Molecular Biology Laboratory, Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Hospital Infection Control Division, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Curr Cancer Drug Targets. 2024;24(5):501-509. doi: 10.2174/0115680096250376231025062652.
Ataxia telangiectasia mutated (ATM), an apical DNA damage response gene, is a commonly mutated gene in tumors, and its mutation could strengthen tumor immunogenicity and alter the expression of PD-L1, which potentially contributes to immune checkpoint inhibitors (ICIs) therapy.
The characteristics of ATM mutation and its relationship with the ICIs-treated clinical prognosis have been analyzed comprehensively in this paper. The overall frequency of ATM mutations has been found to be 4% (554/10953) in the cancer genome atlas (TCGA) cohort.
Both the TMB and MSI levels in patients with ATM mutations were significantly higher than those in patients without mutations (P < 0.0001). The median TMB was positively correlated with the frequency of ATM mutations (r = 0.54, P = 0.003). In the TCGA cohort, patients with ATM mutations had better clinical benefits in terms of overall survival (OS, hazard ratio (HR) = 0.736, 95% CI = 0.623 - 0.869), progression-free survival (PFS, HR = 0.761, 95% CI = 0.652 - 0.889), and disease-free survival (DFS, HR = 0.686, 95% CI = 0.512 - 0.919)] than patients without ATM mutations. Subsequently, the verification results showed ATM mutations to be significantly correlated with longer OS in ICIs-treated patients (HR = 0.710, 95% CI = 0.544 - 0.928). Further exploration indicated ATM mutation to be significantly associated with regulated anti-tumor immunity (P < 0.05).
Our findings highlight the value of ATM mutation as a promising biomarker to predict ICIs therapy in multiple tumors.
共济失调毛细血管扩张症突变基因（ATM）是一种顶端 DNA 损伤反应基因，在肿瘤中常发生突变，其突变可增强肿瘤免疫原性，改变 PD-L1 的表达，从而可能有助于免疫检查点抑制剂（ICI）治疗。
本文全面分析了 ATM 突变的特征及其与 ICI 治疗临床预后的关系。在癌症基因组图谱（TCGA）队列中，ATM 突变的总频率为 4%（554/10953）。
ATM 突变患者的 TMB 和 MSI 水平均显著高于无突变患者（P<0.0001）。中位 TMB 与 ATM 突变频率呈正相关（r=0.54，P=0.003）。在 TCGA 队列中，ATM 突变患者的总生存期（OS，风险比（HR）=0.736，95%CI=0.623-0.869）、无进展生存期（PFS，HR=0.761，95%CI=0.652-0.889）和无病生存期（DFS，HR=0.686，95%CI=0.512-0.919）均有更好的临床获益，而无 ATM 突变的患者则无此获益。随后的验证结果表明，ATM 突变与 ICI 治疗患者的 OS 延长显著相关（HR=0.710，95%CI=0.544-0.928）。进一步的探索表明，ATM 突变与受调控的抗肿瘤免疫有显著关联（P<0.05）。
我们的研究结果强调了 ATM 突变作为一种有前途的生物标志物，可预测多种肿瘤的 ICI 治疗效果。
