Rare EGFR variant linked to sharply elevated lung cancer risk

A rare inherited variant in the EGFR gene was associated with substantially higher lung cancer risk in a peer-reviewed study published in Science , with the strongest association observed among people who had never smoked. Jaclyn LoPiccolo and colleagues analyzed genetic data from 3.37 million people of European ancestry and estimated that carriers of the germline EGFR T790M mutation had about 25 times the overall risk of lung cancer. Among never-smokers, the estimated risk was approximately 62 times higher for carriers than for noncarriers.

The study evaluated the association between inherited EGFR T790M and lung cancer in a population large enough to provide more reliable estimates for a mutation that is extremely rare. T790M can be inherited and has been linked to increased susceptibility to lung adenocarcinoma, particularly when it occurs together with a second cancer-driving EGFR mutation. The investigators found no significant links between the inherited variant and other cancer types or respiratory conditions.

Their analysis therefore identified a risk association that was especially pronounced for lung cancer in people without a smoking history, rather than a general association with multiple forms of cancer or respiratory disease. Smoking was associated with roughly a fourfold increase in lung cancer risk in the same analysis. That estimate was lower than the association observed for inherited EGFR T790M, but the comparisons addressed different exposure groups: smoking was associated with increased risk across the study population, whereas the T790M association was particularly strong among never-smokers.

The researchers’ estimates show that inherited EGFR T790M was associated with a larger relative risk than smoking in these data. The results do not establish that every carrier will develop lung cancer, nor do they determine the absolute probability of cancer for an individual carrying the variant. Genetic data also revealed a pronounced geographic concentration of T790M carriers in the Southern Appalachian region of the United States, especially in Tennessee and Alabama.

LoPiccolo and colleagues suggested that the mutation arose in Europe and was brought to the Southern Appalachian region by British and Irish settlers during the colonial era, after which it became more common among relatively isolated populations. This proposed history is an interpretation of the allele’s distribution and the populations in which it was concentrated, rather than a directly documented lineage tracing the mutation through particular families. The findings identify inherited EGFR T790M as a distinct genetic factor associated with lung cancer risk among never-smokers.

The analysis was restricted to people of European ancestry, so the estimated risks may not apply equally to populations with other ancestry backgrounds. Together, the results point to an inherited risk factor that is associated with an especially pronounced elevation in lung cancer risk among people who do not smoke.

Subject of Research: Inherited EGFR T790M mutations and lung cancer risk in never-smokers

Article Title: Rare inherited genetic mutation raises lung cancer risk in non-smoker humans

Article References: Rare inherited genetic mutation raises lung cancer risk in non-smoker humans. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: EGFR T790M, lung cancer, never-smokers, inherited mutations, germline variation, cancer genetics, Southern Appalachia, lung adenocarcinoma, Rare, inherited, genetic, mutation