Genetic mutation linked to 25x lung cancer risk

Clinical takeaway: Consider genetic counseling referral for patients with a family history of lung cancer, multifocal lung cancers, multiple lung nodules, or Southeastern US ancestry, regardless of smoking history. 

Every clinician runs the same quick math when lung cancer crosses the mind: how much did this patient smoke, and for how long? Pack-years open the door to a low-dose CT. They set the eligibility criteria, frame the shared decision-making conversation, and shape the reflex judgment of which patient's cough warrants imaging. That framework has no place for the patient who never smoked, although lung cancer among never-smokers is a growing share of diagnoses. 

Familial clustering of lung cancer has been recognized for decades, and a rare germline EGFR variant known as T790M has been identified repeatedly in families with unusually high rates of the disease since 2005. Because the variant is exceptionally rare, however, previous studies have largely been limited to case reports and family series, leaving its effect on lung cancer risk uncertain. A new analysis leveraging one of the largest genotyped populations assembled to date provides a quantitative estimate of that risk.

Among more than 3.3 million genotyped research participants, carriers of germline EGFR T790M had 25 times the odds of lung cancer as noncarriers. The variant was identified in roughly 1 in 15,850 individuals. Never-smoking carriers had more than 60-fold higher odds of lung cancer than never-smokers without the variant, whereas carriers who smoked had about 10-fold higher odds than smokers without the variant. Because smoking already substantially increases lung cancer risk, the mutation's relative effect appears larger in never-smokers.

The association was specific to lung cancer risk. Across 17 other common cancers, carriers showed no increased risk, and the effect held regardless of polygenic background, meaning a carrier's risk does not depend on otherwise inheriting a favorable or unfavorable genetic profile. 

In the US the variant appears in 1 in 8,920 people, but it is not spread evenly across the population. In the Southern Appalachian region the figure reaches 1 in 2,078, a concentration that the authors trace to a founder event among British and Irish settlers roughly 200 to 225 years ago. The lineage did not stay confined to those descendants. After the Civil War the variant spread into populations with African and Indigenous American ancestry, so regional roots, not race, define who may carry it. 

The case-control analysis drew on de-identified data from 23andMe research-consented participants, narrowing from more than 10 million to the 3.37 million with both genetic and lung cancer data available. Supporting evidence came from the INHERIT Study, an ongoing Dana-Farber-led cohort recruiting families with inherited lung cancer risk. The work was a collaboration between Dana-Farber Cancer Institute and the 23andMe Research Institute. 

Screening driven by inherited risk rather than smoking history alone is the possibility the authors raise, with confirmation necessary. The open questions are why some carriers develop lung cancer while others never do, as well as how environmental exposures and additional genetic changes shift that risk. Enrollment continues on two fronts: the INHERIT Study is recruiting individuals with inherited lung cancer risk, and the Susan Wojcicki Foundation's Lung Cancer Genetics Study, powered by 23andMe, is open to anyone diagnosed with lung cancer. 

"Today, lung cancer screening is driven almost entirely by smoking history," said Jaclyn LoPiccolo, MD, PhD, attending physician and lung cancer researcher at Dana-Farber Cancer Institute. "Our findings raise the possibility that, in the future, screening could also be dictated by inherited genetic risk. If further studies confirm the benefit, people with EGFR T790M could be identified through genetic testing and offered personalized CT screening to identify lung cancers when they are at their most curable stage." 

Source: LoPiccolo J, et al. (2026 Sep 17) Science. Germline EGFR T790M mutation and lung cancer risk