This Mutation Is More Common in the Southeastern U.S.
People with Southern Appalachian ancestry are about 4 times more likely to carry the mutation than people in the United States as a whole. Genetic evidence suggests it arose in Europe and was carried to America by British and Irish settlers during the colonial period, then underwent what geneticists call a founder event roughly 200 to 225 years ago in Southern Appalachia.
“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 company, shared by LoPiccolo, said that will change. “We’re planning to make our participants’ T790M status available to them in a future report, regardless of when they’ve been tested, 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?
Most lung cancer is still driven by smoking, but not all. Roughly 1 in 5 people who die of lung cancer in the United States never smoked, according to the American Cancer Society, and their disease often looks biologically different, more often driven by an identifiable molecular change than by damage caused by smoking.
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.
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