Genomic Landscape and Subgroup Stratification of Thymic Epithelial Tumors: A Systematic Meta-Analysis of Next-Generation Sequencing Data

Eleonora PardiniSerena BarachiniMarina MontaliIrene Sofia BurziGisella Sardo InfirriDaniele TagliafierroIacopo Petrini^*

• University of Pisa, Pisa, Italy

Thymic epithelial tumors are rare cancers of the anterior mediastinum with heterogeneous clinical behaviors. Despite numerous attempts to characterize their mutational landscape, a comprehensive understanding of their genetic alterations remains limited due to small sample sizes. To address this gap, we conducted a systematic meta-analysis of somatic mutations reported in 729 patients across twenty studies, integrating single-variant data into a unified dataset. This approach identified three molecular subgroups with distinct biological and clinical features. Tumors harboring GTF2I mutations were typically indolent, exhibited low mutational burden, and showed enrichment in pathways related to cell adhesion. Tumors with TP53 mutations displayed high mutational load, activation of receptor tyrosine kinase and mitogenic signaling, and corresponded to aggressive clinical behavior. Tumors lacking both GTF2I and TP53 mutations revealed intermediate profiles, characterized by alterations in epigenetic regulation and extracellular matrix organization. Mutational signature analysis indicated that age-related processes predominate in less aggressive tumors, while DNA repair deficiency characterizes those with TP53 mutations. Network and pathway analyses revealed convergent oncogenic hubs and distinct signaling dependencies across subgroups. This large-scale integrative study provides a refined map of the genetic landscape of thymic epithelial tumors, highlights biologically meaningful heterogeneity, and establishes a framework to guide future research and the development of targeted therapies.