Identification of ATM Mutation as a Potential Prognostic Biomarker for Immune Checkpoint Inhibitors Therapy

Abstract

Background:: 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. Methods:: 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. Results:: 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). Conclusion:: Our findings highlight the value of ATM mutation as a promising biomarker to predict ICIs therapy in multiple tumors.