPiccolo, an attending physician and lung-cancer researcher at Dana Farber Cancer Institute, found that people with a mutation in the EGFR gene had a 25-fold higher risk of developing lung cancer compared to people without the mutation, regardless of whether they smoked. When the researchers looked just at nonsmokers, the risk was even higher: carriers of the mutation had a 60-fold higher risk compared to nonsmokers who didn't have the mutation. Since nonsmokers have a lower chance of developing lung cancer than smokers, this jump in risk reflects how strongly this genetic mutation might impact risk, LoPiccolo says.
The findings add to growing knowledge about what is driving lung cancer in people who don’t smoke. A handful of genetic mutations have been linked to lung cancer in nonsmokers, including some that appear to be more prevalent in Asian people who get lung cancer, as well as inherited mutations like BRCA2, but they aren't well understood. While the specific EGFR mutation in question, called T790M, was first discovered in a European family in 2005 with members who hadn't smoked but had developed lung cancer, it wasn’t clear how much the mutation, which is rare, actually contributed to lung cancer.
LoPiccolo and her team used a large data set of genetic samples from the genetics company 23andMe to determine how much of an impact the mutation has on lung cancer. “While we knew that T790M was associated with lung cancer, we didn’t have a population large enough to determine how common the variant was, how strong its effect, and how the risk varies in different groups,” says LoPiccolo. “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.” About one in 15,000 people in the U.S. carry the mutation, but rates are higher—about one in 2,000—in Southern Appalachia, where scientists believe the first carrier brought the mutation to the U.S. from England or Ireland more than 200 years ago.
The findings open to door to considering how genetic testing might fit into lung-cancer screening. Currently, screening—in which people receive a low-dose radiation CT scan to look for lung cancer—is only recommended for people with a heavy smoking history who are above a certain age. “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,” says Nadia Litterman, executive director of the Susan Wojcicki Foundation, which funded the study. (Wojcicki, the former CEO of YouTube, never smoked, yet she died of lung cancer in 2024.) “That’s the world we are trying to work toward, and this is a major step toward that.”
Litterman points to BRCA genetic testing for breast cancer as a potential model for lung cancer. “The lung-cancer guidelines are not quite there yet, but it’s a pretty clear path of what it could look like for people who are carriers of this mutation,” she says. “They could be screened on a more regular basis, and if they develop cancer, and it’s caught early, they would have a much better trajectory than if they didn’t know about [their genetic] risk.”
That’s what patients like Frank McKenna are counting on. A personal trainer in Virginia Beach, McKenna was diagnosed with lung cancer in 2016, despite never smoking or working in areas where he might have been exposed to environmental risk factors like radon. “I was shocked when I was diagnosed with Stage IV lung cancer after the only symptom I had was a little cough,” the 66 year old says. His doctor ordered a genetic test of fluid drained from his lung and learned he carried the EGFT T790M mutation. A biopsy from his lung lesion confirmed the mutation, and he started on a targeted therapy, which he continues today, designed to specifically neutralize his mutation. “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,” he says. “I had lost weight, and there was cancer in various parts of my body, including in my bones, where it had spread. But I could feel my life coming back.”
A few months later, his daughter, who is now 33, was diagnosed with melanoma in her ear and was asked about her family history of cancer. She joined a study and provided samples to look for markers of cancer, and while she did not carry many common cancer mutations, she did carry T790M. But for now, there are no evidence-based recommendations to follow when it comes to how she should be monitoring her lungs for signs of cancer. “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," says McKenna. "If something were to appear, she can catch it at an early stage, perhaps Stage I, and not go through Stage IV, because there are not as many options, and the outlook is not as positive.”
LoPiccolo is conducting a study, called INHERIT, which includes people from across the country with any inherited genetic risk for lung cancer, including the EGFR T790M mutation. Doctors will work with each participant to understand their family history of lung cancer, smoking history, genetic profile, and any environmental exposures that might contribute to lung cancer before coming up with a personalized plan for how often they should be screened with low-dose CT scans to look for cancer. “The goal is to use CT screening to detect lung cancer at the earliest, most curable stage when it can be removed or cured,” says LoPiccolo.
Such data will be critical to changing lung-cancer screening guidelines and providing families like the McKennas more peace of mind that they are giving themselves the best chance of conquering cancer. “I have scans every six to seven months,” says McKenna. “Because when you read any research on targeted therapies, one of the first things they say is that cancer will find a way to overcome the therapy. Fortunately, my last scan a few weeks ago was still clear, but what if you could catch the cancer early with screening often enough so it’s much easier to treat?"
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