title: Tumor and serum gamma-glutamyl transpeptidase, new prognostic and molecular interpretation of an old biomarker in gastric cancer.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qinchuan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Shu
authors.affiliation: Department of Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Jichun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Rongyue
authors.initials: R
authors.lastname: Teng
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Dong
authors.affiliation: Zhejiang Academy of Medical Science, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Unrology, Hangzhou Chinese Medicine Hospital, Hangzhou, China.
authors.forename: Yasheng
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Shuduo
authors.initials: S
authors.lastname: Xie
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Wenhe
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Linbo
authors.initials: L
authors.lastname: Wang
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D063646:Carcinogenesis; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D016019:Survival Analysis; D005723:gamma-Glutamyltransferase / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D005978:Glutathione; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D005723:gamma-Glutamyltransferase; C117307:KRAS protein, human; C508053:ERBB2 protein, human
keywords: chemotherapy; gamma-glutamyl transpeptidase; gastric cancer; prognosis; serum