Subtype-Dependent Hippo Pathway Deregulation in Thymic Epithelial Tumors (TETs): A RT-qPCR-Based Expression Analysis

Background/Objectives: Thymic epithelial tumors (TETs) are rare, histologically heterogeneous neoplasms lacking robust molecular biomarkers. Hippo pathway dysregulation—driving YAP1/TEAD-dependent transcription—has been implicated across cancers, but transcript-level data in TETs are limited. Methods: We retrospectively profiled 26 formalin-fixed, paraffin-embedded (FFPE) specimens by SYBR real-time quantitative polymerase chain reaction (RT-qPCR) among different World Health Organization (WHO) subtypes with the focus on the hippo kinase core targets YAP1, TEAD4, MST1/STK4, SAV1, LATS1, and MOB1A. Expression was normalized to the geometric mean of HPRT1and TBP and summarized as 2^-ΔΔCq [log₂ fold changes (FC)] relative to pooled normal. Group differences were tested non-parametrically. Results: YAP1 and TEAD4 were upregulated across tumors, most prominently in type A (YAP1 ≈+3.43) and B3 (YAP1 ≈+2.78) thymomas, with TEAD4 strongly increased in thymic carcinoma (TC) (≈+3.49) and elevated in type A/B3. Upstream kinases were reduced, particularly in TC (MST1 ≈−1.38; LATS1 ≈−1.34), and modestly in B1. SAV1 was elevated in type A (≈+2.25) and B3 (≈+2.01), while MOB1A remained near baseline with slight subtype shifts. Differential expression among WHO subtypes was significant for YAP1 (p = 0.003), TEAD4 (p = 0.015), SAV1 (p = 0.004), MST1 (p = 0.012), and LATS1 (p = 0.036, all Kruskal–Wallis), but not for MOB1A (p = 0.09). Conclusions: TETs exhibit subtype-dependent Hippo pathway alterations, characterized by enhanced YAP1–TEAD4 transcriptional output and progressive reduction of the MST1/LATS1 kinase module, most pronounced in TC. These transcript-level patterns support the potential of Hippo-based biomarkers and may guide future therapeutic strategies.