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ATM mutations as an independent prognostic factor and potential biomarker for immune checkpoint therapy in
Lei Sun1, Run-Chang Wang2, Qing Zhang2
1Department of Pathology, Zhujiang Hospital, Southern Medical University, 253 Gongye Road, Guangzhou 510282, China.
Abstract:
The morbidity and mortality of endometrial cancer has been increasing over years. Ataxia telangiectasia mutated (ATM) gene, encoding a protein kinase participated in the response to DNA damage, is frequently mutated in endometrial cancer patients. However, the potential relationship between ATM mutations and the progression of endometrial cancer remains unclear. We performed an integrative bioinformatics analysis to investigate the relationship between ATM mutational status with clinical outcomes and tumor microenvironment in endometrial cancer patients. The whole exome sequencing data, RNA sequencing data and clinical information were collected from The Cancer Genome Atlas (TCGA) dataset. We found that mutation in the ATM gene was an independent prognostic factor for endometrial cancer. Antitumor immune pathways were enriched in endometrial tumors with ATM mutations. The tumor-infiltrating T lymphocytes, especially cytotoxic lymphocytes, were generally more abundant in tumors with ATM mutations. Furthermore, patients with ATM mutations exhibited higher tumor mutational burden, higher neoantigen load and increased expression levels of some immune checkpoints. In conclusion, the present study indicated that ATM mutations were linked to longer overall survival of endometrial cancer. Our findings may add better understanding for potential immunotherapy of endometrial cancer.
Insights
Mutations in the Ataxia Telangiectasia Mutated (ATM) gene are linked to improved survival in endometrial cancer patients. ATM mutations correlate with a more robust anti-tumor immune response, suggesting potential for immunotherapy.
Area of Science:
- Oncology
- Genetics
- Bioinformatics
Background:
- Endometrial cancer presents increasing morbidity and mortality.
- The Ataxia Telangiectasia Mutated (ATM) gene, crucial for DNA damage response, is frequently altered in endometrial cancer.
- The prognostic and immune-related implications of ATM mutations in endometrial cancer are not fully understood.
Purpose of the Study:
- To investigate the association between ATM mutational status and clinical outcomes in endometrial cancer.
- To explore the relationship between ATM mutations and the tumor microenvironment.
- To evaluate the potential of ATM mutations as a biomarker for immunotherapy.
Main Methods:
- Integrative bioinformatics analysis using The Cancer Genome Atlas (TCGA) dataset.
- Analysis of whole exome sequencing, RNA sequencing, and clinical data.
- Assessment of prognostic significance, immune pathway enrichment, and tumor-infiltrating lymphocytes.
Main Results:
- ATM gene mutation is an independent prognostic factor for endometrial cancer.
- Endometrial tumors with ATM mutations show enrichment in antitumor immune pathways.
- Increased abundance of tumor-infiltrating T lymphocytes, higher tumor mutational burden, and elevated neoantigen load observed in ATM-mutated tumors.
- Higher expression of immune checkpoints noted in patients with ATM mutations.
Conclusions:
- ATM mutations are associated with longer overall survival in endometrial cancer.
- ATM mutations may influence the tumor microenvironment, enhancing anti-tumor immunity.
- These findings support the potential utility of ATM mutations in guiding endometrial cancer immunotherapy strategies.
