Germline <i>EGFR</i> Mutations and Familial Lung Cancer.

Abstract

The genomic underpinnings of inherited lung cancer risk are poorly understood. This prospective study characterized the clinical phenotype of patients and families with germline <i>EGFR</i> pathogenic variants (PVs). The Investigating Hereditary Risk from T790M study (ClinicalTrials.gov identifier: NCT01754025) enrolled patients with lung cancer whose tumor profiling harbored possible germline <i>EGFR</i> PVs and their relatives, either in person or remotely, providing germline testing and follow-up. A total of 141 participants were enrolled over a 5-year period, 100 (71%) remotely. Based upon previous genotyping, 116 participants from 59 kindreds were tested for <i>EGFR</i> T790M, demonstrating a pattern of Mendelian inheritance with variable lung cancer penetrance. In confirmed or obligate carriers of a germline <i>EGFR</i> PV from 39 different kindreds, 50/91 (55%) were affected with lung cancer with 34/65 (52%) diagnosed by age 60 years. Somatic testing of lung cancers in carriers revealed that 35 of 37 (95%) had an <i>EGFR</i> driver comutation. Among 36 germline carriers without a cancer diagnosis, 15 had computed tomography (CT) imaging and nine had lung nodules, including a 28-year-old with >10 lung nodules. Given geographic enrichment of germline <i>EGFR</i> T790M in the southeast United States, genome-wide haplotyping of 46 germline carriers was performed and identified a 4.1-Mb haplotype shared by 41 (89%), estimated to originate 223-279 years ago. To our knowledge, this is the first prospective description of familial <i>EGFR</i>-mutant lung cancer, identifying a recent founder germline <i>EGFR</i> T790M variant enriched in the Southeast United States. The high prevalence of <i>EGFR</i>-driver lung adenocarcinomas and lung nodules in germline carriers supports effort to identify affected patients and family members for investigation of CT-based screening for these high-risk individuals.