Germline EGFR mutations and familial lung cancer

The genomic underpinnings of inherited lung cancer risk are poorly understood. A prospective study (The Investigating Hereditary Risk from T790M study) enrolled patients with lung cancer whose tumor profiling harbored possible germline EGFR pathogenic variants (PVs) and their relatives, providing germline testing and follow-up. Based upon previous genotyping, 116 participants from 59 kindreds were tested for EGFR T790M, demonstrating a pattern of Mendelian inheritance with variable lung cancer penetrance. In confirmed or obligate carriers of a germline EGFR PV form 39 different kindreds, 55% were affected by lung cancer with 52% diagnosed by age 60 years. Somatic testing of lung cancers in carriers revealed that 95% had an EGFR driver comutation. Among germline carriers without a cancer diagnosis, CT imaging resulted in observation of lung nodules in 60%, including a 28-year old with more than 10 nodules. Genome-wide haplotyping identified a large and recent haplotype shared by most germline carriers. The authors conclude that the high prevalence of EGFR-driver lung adenocarcinomas and lung nodules in germline carriers support efforts to identify affected patients and family members for investigation of CT-based screening for these high-risk individuals.