WASHINGTON / RankWire.AI / – A rare inherited genetic change has been shown to elevate a person’s overall likelihood of developing lung cancer by approximately 25 times and by about 60 times among those who have never smoked, according to findings published in the journal Science. The research, carried out collaboratively by experts at the Dana-Farber Cancer Institute and the 23andMe Research Institute, analyzed anonymized genomic data from over 3.3 million individuals. The investigators identified the germline variant, known as EGFR T790M, as one of the most significant inherited risk factors for lung cancer discovered to date.
This mutation is located in the epidermal growth factor receptor gene, which plays a crucial role in controlling cell growth and division within lung tissue. While somatic mutations in EGFR acquired during a person’s life are well-known to drive non-small cell lung cancer, the T790M germline variant is inherited from birth and present in every cell of the body. Data from the National Cancer Institute indicates that this mutation affects roughly 1 out of every 15,850 individuals in the United States. Lead author Dr. Jaclyn LoPiccolo emphasized that carriers face approximately a 62-fold increase in lung cancer risk among never-smokers, compared to about 11 times for those with a history of smoking.
Genetic tracing revealed that the EGFR T790M variant is disproportionately found among populations in the Southern Appalachian region, spanning Tennessee and Alabama. Evolutionary geneticists traced its origin to British and Irish settlers who migrated to North America during colonial times, with the mutation becoming more common following a population bottleneck approximately 200 years ago. Senior author Dr. Pasi A. Jänne highlighted that, although lung cancer screening mainly focuses on tobacco use, recognizing strong genetic risk factors could enable targeted low-dose computed tomography screening for non-smoking carriers.
Dana-Farber Cancer Institute Research Analyzes Genomes of Over 3.3 Million Individuals
Supported by the National Institutes of Health, both preclinical and clinical studies confirmed that the mutation has a robust specific association with lung cancer, showing no significant links to 17 other common cancers examined in the dataset. Oncologists pointed out that although tobacco use remains the primary cause of lung cancer overall, the incidence among non-smokers is an increasingly important global health concern. Pharmaceutical companies, such as AstraZeneca, continue to develop targeted tyrosine kinase inhibitors like Tagrisso to treat EGFR-mutated lung cancers once tumors progress.
Co-senior author Dr. Alexander Gusev observed that this research illustrates how a single inherited point mutation can have an exceptionally strong effect on disease susceptibility. Medical professionals advise individuals with multiple family members affected by lung cancer, unexplained multifocal lung nodules, or ancestral roots in Southern Appalachia to seek genetic counseling. The researchers stress that possessing the mutation does not guarantee lung cancer development, as environmental factors and secondary genetic changes also play roles in whether malignant transformation occurs during a lifetime.
EGFR Gene’s Role in Cellular Growth and Division
The research team plans to expand observational efforts through the ongoing INHERIT Study, aiming to investigate additional inherited EGFR variants across diverse racial populations. The longitudinal study will focus on identifying environmental triggers and secondary genetic modifications that influence why some carriers develop tumors while others remain healthy. The detailed population genetics, risk assessments, and screening strategies will continue to be available through peer-reviewed medical repositories and institutional data portals. Future findings will be presented at international oncology conferences to guide updates in screening protocols.