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. 2020 Jan;146(1):75-86.
doi: 10.1007/s00432-019-03087-8. Epub 2019 Nov 21.

High gamma-glutamyl hydrolase and low folylpolyglutamate synthetase expression as prognostic biomarkers in patients with locally advanced gastric cancer who were administrated postoperative adjuvant chemotherapy with S-1

Yukio Maezawa  1   2 , Kentaro Sakamaki  3 , Naohide Oue  4 , Yayoi Kimura  5 , Itaru Hashimoto  1   2 , Kentaro Hara  1   2 , Kazuki Kano  1 , Toru Aoyama  2 , Yukihiko Hiroshima  1 , Takanobu Yamada  1 , Naoto Yamamoto  1 , Takashi Ogata  1 , Hiroyuki Ito  6 , Haruhiko Cho  2   7 , Manabu Shiozawa  1 , Takaki Yoshikawa  2   8 , Soichiro Morinaga  1 , Yasushi Rino  2 , Wataru Yasui  4 , Munetaka Masuda  2 , Yohei Miyagi  9 , Takashi Oshima  10
Affiliations

High gamma-glutamyl hydrolase and low folylpolyglutamate synthetase expression as prognostic biomarkers in patients with locally advanced gastric cancer who were administrated postoperative adjuvant chemotherapy with S-1

Yukio Maezawa et al. J Cancer Res Clin Oncol. 2020 Jan.

Abstract

Purpose: The enzymes gamma-glutamyl hydrolase (GGH) and folylpolyglutamate synthetase (FPGS) regulate intracellular folate concentrations needed for cell proliferation, DNA synthesis, and repair. High GGH expression affects 5-FU thymidylate synthase (TS) inhibition and is a risk factor for various malignancies. Here, the clinical significance of GGH and FPGS expression was investigated in Stage II/III gastric cancer patients undergoing postoperative adjuvant chemotherapy with S-1.

Methods: Surgical specimens of cancer tissue and adjacent normal mucosa, obtained from 253 patients with previously untreated gastric cancer, were examined. GGH and FPGS mRNA expression was measured by qPCR to evaluate their clinicopathological significance in gastric cancer patients after curative resection.

Results: While FPGS expression showed no significant differences between the cancerous and normal samples, GGH expression was higher in cancer tissue than in adjacent normal mucosa. High GGH expression was correlated with age, histological type, and vascular invasion. Overall survival (OS) of patients with high GGH mRNA expression was significantly poorer than of patients with low GGH expression. Multivariate analysis showed that high GGH expression was an independent prognostic factor of OS (HR: 2.58, 95% CI 1.29-5.16). Patients who received S-1 adjuvant treatment showed a significantly poor OS between high GGH/low FPGS and low GGH/high FPGS. Patients without adjuvant treatment showed no significant difference.

Conclusion: GGH expression was significantly higher in gastric cancer tissue than in adjacent normal mucosa. High GGH and low FPGS expression is a useful independent predictor of poor outcomes in stage II/III gastric cancer patients undergoing postoperative adjuvant chemotherapy with S-1.

Keywords: Folylpolyglutamate synthetase (FPGS); Gamma-glutamyl hydrolase (GGH); Gastric cancer; Prognostic factor; S-1.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
a Comparison of expression levels of the GGH gene between gastric cancer tissue and adjacent normal mucosa (P < 0.001). b Comparison of expression levels of the FPGS gene between gastric cancer tissue and adjacent normal mucosa (P = 0.82)
Fig. 2
Fig. 2
a Comparison of overall survival between high and low expression levels of the GGH gene in gastric cancer tissue (P = 0.017). b Comparison of overall survival between high and low expression levels of the FPGS gene in gastric cancer tissue (P = 0.425)
Fig. 3
Fig. 3
Comparison of overall survival between high and low expression levels of the GGH gene in gastric cancer tissue stratified by whether S-1 adjuvant treatment was performed or not. a Patients who did not receive S-1 adjuvant treatment (P = 0.21). b Patients received S-1 adjuvant treatment (P = 0.043)
Fig. 4
Fig. 4
Comparison of overall survival between high and low expression levels of the GGH/FPGS gene in gastric cancer tissue (P = 0.019)
Fig. 5
Fig. 5
Comparison of overall survival between high and low expression levels of the GGH/FPGS gene in gastric cancer tissue stratified by whether S-1 adjuvant treatment was performed or not. a Patients who did not receive S-1 adjuvant treatment (P = 0.525). b Patients received S-1 adjuvant treatment (P = 0.039)
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