Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients

Abstract

Neuregulin 1 (NRG1), a ligand for human epidermal growth factor (HER) 3 and HER4, can activates cell signaling pathways to promote carcinogenesis and metastasis. To investigate the clinicopathologic significance of NRG1 and its receptors, immunohistochemistry was performed for NRG1, HER3, and HER4 in 502 consecutive gastric cancers (GCs). Furthermore, HER2, microsatellite instability (MSI), and Epstein-Barr virus (EBV) status were investigated. NRG1 gene copy number (GCN) was determined by dual color fluorescence in situ hybridization (FISH) in 388 available GCs. NRG1 overexpression was observed in 141 (28.1%) GCs and significantly associated with aggressive features, including infiltrative tumor growth, lymphovascular, and neural invasion, high pathologic stage, and poor prognosis (all P < 0.05), but not associated with EBV, MSI, or HER2 status. HER3 cytoplasmic and membranous expression were observed in 157 (31.3%) and 13 (2.6%), respectively. HER4 cytoplasmic expression was observed in 277 (55.2%), including 115 (22.9%) cases with nuclear expression. In contrast to NRG1, cytoplasmic expression of HER3 and HER4 proteins were not associated with survival, but GC patients with HER3 membranous expression showed significantly worse survival. In addition, HER4 nuclear expression was inveresely correlated with patients outcome in GC. NRG1 overexpression was also closely correlated with HER3 (P = 0.034) and HER4 (P < 0.001) cytoplasmic expression. NRG1 GCN gain (GCN ≥ 2.5) was detected in 14.7% patients, including two cases of amplification, and was moderately correlated with NRG1 overexpression (κ, 0.459

P < 0.001). Multivariate analysis identified NRG1 overexpression as an independent prognostic factor for survival (P = 0.040), unlike HER3 and HER4 expression. In 14 HER2 positive GC with trastzumab combined chemotherapy, coexpression of NRG1 and HER3 was detected in 2 (14.3%) cases, and these GC patients group with coexpression of NRG1 and HER3 also showed a shorter PFS (P = 0.005). Although our results indicate a lack of prognostic significance of HER3 and HER4 overexpression in GC, overexpression of their ligand, NRG1, was associated with aggressive clinical features and represented an independent unfavorable prognostic factor. Therefore, NRG1 is a potential prognostic and therapeutic biomarker in GC patients.