Genomic Correlates of DNA Damage in Breast Cancer Subtypes
Esther Cabañas Morafraile1, Javier Pérez-Peña2, Jesús Fuentes-Antrás1
1Experimental Therapeutics Unit, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC) and Centro de Investigación Biomédica en Red en Oncología (CIBERONC), 28040 Madrid, Spain.
Abstract:
Among the described druggable vulnerabilities, acting on the DNA repair mechanism has gained momentum, with the approval of PARP inhibitors in several indications, including breast cancer. However, beyond the mere presence of BRCA1/BRCA2 mutations, the identification of additional biomarkers that would help to select tumors with an extreme dependence on DNA repair machinery would help to stratify therapeutic decisions. Gene set enrichment analyses (GSEA) using public datasets evaluating expression values between normal breast tissue and breast cancer identified a set of upregulated genes. Genes included in different pathways, such as ATM/ATR, BARD1, and Fanconi Anemia, which are involved in the DNA damage response, were selected and confirmed using molecular alterations data contained at cBioportal. Nineteen genes from these gene sets were identified to be amplified and upregulated in breast cancer but only five of them NBN, PRKDC, RFWD2, UBE2T, and YWHAZ meet criteria in all breast cancer molecular subtypes. Correlation of the selected genes with prognosis (relapse free survival, RFS, and overall survival, OS) was performed using the KM Plotter Online Tool. In last place, we selected the best signature of genes within this process whose upregulation can be indicative of a more aggressive phenotype and linked with worse outcome. In summary, we identify genomic correlates within DNA damage pathway associated with prognosis in breast cancer.
Insights
Identifying new biomarkers for DNA repair in breast cancer is crucial. This study found specific gene signatures linked to aggressive disease and poor prognosis, aiding in treatment stratification.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Targeting DNA repair mechanisms, like with PARP inhibitors, is a growing strategy in breast cancer treatment.
- Biomarker identification beyond BRCA1/BRCA2 mutations is needed to select patients with high dependence on DNA repair.
Purpose of the Study:
- To identify novel gene expression biomarkers within DNA damage response pathways that correlate with breast cancer prognosis.
- To find gene signatures indicative of aggressive phenotypes and worse patient outcomes.
Main Methods:
- Gene set enrichment analysis (GSEA) on public breast cancer datasets to identify upregulated genes.
- Validation of gene alterations using cBioportal and correlation with prognosis via Kaplan-Meier plotter.
- Selection of a gene signature meeting criteria across all breast cancer molecular subtypes.
Main Results:
- Several DNA damage response pathway genes were found to be upregulated in breast cancer.
- Nineteen genes were amplified and upregulated; five genes (NBN, PRKDC, RFWD2, UBE2T, YWHAZ) were consistently identified across subtypes.
- Upregulation of the selected gene signature correlated with poorer relapse-free and overall survival.
Conclusions:
- Genomic alterations within the DNA damage repair pathway serve as prognostic biomarkers in breast cancer.
- The identified gene signature can indicate a more aggressive tumor phenotype and predict worse outcomes.
- These findings support the stratification of therapeutic decisions based on DNA repair pathway biomarkers.
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