Multi‐omics analyses reveal distinct molecular characteristics and transformation mechanisms of stage I–III micropapillary lung adenocarcinoma

Abstract The micropapillary (MIP) pattern is a high‐grade histological subtype of lung adenocarcinoma (LUAD) with poor prognosis. In this study, surgically resected tumor samples from 101 patients with stage I–III MIP–LUAD (MIP ≥30%) were microdissected to separate MIP components from non‐MIP components, all of which underwent RNA and DNA whole‐exome sequencing (WES). The genomic and transcriptomic landscapes of MIP and non‐MIP components within MIP‐enriched tumor tissues demonstrated remarkable similarities, notably marked by high epidermal growth factor receptor (EGFR) alteration frequencies. However, when compared to MIP‐naïve LUAD tissues, MIP components showed higher chromosomal instability and revealed 18 enriched alterations, encompassing EGFR mutations, EGFR amplifications, and CDKN2A/CDKN2B deletions, which all linked to upregulation of cell proliferation pathways and downregulation of immune pathways. Shared mutations were observed in 97.8% (91/93) of patients with paired DNA WES data for MIP and non‐MIP components within the same tissues, suggesting a common origin. The recurrence‐free survival analysis identified MACF1, PCLO, ADGRV1, and Fanconi Anemia pathway mutations as negative indicators. In all, we conducted an in‐depth analysis of the molecular characteristics and transformation mechanisms of MIP–LUAD, employing microdissection techniques to investigate the genomic and transcriptomic levels within a substantial cohort, providing insights for precision medicine of this aggressive cancer subtype. © 2025 The Pathological Society of Great Britain and Ireland.