Differential expression of HER2 and downstream proteins in prediction of advanced tumor phenotypes and overall survival of patients with Epstein-Barr virus-positive vs. negative gastric cancers |
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| Affiliation: | 1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8;2. Department of Anatomic Pathology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada M4N 3M5;3. Department of Pathology, Toronto East General Hospital, Toronto, ON, Canada M4C 3E7;4. Department of Laboratory Medicine, St Michael''s Hospital, Toronto, ON, Canada M5B 1W8;1. Department of Pathology, University of Chicago, IL, USA 60637;2. Department of Pathology, Catholic Kwandong University College of Medicine, International St. Mary''s Hospital, Incheon, Republic of Korea 22711;3. Konkuk University School of Medicine, Seoul, South Korea 501-600;4. Department of Pathology, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Busan, Republic of Korea 602-739;5. Department of Pathology, H Lee Moffitt Cancer Center and Research Institute, Departments of Oncological Sciences, Pathology and Cell Biology, University of South Florida, Tampa, Florida, USA 33612 |
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| Abstract: | This study evaluated the associations of HER2 protein, HER2 gene amplification, and positivity for p-AKT, p-ERK, and p-PLCγ proteins with clinicopathological status and overall survival (OS) of patients who had Epstein-Barr virus-associated gastric cancer (EBVaGC; n = 58) or EBV-negative GC (EBVnGC; n = 329). Tissue samples were subjected to immunohistochemistry and fluorescence in situ hybridization (FISH). Results showed that EBVaGC less expressed HER2 and amplified HER2 gene. p-AKT (p = 0.035) and p-ERK (p = 0.001) were inhibited in EBVaGC than in EBVnGC, while p-PLCγ (p = 0.034) was upregulated. Among EBVaGC patients, p-ERK positivity was associated with Lauren classification (p = 0.023), and p-PLCγ positivity was inversely associated with TNM stage (p = 0.041) and lymph node metastasis (p = 0.041). In contrast, among EBVnGC patients, HER2 expression was associated with distant metastasis (p = 0.043) and p-AKT positivity was associated with intestinal subtype (p < 0.004), lymph node metastasis (p = 0.031), distant metastasis (p < 0.001), and elder age (>60y, p < 0.004). Overall analysis showed that EBVaGC patients presented better OS than EBVnGC patients (p = 0.044). Among EBVaGC patients, p-AKT positivity (p = 0.008) was associated with worse OS; as well as, HER2 high expression (p < 0.001), p-AKT positivity (p = 0.010), and p-PLCγ (p < 0.001) were associated with worse OS in EBVnGC patients. Multivariate analysis showed that distant metastasis (95% CI: 1.559 to 4.028, p < 0.001), HER2 high expression (95% CI: 1.058 to 2.454, p = 0.026), and p-PLCγ positivity (95% CI: 1.056 to 2.435, p = 0.027) were independent prognostic predictors of OS in EBVnGC patients. Our results indicated that p-AKT positive patients presented worse OS than p-AKT negative ones in EBVaGC, as well as, HER2, p-AKT, and p-PLCγ are prognostic biomarkers for OS in EBVnGC patients. |
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| Keywords: | Gastric cancer HER2 Epstein-Barr virus Biomarker Prognosis |
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