Abstract 4020: Correlation between the expression of glutathione metabolism-related genes and prognosis in ovarian clear cell carcinoma
Authors: Asano Hiroshi , Matsuoka Ryosuke , Hatanaka Kanako C. , Hatanaka Yutaka , Kato Tatsuya , Konno Yosuke , Mitamura Takashi , Akita Hirotoshi , Matsuno Yoshihiro , Watari Hidemichi 
Published: August 2019

Background: Ovarian clear cell carcinoma (OCCC) is more prevalent in Japan than western countries, exhibits chemoresistant phenotype and poor survival. Although the expression of the genes related to glutathione (GSH) metabolism had been reported as one of the possible chemoresistant mechanisms, correlation between the expressions of these genes and prognosis in OCCC patients remains unclear. In this study, we aim to investigate 1) enrichment pathway analysis in OCCC in comparison with high-grade serous carcinoma (HGSC), and 2) correlation between the expression of gamma-glutamyl transpeptidase 1 (GGT1), one of the enzymes in GSH metabolism and prognosis.

Methods: We consecutively collected surgically resected tissue specimens from 33 ovarian cancer patients; 15 patients with OCCC and 18 patients with HGSC. The tissue specimens were collected in the vials containing RNA later® within 10 min. after resection of tumors. Total RNAs were extracted from the tumor tissues, and comprehensive gene expression analysis was performed using Ion AmpliSeq™ Transcriptome Human Gene Expression Kit (Thermo Fisher Scientific). For prognostic analysis, we used a tissue microarray (TMA) from 56 consecutive patients pathologically diagnosed with OCCC in our hospital, and assessed by immunohistochemistry (IHC) using H-score ranging from 0 to 300. Overall survival (OS) was estimated by Kaplan-Meier method, and analyzed by Cox-regression hazard model in multivariate analysis.

Results: Gene expression profiles revealed that TCF1/2 target genes were up-regulated in OCCC samples in comparison with HGSC. In addition, genes related with amino-acid transporters, such as SLC3A1, a cystine transporter, and genes related to GSH metabolism, including GGT1, CSE, and GPX3 were also up-regulated. In the OCCC patients with high expression level of GSH-related genes, FOXP3 was down-regulated but the T-cell inflamed genes were not varied compared to the OCCC patients with low expression level. The expression level of GGT1 in gene expression analysis was strongly correlated with H-score of GGT1 in IHC (r = 0.7850, p = 0.0023). In prognostic analysis, there were no significant differences during follow up period (57.5 months vs. 53 months), FIGO stage (I: 50% vs 64%), optimal surgery (92% vs. 98%), or recurrent rate (42% vs. 30%) between GGT1 positive (n = 44) and negative (n = 12) OCCC in IHC. However, platinum-drug resistant recurrent rate was significantly higher in GGT1 negative OCCC than GGT1 positive OCCC (42% vs 14%, p = 0.027). OS in GGT1 negative OCCC was significantly worse than that of GGT1 positive OCCC (5-year OS was 42% vs 72%, p = 0.0226), and negative expression of GGT1 was one of the independent poor prognostic factors in OCCC.

Conclusion: Negative expression of GGT1 in OCCC might be a poor prognostic maker via recruitment of regulatory T cells in tumor microenvironments.

Citation Format: Hiroshi Asano, Ryosuke Matsuoka, Kanako C. Hatanaka, Yutaka Hatanaka, Tatsuya Kato, Yosuke Konno, Takashi Mitamura, Hirotoshi Akita, Yoshihiro Matsuno, Hidemichi Watari. Correlation between the expression of glutathione metabolism-related genes and prognosis in ovarian clear cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4020.