微卫星不稳定型胃癌表现出胸苷酸合成酶表达增加。

Gastric cancer with microsatellite instability displays increased thymidylate synthase expression.

机构信息

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.

出版信息

J Surg Oncol. 2022 Jul;126(1):116-124. doi: 10.1002/jso.26822.

DOI:10.1002/jso.26822

PMID:35689583

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.

摘要

背景

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。

方法

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）。

结果

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。