Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China.
Gene. 2021 May 20;781:145534. doi: 10.1016/j.gene.2021.145534. Epub 2021 Feb 23.
Microsatellite instability (MSI) is closely related to the prognosis and therapy response of colon cancer. Colon cancer patients with MSI show resistance to 5-Fluorouracil (5-FU) but sensitivity to immunosuppressive checkpoint inhibitors (ICIs). The relevant mechanism behind the opposite response remains unclear. Multi-omics research data of colon cancer patients were acquired from The Cancer Genome Atlas (TCGA) database, GEO database, and DAFI dataset. Transcriptome data were normalized to gene expression data through the R software package "Limma". Somatic mutations data were analyzed and visualized through the R software package "maftools". CIBERSORT algorithm was used to estimate the relative proportion of 22 infiltrating immune cell types. We demonstrated MSI patients showed both overexpressed immune checkpoints (mRNA level) and activated tumor-infiltrating lymphocytes (TILs), which may explain the satisfying response of ICIs. The additionally, we also demonstrated MSI promoted the mRNA expression of thymidylate synthase (TYMS) through regulating its copy number variation. As a main target of 5-FU, overexpressed TYMS promoted the resistance of 5-FU. Furthermore, we demonstrated MSI patients showed significantly increased somatic mutations compared with microsatellite stability (MSS) patients, except APC, TP53, and KRAS mutations. The substitutions and location of somatic mutations in different genes were at variance between MSS and MSI patients. In conclusion, our research determined mechanisms of MSI associated treatment response, and may provide potential value for improving the survival of colon cancer patients.
微卫星不稳定性（MSI）与结肠癌的预后和治疗反应密切相关。MSI 阳性的结肠癌患者对 5-氟尿嘧啶（5-FU）表现出耐药性，但对免疫抑制检查点抑制剂（ICIs）敏感。相反反应背后的相关机制尚不清楚。从癌症基因组图谱（TCGA）数据库、GEO 数据库和 DAFI 数据集获取了结肠癌患者的多组学研究数据。通过 R 软件包“Limma”将转录组数据归一化为基因表达数据。通过 R 软件包“maftools”分析和可视化体细胞突变数据。使用 CIBERSORT 算法估计 22 种浸润免疫细胞类型的相对比例。我们证明 MSI 患者既表现出免疫检查点的过表达（mRNA 水平），又表现出肿瘤浸润淋巴细胞（TILs）的激活，这可能解释了 ICI 的满意反应。此外，我们还证明 MSI 通过调节胸苷酸合成酶（TYMS）的拷贝数变异来促进其 mRNA 表达。作为 5-FU 的主要靶点，过表达的 TYMS 促进了 5-FU 的耐药性。此外，我们证明与微卫星稳定性（MSS）患者相比，MSI 患者的体细胞突变明显增加，除 APC、TP53 和 KRAS 突变外。MSS 和 MSI 患者之间不同基因的体细胞突变的取代和位置存在差异。总之，我们的研究确定了 MSI 相关治疗反应的机制，可能为提高结肠癌患者的生存率提供潜在价值。
