Targeted next-generation sequencing for analyzing the genetic alterations in atypical adenomatous hyperplasia and adenocarcinoma in situ.

PURPOSE: Atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) have been defined as preinvasive pulmonary adenocarcinoma lesions according to the 2015 World Health Organization lung adenocarcinoma classification. We aimed to search for the most common gene mutations in patients with AAH and AIS and investigate the distinctions between the two groups at the molecular level.

METHODS: We performed targeted next-generation sequencing on 18 cases with AAH and 28 cases with AIS to screen for mutations with the Ion Torrent Oncomine Solid Tumor DNA panel. ALK and ROS1 fusions were detected by real-time PCR.

RESULTS: Forty-six mutations were identified in 29 cases (76.1%), including 9 (50%) of 18 cases with AAH and 20 (71.4%) of 28 cases with AIS, in the following genes: EGFR, BRAF, KRAS, ERBB2, TP53, and FGFR3. The mutations in EGFR, BRAF, KRAS, ERBB2, and TP53 genes were more common in AIS lesions than in AAH lesions, whereas the FGFR3 gene was more frequently mutated in AAH compared to AIS. ALK and ROS1 fusions were not detected in any of the lesions.

CONCLUSIONS: Based on the molecular evidence, the proposal that AAH and AIS are preinvasive lesions of pulmonary adenocarcinomas is of great significance, and it is necessary to distinguish AAH from AIS. Our study provided insights into the genetic alterations in the early stage of lung adenocarcinoma, which could be beneficial for the pathologic diagnosis and early detection of these lesions.