Abstract
PurposeThe 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.MethodsSurgical 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.ResultsWhile 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.ConclusionGGH 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.
Highlights
Gastric cancer was the fifth most common in new cases of cancer (1,033,701 cases) and the third most common in cancer-related deaths (781,631 deaths) in 2018 (Bray et al 2018)
Comparison of overall survival rates by expression levels of Gamma-glutamyl hydrolase (GGH) or folylpolyglutamate synthetase (FPGS) mRNA in gastric cancer tissue
We measured the levels of GGH and FPGS mRNA expression in cancer tissues and adjacent normal mucosa in patients with stage II/III gastric cancer
Summary
Gastric cancer was the fifth most common in new cases of cancer (1,033,701 cases) and the third most common in cancer-related deaths (781,631 deaths) in 2018 (Bray et al 2018). (DS) therapy; fluoropyrimidine is still the key drug used in the postoperative adjuvant chemotherapy for gastric cancer (Sakuramoto et al 2007; Bang et al 2012; Noh et al 2014). The outcomes of treatment are still insufficient, as recurrence occurs in 20–60% of patients, even after a complete resection and the administration of the appropriate adjuvant therapy (Maehara et al 2000; Rivera et al 2007). The personalization of postoperative adjuvant chemotherapy treatment using biomarkers is a promising strategy to improve the survival of patients with localized advanced gastric cancer. A specific biomarker for use in predicting the therapeutic effects of fluorinated pyrimidine and the long-term outcomes of patients with locally advanced gastric cancer has yet to be identified (Pizzorno et al 1988; Shubbar et al 2013; Melling et al 2017)
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