Rare gene mutation raises lung cancer risk 60-fold in nonsmokers, study finds

A rare inherited mutation in the EGFR gene is associated with a 25-fold increased risk of lung cancer — and among people who have never smoked, the risk jumps to more than 60-fold — according to a study published Thursday in the journal Science by researchers at Dana-Farber Cancer Institute and 23andMe Research Institute.time+1

The variant, called EGFR T790M, is now considered one of the strongest inherited risk factors for lung cancer ever identified. The finding could reshape how clinicians think about screening for a disease long associated almost exclusively with tobacco use.

A Mutation Traced to Colonial Settlers

The study drew on genetic and health data from more than 3.3 million 23andMe research participants of European ancestry. Among them, 641 carried the T790M variant — a sample large enough to produce reliable risk estimates for the first time. By comparison, two of the largest public genetic databases, the UK Biobank and All of Us, contained just two and 19 carriers, respectively.livescience+1

About 1 in 15,000 Americans carry the mutation overall, but in parts of the southeastern United States — particularly Alabama, Mississippi, and Tennessee — rates climb to roughly 1 in 2,000. Researchers traced the variant to British and Irish settlers who arrived in the early 1700s. Demographic isolation in Southern Appalachia created a genetic bottleneck that amplified its prevalence over generations.23andme+3

"To my knowledge it's one of the strongest, if not the strongest, cancer risk-increasing mutations that has ever been found," said Alexander Gusev, a quantitative geneticist at Dana-Farber and co-senior author of the study.medicalxpress

Implications for Screening

Current lung cancer screening guidelines rely almost entirely on smoking history and age. The new findings raise the prospect of incorporating genetic risk. The mutation was not linked to any of 17 other common cancers studied, suggesting its effects may be largely specific to lung cancer.livescience+1

People with T790M developed lung cancer about five years earlier on average than those without it, underscoring "the need to begin screening at an earlier age and irrespective of smoking status," said Chris Amos, a genetic epidemiologist at Baylor College of Medicine who was not involved in the study.livescience

A clinical trial called INHERIT, led at Dana-Farber, is now recruiting participants with inherited genetic risk for lung cancer to evaluate personalized CT screening strategies. "The goal is to use CT screening to detect lung cancer at the earliest, most curable stage when it can be removed or cured," said Jaclyn LoPiccolo, an attending physician at Dana-Farber who co-led the study.medicalxpress+1

A Personal Stakes

Frank McKenna, a 66-year-old personal trainer in Virginia Beach who never smoked, was diagnosed with Stage IV lung cancer in 2016 and found to carry the T790M mutation. Targeted therapy transformed his prognosis. His daughter, now 33, was later found to carry the same variant — but no evidence-based screening guidelines exist for her yet.time

"If something were to appear, she can catch it at an early stage," McKenna said, "and not go through Stage IV, because there are not as many options, and the outlook is not as positive".time