RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
DNA 修复相关基因作为反映结直肠癌 MSI、TMB 和 TIL 的生物标志物的鉴定
英文原题：Identification of DNA Repair-related Genes as Biomarkers Reflecting MSI, TMB, and TIL in Colorectal Cancer.
查看英文原题
Identification of DNA Repair-related Genes as Biomarkers Reflecting MSI, TMB, and TIL in Colorectal Cancer.
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
研究概要
ATR、LIG4、RAD52、GADD45B、SMUG1 和 XRCC6 基因的 mRNA 表达水平降低与高细胞毒性 T 细胞和 TMB 水平相关，提示这些基因可作为 pMMR 病例中 ICI 疗效的生物标志物。
研究思路结论见上方概要
背景
在微卫星稳定（MSS）或错配修复功能完整（pMMR）的结直肠癌（CRC）中，尚无已确立的免疫检查点抑制剂（ICI）生物标志物。因此，本研究旨在通过分析参与高免疫原性和免疫反应的DNA修复相关下调基因，并比较其表达水平和临床特征，以确定pMMR患者中ICI获益的生物标志物。
方法
对13例CRC病例进行了错配修复（MMR）、TIL（肿瘤浸润淋巴细胞）和肿瘤突变负荷（TMB）评估，并检测了95个DNA修复相关基因的mRNA表达水平。在高免疫原性和高免疫应答组中鉴定出mRNA表达降低的DNA修复相关基因。随后，在135例CRC患者中检测了所鉴定DNA修复相关基因的mRNA表达水平。利用mRNA表达水平进行层次聚类分析，以比较各聚类的临床病理特征。
结果
ATR、LIG4和RAD52 mRNA水平在高免疫原性组中显著下调。GADD45B、SMUG1和XRCC6 mRNA水平在高免疫反应组中显著下调。这六个基因mRNA表达降低的聚类中的病例为pMMR病例。该聚类中CD8 mRNA表达水平高于其他聚类。
展开英文摘要原文
MATERIALS AND METHODS
Mismatch repair (MMR), tumor-infiltrating lymphocytes (TIL), and tumor mutation burden (TMB) were evaluated in 13 CRC cases and mRNA expression levels of 95 DNA repair-related genes were measured. DNA repair-related genes with reduced mRNA expression in the high immunogenicity and high immune response groups were identified. Then, the mRNA expression levels of the identified DNA repair-related genes were measured in 135 patients with CRC. Hierarchical cluster analysis was performed using the mRNA expression levels to compare the clinicopathological characteristics of each cluster.
RESULTS
ATR, LIG4, and RAD52 mRNA levels were significantly down-regulated in the high immunogenicity group. GADD45B, SMUG1, and XRCC6 mRNA levels were significantly down-regulated in the high immune response group. Cases in the cluster with reduced mRNA expression of the six genes were pMMR cases. CD8 mRNA expression level was higher in this cluster than in the other clusters.
CONCLUSION
Decreased mRNA expression levels of ATR, LIG4, RAD52, GADD45B, SMUG1, and XRCC6 genes were associated with high cytotoxic T cell and TMB levels, suggesting that these genes could serve as biomarkers for ICI efficacy in pMMR cases.
论文信息
- 作者
- Fukuda J、Sudo T、Kikuchi M、Kawahara A、Shigyo H、Kawamoto Y、Shimamura S、Koga F
- 第一作者单位
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan; fukuda_junya@kurume-u.ac.jp.Japan
- 通讯作者单位
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan; sudo_tomoya@kurume-u.ac.jp.Japan
- 期刊
- Anticancer research2024 Aug
- 原文标识
- PubMed 39060055 · DOI 10.21873/anticanres.17179