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Updated: Aug 1, 2025
Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays
Published on: February 24, 2023
Somatic Variants in DNA Damage Response Genes in Ovarian Cancer Patients Using Whole-exome Sequencing
Joanna Lopacinska-Joergensen1, Douglas V N P Oliveira1, Tim Svenstrup Poulsen1
1Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
Background/Aim:
Several clinical trials have investigated homologous recombination deficiency and BRCA1/2 status to select ovarian cancer patients for treatment with poly(ADP-ribose) polymerase-inhibitors (PARPi), but less attention has been given to other DNA-damage response (DDR) pathways. Therefore, we investigated somatic single/multiple nucleotide variants and small insertions/deletions in exonic and splice-site regions of 356 DDR genes to examine whether genes other than BRCA1/2 are altered.
Materials And Methods:
Whole-exome sequencing data from eight high-grade serous adenocarcinoma (HGSC) and four clear cell carcinoma (oCCC) patients were analyzed.
Results:
Forty-two variants (pathogenic, likely pathogenic or variants of uncertain significance) in 28 genes from DDR pathways were identified. Seven out of nine TP53 variants were previously described in The Cancer Genome Atlas Ovarian Cancer; other variants were found in 23 out of 28 unique genes, whereas no variants were reported in FAAP24, GTF2H4, POLE4, RPA3, and XRCC4.
Conclusion:
As the identified variants were not only limited to well-known TP53, BRCA1/2, and HR-associated genes, our study might contribute to the better understanding of which DDR pathways potentially influence disease progression. Moreover, they may display a potential role as biomarkers to predict platinum-based chemotherapy or PARPi treatment response or disease progression, as differences in disrupted DDR pathways were observed between patients with long and short overall survival in HGSC and oCCC groups.
Insights
This study identified numerous DNA-damage response (DDR) gene variants beyond BRCA1/2 in ovarian cancers, suggesting these alterations could predict treatment response and disease progression, impacting patient survival.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Ovarian cancer treatment selection often focuses on BRCA1/2 mutations and homologous recombination deficiency (HRD).
- Other DNA-damage response (DDR) pathways' roles in ovarian cancer are less understood.
- Investigating a broader range of DDR genes is crucial for comprehensive patient stratification.
Purpose of the Study:
- To identify somatic variants in 356 DDR genes beyond BRCA1/2 in ovarian cancer.
- To explore the potential of these DDR gene alterations as biomarkers for treatment response and disease progression.
Main Methods:
- Whole-exome sequencing data from 12 ovarian cancer patients (8 HGSC, 4 oCCC) were analyzed.
- Somatic single/multiple nucleotide variants and small insertions/deletions in exonic and splice-site regions of 356 DDR genes were examined.
Main Results:
- Forty-two variants in 28 DDR genes were identified (pathogenic, likely pathogenic, or variants of uncertain significance).
- TP53 variants were common, with other variants found in 23 unique genes.
- No variants were found in FAAP24, GTF2H4, POLE4, RPA3, and XRCC4.
Conclusions:
- Identified DDR gene variants extend beyond TP53 and BRCA1/2, offering insights into pathways influencing ovarian cancer progression.
- Disrupted DDR pathways correlated with survival differences in HGSC and oCCC patients.
- These variants may serve as biomarkers for predicting response to platinum-based chemotherapy or PARPi treatment.
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