Gastric cancer with microsatellite instability displays increased thymidylate synthase expression

Author(s)

Pereira, Marina A. ; Dias, Andre R. ; Ramos, Marcus F. K. P. ; Cardili, Leonardo ; Moraes, Rafael D. R. ; Zilberstein, Bruno ; Nahas, Sergio C. ; Mello, Evandro S. ; Ribeiro Jr, Ulysses

• Document type: Journal article
• Source: JOURNAL OF SURGICAL ONCOLOGY; v. 126, n. 1, p. 9-pg., 2022-07-01.

Abstract

Background Gastric cancer (GC) with microsatellite instability (MSI) is a less aggressive disease and associated with resistance to 5-fluorouracil (5-FU)-based chemotherapy (CMT). Thymidylate synthase (TS) is inhibited by 5-FU, and another potential mediator of therapeutic resistance to 5-FU. Therefore, we aimed to analyze the association between MSI and TS expression in GC, and its impact on disease outcomes. Methods We retrospectively evaluated GC who underwent D2-gastrectomy. MSI and TS were analyzed by immunohistochemistry. We also investigated p53 expression, PD-L1 status, and tumor-infiltrating lymphocytes (CD4 and CD8). Results Out of 284 GC, 60 (21.1%) were MSI. Median TS-score for all cases was 16.5. TS expression was significantly higher in MSI compared to microsatellite-stable (MSS; p < 0.001). Considering both status, GC were classified in four groups: 167 (58.8%) MSS + TS-low; 57 (20.1%) MSS + TS-High; 24 (8.5%) MSI + TS-low; and 36 (12.7%) MSI + TS-high. MSI + TS-high group had less advanced pTNM stage, higher CD8+T cells levels (p < 0.001) and PD-L1 positivity (p < 0.001). Normal p53 expression was related to MSI GC (p < 0.001). Improved survival was observed in MSI + TS-high, but no survival benefit was seen with CMT. Conclusion MSI GC was associated with high TS levels, which may explain therapeutic resistance to 5-FU. Additionally, MSI + TS-high showed better survival, but without improvement with CMT. (AU)

• FAPESP's process: 16/25524-0 - Characterization of Helicobacter pylori infection, Epstein-Barr virus and gene-protein expression profile in gastric adenocarcinomas
• Grantee: Ulysses Ribeiro Júnior
• Support Opportunities: Regular Research Grants