What did a Science study by researchers at Dana Farber Cancer Institute and the 23andMe Research Institute find about the inherited EGFR T790M mutation’s association with lung cancer risk—especially among never smokers—including the study’s sample of more than 3.3 million people

The study found that inherited EGFR T790M is an unusually strong, lung-cancer-specific risk variant: carriers had about 25-fold higher overall odds of lung cancer, and never-smoker carriers had an estimated 62-fold higher risk than never-smokers without it. 67

Key findings

• In the 23andMe dataset, researchers analyzed more than 3.3 million participants of European ancestry and identified 641 carriers. The variant was estimated to be substantially more common than prior public-database estimates—about tenfold higher in the wider consented research cohort. 7

• The excess risk was especially striking among never-smokers: about 62-fold, versus roughly tenfold among smokers in reported subgroup estimates. 6

• The association appeared specific to lung cancer: the study found no significant association with 17 other common cancers. Carriers who developed lung cancer did so about five years earlier, on average, than noncarriers.

• Genetic and geographic analyses indicated a founder effect: the variant likely arrived with British and Irish settlers in the early 1700s, then became enriched through demographic isolation—a Southern Appalachian genetic bottleneck. It is concentrated particularly among people with roots in Alabama, Mississippi, and Tennessee. 6

Clinical implications

• Because current U.S. CT-screening eligibility is largely based on age and smoking exposure, this evidence suggests that confirmed T790M carriers could warrant lung-cancer surveillance regardless of smoking history—and potentially at younger ages. This is a research implication, not yet an evidence-based population screening recommendation.

• The ongoing INHERIT trial (NCT05587439) is studying people and families with inherited susceptibility to thoracic cancers, especially where tobacco exposure is minimal, to improve risk assessment and assess personalized approaches such as CT screening. 4

• Frank McKenna’s case illustrates the gap: as a never-smoker with familial T790M-associated lung cancer, and with a daughter who may face inherited risk, the family lacks established, evidence-based guidance on when and how often an unaffected carrier should receive CT scans. The study strengthens the rationale for trials and individualized specialist care, but it does not itself establish a screening schedule. 46