Rare Genetic Mutation Found to Skyrocket Lung Cancer Risk in Nonsmokers

A significant proportion of lung cancer diagnoses occur in individuals who have never smoked, and new research published in the journal Science has identified a specific inherited genetic mutation responsible for dramatically elevating risk in this population. Led by Dr. Jaclyn LoPiccolo, an oncologist and researcher at the Dana-Farber Cancer Institute, the study found that people carrying a mutation in the EGFR gene faced a 25-fold increased risk of lung cancer compared to non-carriers, regardless of their smoking status.

The risk was even more pronounced among nonsmokers. Those with the mutation had a 60-fold higher likelihood of developing the disease compared to nonsmokers without it. LoPiccolo noted that because the baseline risk of lung cancer is low in people who do not smoke, this substantial increase highlights the powerful impact of the genetic variant.

The specific variant, known as T790M, was initially identified in 2005 in a European family where members developed lung cancer despite never smoking. However, its rarity made it difficult to quantify its contribution to cancer risk until now. The researchers utilized a vast dataset from the genetics company 23andMe to overcome these limitations. They estimated that approximately one in 15,000 people in the United States carries the mutation, though prevalence is significantly higher in Southern Appalachia—about one in 2,000—where scientists believe a single ancestor introduced the variant from England or Ireland over two centuries ago.

These findings have sparked discussion about the potential for genetic screening to expand current lung cancer detection protocols. At present, low-dose CT scans are recommended primarily for older adults with a history of heavy smoking. Nadia Litterman, executive director of the Susan Wojcicki Foundation, which funded the study, emphasized the importance of integrating genetic risk factors into screening decisions. Litterman’s foundation is named after the late YouTube CEO, who never smoked but died of lung cancer in 2024.

“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,” Litterman said. She suggested that BRCA genetic testing, widely used for breast cancer risk assessment, could serve as a model for lung cancer screening guidelines.

For patients like Frank McKenna, a personal trainer from Virginia Beach, the implications are deeply personal. Diagnosed with Stage IV lung cancer in 2016 despite never smoking, McKenna learned he carried the EGFR T790M mutation. He began a daily targeted therapy pill that alleviated his symptoms and improved his quality of life.

McKenna’s daughter, now 33, was also diagnosed with melanoma and subsequently tested for the family’s cancer markers. While she did not inherit common cancer mutations, she does carry T790M. Currently, there are no evidence-based guidelines dictating how she should monitor her lung health, a gap that McKenna is eager to see filled.

“I’m pushing for how we can screen younger people, knowing that she has a genetic risk,” McKenna said. “If something were to appear, she can catch it at an early stage, perhaps Stage I, and not go through Stage IV.”

To address such uncertainties, LoPiccolo is conducting a study called INHERIT, which enrolls participants with inherited genetic risks for lung cancer across the country. The study aims to develop personalized screening schedules based on family history, genetic profiles, and environmental exposures. The ultimate goal is to detect cancer at its earliest, most treatable stages.

McKenna, who undergoes scans every six to seven months, remains vigilant. “Cancer will find a way to overcome the therapy,” he said. “What if you could catch the cancer early with screening often enough so it’s much easier to treat?”