Enhancer of Zeste Homolog 2 (EZH2) Is a Marker of High-Grade Neuroendocrine Neoplasia in Gastroenteropancreatic and Pulmonary Tract and Predicts Poor Prognosis

Abstract

Tumor grading is a robust prognostic predictor in patients with neuroendocrine neoplasms (NEN) and guides therapy, especially in tumors with high proliferation. NEN can be separated into well-differentiated and poorly differentiated types. The more aggressive NEN have been further separated into neuroendocrine tumors (NET G3) with a better prognosis and neuroendocrine carcinomas (NEC) with a worse prognosis. Despite this distinction’s tremendous clinical and therapeutic relevance, optimal diagnostic biomarkers are still lacking. In this study, we analyzed the protein expression and prognostic impact of Enhancer of Zeste Homolog 2 (EZH2) by immunohistochemistry in 219 tissue samples of gastroenteropancreatic (GEP-NEN) and pulmonary NEN (P-NEN). EZH2 was almost exclusively expressed in NEN with a proliferation rate above 20% (G3), while all low-grade tumors were nearly negative. Among high-grade NEN, 65% showed high and 35% low expression of EZH2. In this group, the high expression of EZH2 was significantly associated with poor overall survival and NEC histology. Interestingly, EZH2 seems to act independently of Polycomb Repressive Complex 2 (PRC2) in NEN. In conclusion, we propose EZH2 as a robust biomarker for distinguishing between NET G3 and NEC among gastroenteropancreatic and pulmonary NEN.

Expression and clinical value of CXCR4 in high grade gastroenteropancreatic neuroendocrine neoplasms

“…Liverani et al found that DLL3 is expressed in poorly differentiated NEC but not in NET G3 and is associated with poor prognosis. They concluded that DLL3 is considered to serve as a NEC diagnostic marker and potential therapeutic target (21). Bremer et al similarly used immunohistochemistry to find that high expression of Enhancer of Zeste Homolog 2 (EZH2) in high-grade NENs was associated with poorer OS and was also significantly correlated with histological manifestations of NEC, proposing that EZH2 could be used as a biomarker to differentiate NET G3 from NEC (22).…”

CRISPR/Cas9‑mediated EZH2 knockout suppresses the proliferation and migration of triple‑negative breast cancer cells

“…Recent research has suggested that enhancer of zeste homolog 2 (EZH2) serves as a key component of polycomb repressive complex 2 (PRC2) (12). EZH2 serves a role in chromosomal structure formation, cell cycle regulation, senescence, cell differentiation and promotion of tumor growth and metastasis in malignant tumor models (13)(14)(15).…”