Abstract
Otago BMLSc student research project abstract.
Objectives: High-grade serous ovarian cancer (HGSOC) is the most aggressive subtype of ovarian cancer (OC) and is frequently diagnosed at stage IlIc. Approximately 50% of OC cases exhibit homologous recombination deficiency (HRD), commonly due to pathogenic variants in BRCA /2 or other homologous recombination repair (HRR) genes. The remaining cases are homologous recombination proficient (HRP). HRD status is a key biomarker for determining eligibility for poly (ADP-ribose) polymerase inhibitors (PARPi), which target defective DNA repair pathways. Access to HRD testing in Aotearoa is limited, involving expensive overseas processing. In 2024, PHARMAC approved the use of Niraparib, a PARPi, regardless of HRD status, raising safety concerns for HRP patients.
Methods: Formalin-fixed paraffin-embedded (FFPE) ovarian cancer tissue from 45 Polish patients was processed for DNA extraction, quality assessment, and targeted library preparation using Qiagen HRD assay. Sequencing was analysed via the CLC Genomics Workbench. HRD scoring was based on the detection of loss of heterozygosity (LOH), large-scale state transitions (LST), and telomeric allelic imbalance (TAI) from 13,809 SNPs. Pathogenic variants were curated following ClinGen/CGC/VICC guidelines.
Results: Among the 45 samples, 23 harboured germline BRCA1/2 mutations, 13 somatic mutations, and 9 had no BRCA1/2 alterations. HRD (score 50) was observed in 30 cases. 12 patients exhibited both germline BRCA1 and somatic BRCA2 mutations, suggesting dual HRR pathway disruption. Samples with low tumour tissue content or sequencing depth were flagged for cautious interpretation. The assay performed well across varying DNA quality, with unique molecular indices (UMIs) enhancing variant reliability.
Conclusion: HRD scoring needs to be considered for various factors, including tumour tissue content, depth coverage and specific mutations. Comparison with the Agilent HRR17 panel and using New Zealand Aotearoa samples are recommended for further studies.