Genomic characterization of pulmonary sarcomatoid adenocarcinoma: a paired whole-exome sequencing study of carcinomatous and sarcomatous components

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare and highly aggressive subtype of non-small cell lung cancer characterized by the coexistence of carcinomatous (CA) and sarcomatous (SA) components. Their clonal relationship and genomic divergence remain poorly defined, particularly in adenocarcinoma-derived PSC. Methods: We performed comparative whole-exome sequencing (WES) on microdissected CA and SA components from six pulmonary sarcomatoid adenocarcinomas (PSAdC). Histopathology and immunohistochemistry were used to characterize epithelial and mesenchymal phenotypes. Somatic mutations were identified using a standard bioinformatics pipeline, followed by gene set enrichment analysis with g:Profiler. Results: showed component-specific distributions. Enrichment analysis revealed over-representation of pathways related to multicellular organism development, chromatin remodeling, transcription factor binding, and DNA double-strand break repair, as well as non-small cell lung cancer signaling. These alterations correlated with epithelial-mesenchymal transition (EMT) features in SA components, including vimentin upregulation and E-cadherin loss. Conclusions: PSAdC exhibits a monoclonal origin with subsequent genomic diversification between components. Microdissection-based WES reveals pronounced spatial heterogeneity and lineage-specific mutations. Dysregulated chromatin remodeling and DNA repair pathways, together with EMT-associated phenotypes, provide a mechanistic framework for sarcomatoid differentiation and lineage plasticity in this aggressive tumor subtype.