AbstractBackgroundDue to the low incidence and histological heterogeneity, the molecular features and underlying carcinogenic mechanisms of thymic epithelial tumors (TETs) are yet to be fully elucidated, especially for different subtypes of TETs.MethodsTumor tissue samples of 43 TETs with distinct histological subtypes were collected. We analyzed the molecular characteristics in different subtypes based on whole exome sequencing data.ResultsThe mutational profiles of the different subtypes of TETs varied. Compared with thymomas, thymic carcinomas (TCs) had a higher mutation frequency ofMYO16(33% vs. 3%,p= 0.024) and a lower frequency ofZNF729mutations (0% vs. 35%,p= 0.044). No significant difference was observed in the median tumor mutation burden across different subtypes. The value of copy number variation burden, weighted genome instability index, and the number of amplified segments were all higher in TCs than thymomas, and they also tended to be higher in B3 thymoma than in non‐B3 thymomas, while they had no significant differences between B3 thymoma and TCs. Clustering analyses revealed that Wnt, MAPK, Hedgehog, AMPK, and cell junction assembly signaling pathways were exclusively enriched in non‐B3 thymomas, lysine degradation pathway in B3 thymoma, and extracellular matrix‐receptor (ECM‐receptor) interaction, positive regulation of cell cycle process, and activation of innate immune response pathways in TCs.ConclusionsThis study revealed distinct molecular landscapes of different subtypes of TETs, suggesting diverse pathogenesis of non‐B3 thymomas, B3 thymomas, and TCs. Our findings warrant further validation in future large‐scale studies and may provide a theoretical basis for potential personalized therapeutic strategies.