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

Qinchuan Wang,Linbo Wang,Xu Qi,Wenhe Zhao,Jianguo Shen,Yong Dong,Xiaoming Yuan,Mingjun Dong,Wenjun Chen,Yasheng Huang,Yongxia Chen,Qun Wei,Xiang Shu,Jichun Zhou,Shuduo Xie,Wenjun Zhang,Rongyue Teng

doi:10.18632/oncotarget.15609

Abstract

BackgroundGastric 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.ResultsAmong 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.MethodsTumor 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.ConclusionBoth 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.

Highlights

Gastric cancer was the world’s third leading cause of cancer deaths, which was estimated to be responsible for nearly 723,000 deaths in 2016 [1]
High Gamma-glutamyl transpeptidase (GGT) expressions in tumor are associated with gastric cancer subtypes and lymph node metastasis
IHC staining of GGT was performed on 322 cases of gastric cancer. 82 (25.4%) out of 322 patients were identified as GGT positive (IHC 2+ and 3+)

Summary

Introduction

Gastric cancer was the world’s third leading cause of cancer deaths, which was estimated to be responsible for nearly 723,000 deaths in 2016 [1]. In China, there are estimated 679,000 new cases and 498,000 deaths from gastric cancer in 2015 [2]. The classification of gastric cancer subtypes is mainly based on histology, for instance, Lauren classification and World Health Organization classification [4]. The two biomarkers can be used to guide the use of trastuzumab in gastric cancer treatment. A project was conducted by The Cancer Genome Atlas (TCGA) to develop molecular classifiers of gastric adenocarcinoma, which subdivided the cancer into 4 subtypes based on its genomic alterations [6]. The clinical values of these classifiers await further verifications, and more biomarkers and targets are urgently needed for the detection and treatment of gastric cancer. We aim to explore the clinical value of GGT in gastric cancer

Objectives

Methods

Results

Conclusion