Tumor and serum gamma-glutamyl transpeptidase, new prognostic and molecular interpretation of an old biomarker in gastric cancer

// Qinchuan Wang 1 , Xiang Shu 4 , Yong Dong 2 , Jichun Zhou 1 , Rongyue Teng 1 , Jianguo Shen 1 , Yongxia Chen 1 , Mingjun Dong 1 , Wenjun Zhang 3 , Yasheng Huang 5 , Shuduo Xie 1 , Qun Wei 1 , Wenhe Zhao 1 , Wenjun Chen 1 , Xiaoming Yuan 1 , Xu Qi 1 and Linbo Wang 1 1 Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China 2 Department of Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China 3 Zhejiang Academy of Medical Science, Zhejiang University School of Medicine, Hangzhou, China 4 Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA 5 Department of Unrology, Hangzhou Chinese Medicine Hospital, Hangzhou, China Correspondence to: Linbo Wang, email: wanglinbo@medmail.com.cn Keywords: gamma-glutamyl transpeptidase, gastric cancer, prognosis, serum, chemotherapy Received: November 01, 2016     Accepted: January 24, 2017     Published: February 22, 2017 ABSTRACT Background: Gastric Cancer is one of the most lethal malignancies worldwide. Gamma-glutamyl transpeptidase (GGT) is an enzyme mainly involved in cellular glutathione homeostasis. We aim to explore the clinical value of GGT in gastric cancer. Results: Among 322 patients enrolled, 65/82 patients were determined as GGT positive in serum/tumor, respectively. High tumor GGT expression is significantly associated with lymph node metastasis, histological subtype, and Her2 expression. Kaplan-Meier curve shows that high tumor GGT patients have shorter overall survival ( P log-rank =0.001) and progress-free survival ( P log-rank =0.001). Patients with both high tumor and serum GGT have the poorest prognosis. The multivariable Cox analysis shows that the hazard ratio of overall survival for high tumor GGT is 1.69 (95% CI 1.19-2.37). High serum GGT is a poor prognostic factor in adjuvant chemotherapy hazard ratio=2.18, 95%CI (1.15-4.47). These findings were further validated in six online datasets. Gene Sets Enrichment Analysis showed that GGT promotes cancer progression through EMT, KRAS, SRC and PKCA pathways. Methods: Tumor GGT and serum GGT levels were evaluated with immuno-histochemistry staining and enzymatic assay, respectively. Kaplan-Meier curve and Cox regression model were used to test the association between GGT and gastric cancer prognosis. Independent datasets from Gene Expression Omnibus and Gene Sets Enrichment Analysis were applied to validate the findings and explore the potential mechanisms. Conclusion: Both tumor GGT and serum GGT are poor prognostic factors in gastric cancer. Patients with high tumor and serum GGT levels require more intense treatment and follow-up.