Genetic Alterations in HRR Genes and Prognostic Impact in Gliomas
Overview
This study analyzed 1352 glioma samples to characterize homologous recombination repair (HRR) gene loss-of-function (LOF) mutations and their prognostic implications. HRR LOF mutations were associated with distinct molecular profiles and immune microenvironment features, with survival correlations confirmed in an independent TCGA cohort.
Background
Gliomas are the most common primary malignant brain tumors with heterogeneous molecular and clinical features affecting treatment response and prognosis. Homologous recombination repair (HRR) is critical for DNA double-strand break repair, and HRR deficiency (HRD) due to gene mutations is implicated in various cancers. Tumors with HRD often respond better to PARP inhibitors and platinum-based chemotherapy. However, the role of HRR gene alterations in gliomas remains underexplored, necessitating comprehensive molecular and clinical analyses.
Data Highlights
Group
Number of Patients
Germline HRR-LOF
83
Somatic HRR-LOF
497
NonHRR-LOF
772
Key Findings
Among 1352 glioma patients, 83 had germline HRR-LOF mutations, 497 had somatic HRR-LOF mutations, and 772 had no HRR-LOF mutations.
Somatic HRR-LOF mutations were associated with higher tumor mutational burden (TMB) and copy number variation (CNV) burden compared to non-HRR-LOF gliomas.
Distinct mutation patterns and molecular characteristics were observed in HRR-LOF gliomas, including alterations in key HRR genes such as ATM, ATRX, BRCA1/2, and CHEK2.
Immune microenvironment analysis revealed differential immune cell infiltration and immune-related gene expression profiles in HRR-LOF gliomas, suggesting an altered tumor-immune interaction.
Survival analysis in the TCGA cohort demonstrated that somatic HRR-LOF status correlated with patient prognosis, indicating potential prognostic value.
Clinical Implications
Identification of HRR LOF mutations in gliomas may guide personalized therapeutic strategies, including the potential use of PARP inhibitors or platinum-based chemotherapy. Furthermore, the distinct immune microenvironment in HRR-LOF gliomas suggests opportunities for immunotherapy approaches. Routine molecular profiling of HRR genes could enhance prognostic stratification and treatment decision-making in glioma patients.
Conclusion
HRR gene loss-of-function mutations define a molecularly and clinically distinct subset of gliomas with prognostic significance and unique immune features. These findings support further exploration of HRR-targeted therapies and immune modulation in glioma management.
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