Integrated Molecular and Clinical Analysis of Thymic Epithelial Tumors

Thymic epithelial tumors (TETs), which include thymomas and thymic carcinomas (TCs), are the most common neoplasms of the anterior mediastinum. To develop more effective therapeutics, it is necessary to better understand their molecular characteristics.

TET samples were profiled using next-generation sequencing (NGS) of DNA (592-gene panel or whole-exome sequencing) and RNA (whole-transcriptome sequencing). Pathogenic single nucleotide variations/indels, deficient mismatch repair/microsatellite instability (dMMR/MSI) status (via immunohistochemistry and NGS), PD-L1 expression, and tumor mutational burden (TMB ≥10 mutations/Mb) were assessed. Expression of genes encoding cell surface proteins was quantified, and pathway enrichment was evaluated using Gene Set Enrichment Analysis (GSEA). Immune cell fractions were estimated using the quanTIseq method.

Among 138 TETs, 48 (34.8%) were TCs and 90 (65.2%) thymomas. TP53 was the most frequently mutated gene, followed by KIT and CDKN2A. Alterations in cell cycle (13.8%), DNA repair (8.0%), and chromatin remodeling (19.6%) genes were more common in TCs. Deletions in CDKN2A, CDKN2B, and MTAP were significantly enriched in TCs. dMMR/MSI-H was observed in five cases, primarily TCs, and correlated with TMB-H in 80% of these. GSEA showed enrichment of MYC, angiogenesis, epithelial-mesenchymal transition, and mTORC1 pathways in TCs. ERBB2, ERBB3, TACSTD2, NECTIN4, and MSLN were overexpressed in TCs, while EGFR was more highly expressed in thymomas. TETs exhibited high PD-L1 expression, low TMB, and subtype-specific immune profiles. TP53 mutations were significantly associated with worse survival.

Integrated profiling of TETs reveals distinct genomic, transcriptomic, and immune features across subtypes of TETs and identifies potentially actionable therapeutic targets that may inform future treatment strategies.