Gastric cancer with microsatellite instability displays increased thymidylate synthase expression

Abstract

AbstractBackgroundGastric 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.MethodsWe 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).ResultsOut 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.ConclusionMSI 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.