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Identification of ATM Mutation as a Potential Prognostic Biomarker for Immune Checkpoint Inhibitors Therapy
Saijin Cui1, Tianyu Chen1, Yaning Zhao1
1Molecular Biology Laboratory, Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
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.
Insights
Ataxia telangiectasia mutated (ATM) gene mutations are linked to better outcomes in cancer patients treated with immune checkpoint inhibitors (ICIs). ATM mutations may serve as a biomarker for predicting response to ICIs therapy.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Ataxia telangiectasia mutated (ATM) is a key DNA damage response gene frequently mutated in various cancers.
- ATM mutations can enhance tumor immunogenicity and influence PD-L1 expression, impacting immunotherapy efficacy.
Purpose of the Study:
- To comprehensively analyze ATM mutation characteristics and their correlation with clinical prognosis in patients undergoing immune checkpoint inhibitor (ICI) therapy.
- To evaluate the potential of ATM mutations as a predictive biomarker for ICI treatment response across multiple tumor types.
Main Methods:
- Analysis of ATM mutation frequency and its association with tumor mutational burden (TMB) and microsatellite instability (MSI) in The Cancer Genome Atlas (TCGA) cohort.
- Evaluation of the impact of ATM mutations on overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) in TCGA and ICI-treated patient cohorts.
Main Results:
- ATM mutations were identified in 4% of the TCGA cohort and were significantly associated with higher TMB and MSI levels.
- Patients with ATM mutations demonstrated improved OS, PFS, and DFS compared to those without mutations.
- ATM mutations were significantly correlated with longer OS in patients receiving ICIs and associated with enhanced anti-tumor immunity.
Conclusions:
- ATM mutation status is a valuable biomarker for predicting the efficacy of immune checkpoint inhibitor therapy in diverse cancers.
- Targeting or considering ATM mutation status could optimize treatment strategies for patients undergoing immunotherapy.
