Transl Lung Cancer Res | YAP1 Expression Defines Molecular Subtypes of Pulmonary Large Cell Neuroendocrine Carcinoma

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 molecular biomarkers for immunotherapy and targeted therapy.

 

Literature Overview
This article 'YAP1 Expression Defines Molecular Subtypes of Pulmonary Large Cell Neuroendocrine Carcinoma with Divergent 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
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive pulmonary neuroendocrine tumor accounting for 3% of primary lung malignancies. Its complex molecular features lack unified treatment guidelines. LCNEC contains two molecular subtypes: Type I (NSCLC-like) and Type II (SCLC-like), with distinct mutational profiles. YAP1, a core transcriptional regulator in the Hippo signaling pathway, has been established as a subtype classification marker in small cell lung cancer (SCLC), but its role in LCNEC remains unclear. While preliminary evidence suggests YAP1 may correlate with immunotherapy responses, its clinical relevance 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 strategies.

 

 

Research Methods and Experiments
The study included 42 surgically resected LCNEC samples, with 39 undergoing whole-exome sequencing (WES) and immunohistochemistry (IHC) analysis. IHC evaluated ASCL1, NEUROD1, POU2F3, YAP1, DLL3, and MHC I/II expression using H-score quantification. Additionally, PD-L1 expression, CD8+ T-cell infiltration density, and tumor mutation burden (TMB) were assessed. Correlations between molecular subtypes, YAP1 status, clinical parameters (TNM staging, STAS, vascular invasion), and survival outcomes were analyzed.

Key Conclusions and Perspectives

• Among 42 LCNEC samples, 71.4% (30/42) demonstrated YAP1 positivity, forming YAP1-positive (n=30) and YAP1-negative (n=12) cohorts.
• YAP1 expression showed no significant association with molecular subtypes (P=0.15), but YAP1-negative tumors exhibited higher ASCL1 (P=0.003) and DLL3 (P=0.003) expression, while YAP1-positive tumors showed elevated MHC II (P=0.04).
• Negative correlation between ASCL1 and YAP1 (rho=−0.326, P=0.04), positive correlation between NEUROD1 and YAP1 (rho=0.349, P=0.02).
• Type II LCNEC demonstrated higher TMB (P=0.002) and POU2F3 expression (P=0.04).
• No significant survival differences were observed between molecular subtypes or YAP1 status (P>0.05).

Research Significance and Prospects
This is the first systematic analysis of YAP1 expression in LCNEC and its relationships with molecular subtypes, immune markers, and therapeutic responses. The findings suggest YAP1 expression operates independently of molecular subtypes but correlates with distinct therapeutic biomarkers, indicating potential for guiding personalized treatment strategies. Future prospective studies are needed to validate YAP1's molecular mechanisms and therapeutic applications in immunotherapy and targeted treatment approaches.

 

 

Conclusion
This retrospective analysis of 42 LCNEC patients characterized YAP1 expression patterns and their associations with therapeutic biomarkers. YAP1 positivity correlated with NEUROD1 expression, while YAP1 negativity associated with elevated ASCL1 and DLL3 levels, suggesting YAP1 as a potential stratification biomarker. Despite lacking significant associations with molecular subtypes (Type I/II), YAP1 expression patterns may better guide targeted therapies including immunotherapy and DLL3-targeted treatments. These findings provide preliminary evidence for YAP1-based precision medicine strategies, though larger prospective studies are required for validation. This research offers new perspectives for molecular classification and therapeutic selection in pulmonary neuroendocrine tumors, advancing personalized medicine applications in LCNEC.

 

Yanli Zhu, Haiyue Wang, Jingjing Wang, Minglei Zhuo, and Dongmei Lin. Expression of YAP1 delineates distinct subtypes of pulmonary large cell neuroendocrine carcinoma with divergent therapeutic implications. Translational Lung Cancer Research.