背景:共济失调毛细血管扩张症突变(ATM),顶端DNA损伤反应基因,是肿瘤中常见的突变基因,其突变可以增强肿瘤的免疫原性并改变PD-L1的表达,这可能有助于免疫检查点抑制剂(ICIs)的治疗。
方法:本文综合分析了ATM突变的特点及其与ICIs治疗临床预后的关系。在癌症基因组图谱(TCGA)队列中,已发现ATM突变的总频率为4%(554/10953)。
结果:有ATM突变的患者的TMB和MSI水平均明显高于无突变的患者(P<0.0001)。TMB中位数与ATM突变频率呈正相关(r=0.54,P=0.003)。在TCGA队列中,具有ATM突变的患者在总生存期方面具有更好的临床益处(OS,危险比(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),和无病生存率(DFS,HR=0.686,95%CI=0.512-0.919)]比无ATM突变的患者。随后,验证结果显示,在ICIs治疗的患者中,ATM突变与较长的OS显著相关(HR=0.710,95%CI=0.544~0.928).进一步研究表明,ATM突变与抗肿瘤免疫调节显著相关(P<0.05)。
结论:我们的研究结果强调了ATM突变作为预测多种肿瘤ICIs治疗的一个有前景的生物标志物的价值。
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.