An inherited genetic mutation may increase lung cancer risk among people who have never smoked, with carriers of the rare EGFR T790M variant facing roughly 25 times the risk of lung cancer overall and 62 times the risk among never-smokers, according to a new study. What's more, the authors traced the occurrence of the mutation to Southern Appalachian populations in the United States, where it likely arrived with British and Irish settlers during the colonial era. Although most lung cancer cases are tobacco-use related, lung cancer in individuals who have never smoked is an increasingly important global health concern – one that will persist even as smoking-related lung cancers continue to decline. Yet the inherited genetic factors that contribute to these cancers remain poorly understood. One important example is the EGFR T790M mutation, which can be inherited and significantly increase the risk of lung adenocarcinoma, particularly when paired with a second, cancer-driving EGFR mutation. However, because this mutation is extremely rare, previous studies have not been able to precisely quantify its prevalence nor the cancer risk it confers.
To obtain more reliable estimates, Jaclyn LoPiccolo and colleagues analyzed genetic data from 3.37 million people of European ancestry to evaluate the association between EGFR T790M and lung cancer. LoPiccolo et al. found that carrying the inherited EGFR T790M mutation was associated with about a 25-fold higher risk of lung cancer, with the association particularly strong among never-smokers, who had roughly a 62-fold higher risk. By contrast, smoking was associated with a roughly 4-fold increase in risk, indicating that T790M was a powerful risk factor for lung cancer, especially in people who have never smoked. Moreover, the authors found that the mutation had no significant links to other types of cancer or respiratory conditions. LoPiccolo et al. also found that EGFR T790M carriers were disproportionately concentrated in the United States' Southern Appalachian regions, especially in Tennessee and Alabama. This suggests the mutation arose in Europe and was brought to the Southern Appalachian region by British and Irish settlers during the colonial era, where it became more common among the region's relatively isolated populations. In a related Perspective, Stephen Chanock discusses the study and its findings in greater detail.
