This study reveals that YAP1 expression in pulmonary large cell neuroendocrine carcinoma (LCNEC) is independent of molecular subtypes and significantly correlates with ASCL1, DLL3, and MHC II expression, providing potential biomarkers for immunotherapy and targeted therapy.
Literature Overview
This article "YAP1 expression defines molecular subtypes of pulmonary large cell neuroendocrine carcinoma with distinct therapeutic implications" published in Transl Lung Cancer Res reviews molecular subtypes (Type I and Type II) of LCNEC and the clinical significance of YAP1 expression. It focuses on analyzing biological characteristics, treatment-related biomarkers, and survival data across subtypes to inform precision therapy strategies.
Background Knowledge
LCNEC is a rare and aggressive pulmonary neuroendocrine tumor accounting for 3% of primary lung malignancies. With complex molecular features and lacking unified treatment guidelines, LCNEC is categorized into two molecular subtypes: Type I (NSCLC-like) and Type II (SCLC-like), each with distinct mutation profiles. While YAP1 serves as a core transcriptional regulator in the Hippo signaling pathway and has been used for subtype classification in small cell lung cancer (SCLC), its role in LCNEC remains unclear. Although existing studies suggest YAP1 may correlate with immunotherapy response, its clinical significance in LCNEC requires further validation. This study employs retrospective analysis of surgically resected LCNEC samples combined with NGS and IHC techniques to evaluate associations between molecular subtypes and YAP1 expression, offering novel insights for precision medicine.
Research Methods and Experiments
The study included 42 resected LCNEC samples, with 39 undergoing whole-exome sequencing (WES) and IHC analysis. Biomarker expression (ASCL1, NEUROD1, POU2F3, YAP1, DLL3, MHC I/II) was assessed by IHC using H-score quantitative evaluation. Immune-related indicators including PD-L1 expression, CD8+ T-cell infiltration density, and TMB were also analyzed. The study further investigated associations between molecular subtypes/YAP1 status and clinical characteristics (TNM staging, STAS, vascular invasion) as well as survival curves.
Key Conclusions and Perspectives
Research Significance and Prospects
This study systematically analyzes YAP1 expression in LCNEC and its relationships with molecular subtypes, immune markers, and treatment response. Results indicate YAP1 expression operates independently of molecular subtypes yet correlates with distinct therapeutic biomarkers, suggesting potential for guiding personalized treatment. Future prospective studies should validate YAP1's molecular mechanisms in LCNEC and its application value in immunotherapy and targeted therapy.
Conclusion
Through retrospective analysis of 42 LCNEC patients, this study characterized YAP1 expression patterns and their associations with therapeutic biomarkers. YAP1 positivity correlated with NEUROD1 expression, while YAP1 negativity associated with upregulated ASCL1 and DLL3, highlighting YAP1 as a potential therapeutic stratification marker. Although molecular subtypes (Type I/II) showed no significant correlation with YAP1 status, its expression pattern may better inform targeted therapies such as immunotherapy or DLL3-targeted treatments. These findings provide preliminary evidence for future YAP1-based precision therapy strategies, though larger prospective studies are required for validation. This research offers novel perspectives for molecular classification and treatment selection in pulmonary neuroendocrine tumors, advancing personalized medicine applications in LCNEC.
