Rare gene mutation linked to Southern Appalachian settlers raises lung cancer risk sixtyfold in non-smokers

What happened?

A rare inherited genetic mutation has been found to raise the risk of lung cancer in people who have never smoked by more than 60-fold.

The discovery, published in the journal Science, links the mutation to a single genetic lineage that can be traced back more than two centuries to settlers in Southern Appalachia.

Researchers from the Dana-Farber Cancer Institute and the genetics company 23andMe analysed data from more than 3.3 million people. They found that carriers of the mutation, known as EGFR T790M, are 25 times more likely to develop lung cancer than non-carriers. For those who have never smoked, the risk is even more stark: they are 62 times more likely to get the disease.

Unlike more common mutations that appear randomly in lung tumours later in life, this variant is "germline", meaning it is inherited and present in every cell from birth.

"We’ve known about germline EGFR T790M from individual patients and families for years," said Dr Jaclyn LoPiccolo, a lung cancer researcher at Dana-Farber and lead author of the study. "But the mutation is so rare that we needed to study millions of people to quantify just how strong that risk is."

How was the mutation traced?

The sheer scale of 23andMe’s database made the breakthrough possible. While traditional scientific databases were too small to track such a rare variant, the commercial database contained 641 people carrying the mutation out of the 3.37 million who provided both genetic data and health surveys.

The data allowed scientists to map the mutation’s history. They believe it arose in the British Isles before being carried to America some 200 to 225 years ago. It then multiplied through what geneticists call a "founder event" in Southern Appalachia—particularly in Tennessee and Alabama—where an isolated population grew.

Today, about one in 15,000 people across the United States carry the gene. In Southern Appalachia, that figure rises to one in 2,000.

For families carrying the gene, the diagnosis can be a quiet, multi-generational threat. Caroline Blanchard, a 35-year-old nurse practitioner from New Orleans, lost her non-smoking aunt to lung cancer at age 45. Years later, her grandmother was diagnosed at 80 and tested positive for the EGFR T790M mutation. Subsequent scans revealed that both Blanchard and her mother also carried the mutation and already had nodules on their lungs.

What happens next?

The discovery could reshape how doctors think about lung cancer screening. Currently, health guidelines reserve preventative CT scans for older adults with a heavy history of smoking. Non-smokers, even those with high genetic risks, are excluded.

"Our goal is to determine whether genetics can eventually identify additional people who would benefit from CT screening," LoPiccolo said, noting that this is currently being evaluated in an ongoing clinical study called INHERIT.

Currently, 23andMe does not notify users if they carry the EGFR T790M variant, but the company stated it plans to include the findings in future reports so customers can discuss the results with their doctors.

Experts urge caution, noting that the mutation remains very rare and that smoking remains the primary cause of most lung cancers. However, for non-smokers, who make up about one in five lung cancer deaths in the US, the gene offers a valuable clue.

"It doesn’t seem to increase the risk of any other cancer," said Dr Sarah Goldberg, a thoracic oncologist at Yale Medicine who was not involved in the research. "It really is something specific about this mutation."