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

• Published in: Journal of cancer research and clinical oncology 2020-01, Vol.146 (1), p.75-86
• Main Authors: Maezawa, Yukio, Sakamaki, Kentaro, Oue, Naohide, Kimura, Yayoi, Hashimoto, Itaru, Hara, Kentaro, Kano, Kazuki, Aoyama, Toru, Hiroshima, Yukihiko, Yamada, Takanobu, Yamamoto, Naoto, Ogata, Takashi, Ito, Hiroyuki, Cho, Haruhiko, Shiozawa, Manabu, Yoshikawa, Takaki, Morinaga, Soichiro, Rino, Yasushi, Yasui, Wataru, Masuda, Munetaka, Miyagi, Yohei, Oshima, Takashi
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - genetics; Cancer Research; Cell proliferation; Chemotherapy; Chemotherapy, Adjuvant; DNA biosynthesis; DNA repair; Drug Combinations; Female; Folic acid; gamma-Glutamyl Hydrolase - biosynthesis; gamma-Glutamyl Hydrolase - genetics; Gastric cancer; Gastric Mucosa - enzymology; Gene Expression; Hematology; Humans; Hydrolase; Internal Medicine; Male; Medicine; Medicine & Public Health; Middle Aged; Mucosa; Multivariate analysis; Neoplasm Staging; Oncology; Original Article – Cancer Research; Original – Cancer Research; Oxonic Acid - administration & dosage; Patients; Peptide Synthases - biosynthesis; Peptide Synthases - genetics; Risk factors; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Stomach Neoplasms - drug therapy; Stomach Neoplasms - enzymology; Stomach Neoplasms - pathology; Stomach Neoplasms - surgery; Tegafur - administration & dosage; Thymidylate synthase
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-019-03087-8

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.