Jaclyn LoPiccolo, Steven Micheletti, Jing Shi, Wei Wang, Shubham Saini, Keng-Han Lin, Wanwan Xu, Pierre Fontanillas, 23andMe Research Team3‡, Diane R Koeller, Helen Yatzus, Victoria G Williamson, Jose A Avila, Raphael B Liautaud, Noah D Fields, Allison Harper, Virginia Kotait, Ericka Izzo, Andrew Ciupek, Courtney A Granville, Ryan L Collins, Judy E Garber, David C Christiani, Stella Aslibekyan, Julie M Granka, Alexander Gusev, Pasi A Jänne, A Auton, R K Bell, K K Bond, Z Cochinwala, S Das, K de Brito, E DelloRusso, C Eijsbouts, S L Elson, C German, J M Granka, B Hicks, D A Hinds, R Jabal, A Khan, M J Kmiecik, A Kwong, Y Liang, K-H Lin, M H McIntyre, S Saini, A J Shastri, J Shi, S Shringarpure, Q J Su, V Tran, J Y Tung, C H Weldon, W Xu
Most lung cancers are tobacco related, with genetic factors influencing smoking behavior identified through genome-wide association studies. However, inherited risk in familial and non-smoking-related lung cancers, including risk in carriers of EGFR T790M, remains poorly understood. Here, in more than 3.3 million individuals, the EGFR T790M germline variant is significantly associated with lung cancer risk, with no increased risk for 17 other cancers and no interaction with polygenic risk. This risk exceeds that conferred by smoking and is several-fold higher in never-smokers. Global geographic and ancestry analyses show higher T790M prevalence in the US than in British- and Irish-descendant populations, reflecting a Southern Appalachian founder event about 200 to 225 years ago, increasing regional prevalence and affecting those of British, Irish, and African descent. Recognition of high-risk carriers may inform targeted genetic testing and screening strategies.