Integrative sWGS: A New Paradigm for HRD Detection in Ovarian Cancer
Dan Corneliu Jinga1,2, Georgiana Duta-Cornescu3, Danut Cimponeriu3
1Neolife Medical Center, 013975 Bucharest, Romania.
International Journal of Molecular Sciences
|December 30, 2025
Summary
This study validates a shallow whole-genome sequencing (sWGS) method for assessing genomic instability (GI) to detect homologous recombination deficiency (HRD) in ovarian cancer, improving personalized treatment strategies.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- Homologous recombination deficiency (HRD) is a key biomarker for predicting PARP inhibitor sensitivity in ovarian cancer.
- Accurate and accessible HRD testing is crucial for personalized cancer therapy and improved patient outcomes.
- Current HRD testing methods require validation for broader clinical application.
Purpose of the Study:
- To evaluate a combined shallow whole-genome sequencing (sWGS) and targeted gene panel approach for assessing genomic instability (GI) and detecting HRD in ovarian cancer.
- To validate the performance of this novel HRD testing strategy against a reference standard.
- To analyze the prevalence of HRD and associated genetic alterations in a Romanian cohort of ovarian cancer patients and correlate findings with clinical response.
Main Methods:
- A shallow whole-genome sequencing (sWGS) approach for GI assessment was combined with a 52-gene targeted panel.
- The assay's performance was validated using reference materials and 24 archival ovarian cancer samples with known HRD status, compared against the Myriad myChoice® HRD test.
- A prospective cohort of 124 newly diagnosed ovarian cancer patients was analyzed.
Main Results:
- The sWGS-derived GI status demonstrated high concordance (95.8% agreement, κ=0.913) with the reference HRD test.
- Pathogenic BRCA1/2 variants were identified in 24.19% of patients; an additional 22.76% were BRCA1/2-negative but GI-positive, resulting in an overall HRD prevalence of 47.15%.
- HRD-positive patients showed high platinum sensitivity (90.0%), and preliminary PARP inhibitor response rates were encouraging (ORR 66.7%, DCR 83.3%).
- TP53 alterations were most common (62.90%), followed by BRCA1 (19.35%) and BRCA2 (4.83%). Other HR-pathway gene variants were found in 9.57% of BRCA-wild-type cases.
- Two cases with BRCA2 variants and microsatellite instability suggested potential for combined PARP inhibitor and anti-PD-1/PD-L1 therapy.
Conclusions:
- Integrating sWGS-based GI assessment with BRCA testing offers a robust approach for improved HRD detection in ovarian cancer.
- The study highlights the genetic heterogeneity of HR-pathway alterations in Romanian ovarian cancer patients.
- Preliminary clinical data support the association between HRD status and treatment response, warranting further investigation in larger cohorts.
