Brief report: Genomic evolution in a lung adenocarcinoma patient with a germline EGFR T790M mutation

Abstract Introduction A subset of lung adenocarcinomas have somatic activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor gene (EGFR), associated with response to EGFR tyrosine kinase inhibitor therapy. Rare germline mutations within this domain, including EGFR T790M, have been associated with genetic susceptibility to lung adenocarcinomas. Using high-throughput sequencing, we elucidate genomic evolution in tissues from a lung adenocarcinoma patient carrying a germline EGFR T790M mutation. Methods We performed microdissection, targeted panel and whole-exome sequencing (WES) to molecularly characterize multiple foci of atypical adenomatous hyperplasia (AAH), in situ and invasive components of adenocarcinoma, normal lung tissue, and whole blood from the patient. Normal lung tissue was analyzed for potential acquired somatic genome alterations ("field effect"). Results All lesions harbored a secondary somatic EGFR mutation, either L858R or L861Q, in addition to the germline T790M mutation. Clear overlap was observed between the somatic profiles of in situ and invasive adenocarcinoma components, confirming clonal relatedness. AAH lesions shared few to no somatic alterations with the adenocarcinoma, suggesting clonal independence. No robust evidence of field effect was identified in the normal lung tissue. Conclusions Somatic EGFR mutations are early events in the pathogenesis of lung adenocarcinomas arising in the context of germline EGFR T790M. Synchronous AAH lesions appear to be independent. Stepwise genomic evolution is observed in association with invasiveness of the neoplastic cell population.