Whole-Exome Sequencing Reveals the Genomic Features of the Micropapillary Component in Ground-Glass Opacities

SIMPLE SUMMARY: The micropapillary component in lung adenocarcinoma has a valid predictive role for patient prognosis. To investigate targeted clinical strategies, we collected 31 stage I lung adenocarcinoma samples and performed microdissection to separate micropapillary and non-micropapillary components, followed by whole exome sequencing. We focused on the genomic features, evolutionary advantages, and associated clinical implications of the micropapillary component, and we proposed and validated the possible presence of essential mutations, TP53 and ZNF469, in the formation of the micropapillary component. These features may be associated with the formation of high-grade invasive patterns in this component. ABSTRACT: Background: Micropapillary components are observed in a considerable proportion of ground-glass opacities (GGOs) and contribute to the poor prognosis of patients with invasive lung adenocarcinoma (LUAD). However, the underlying mutational processes related to the presence of micropapillary components remain obscure, limiting the development of clinical interventions. Methods: We collected 31 GGOs, which were separated into paired micropapillary and non-micropapillary components using microdissection. Whole-exome sequencing (WES) was performed on the GGO components, and bioinformatics analysis was conducted to reveal the genomic features of the micropapillary component in invasive LUAD. Results: The micropapillary component had more genomic variations, including tumor mutation burden, intratumoral heterogeneity, and copy number variation. We also observed the enrichment of AID/APOBEC mutation signatures and an increased activation of the RTK/Ras, Notch, and Wnt oncogenic pathways within the micropapillary component. A phylogenetic analysis further suggested that ERBB2/3/4, NCOR1/2, TP53, and ZNF469 contributed to the micropapillary component’s progression during the early invasion of LUAD, a finding that was validated in the TCGA cohort. Conclusions: Our results revealed specific mutational characteristics of the micropapillary component of invasive LUAD in an Asian population. These characteristics were associated with the formation of high-grade invasive patterns. These preliminary findings demonstrated the potential of targeting the micropapillary component in patients with early-stage LUAD.