Department of Gastroenterology, Department of Pathology, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil.
J Surg Oncol. 2022 Jul;126(1):116-124. doi: 10.1002/jso.26822.
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.
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).
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.
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.
微卫星不稳定（MSI）的胃癌（GC）是一种侵袭性较低的疾病，与对 5-氟尿嘧啶（5-FU）为基础的化疗（CMT）的耐药性相关。胸苷酸合成酶（TS）被 5-FU 抑制，而另一种 5-FU 治疗耐药的潜在介质。因此，我们旨在分析 GC 中 MSI 与 TS 表达之间的关联及其对疾病结果的影响。
我们回顾性评估了接受 D2 胃切除术的 GC 患者。通过免疫组织化学分析 MSI 和 TS。我们还研究了 p53 表达、PD-L1 状态和肿瘤浸润淋巴细胞（CD4 和 CD8）。
在 284 例 GC 中，有 60 例（21.1%）为 MSI。所有病例的中位数 TS 评分均为 16.5。MSI 组的 TS 表达明显高于微卫星稳定（MSS；p<0.001）。考虑到两种状态，GC 被分为四组：167 例（58.8%）MSS+TS-低；57 例（20.1%）MSS+TS-高；24 例（8.5%）MSI+TS-低；36 例（12.7%）MSI+TS-高。MSI+TS-高组的 pTNM 分期较晚，CD8+T 细胞水平较高（p<0.001），PD-L1 阳性率较高（p<0.001）。正常 p53 表达与 MSI GC 相关（p<0.001）。MSI+TS-高组的生存得到改善，但 CMT 没有改善生存获益。
MSI GC 与高 TS 水平相关，这可能解释了对 5-FU 的治疗耐药性。此外，MSI+TS-高组的生存较好，但 CMT 不能提高生存获益。
