Journal
CANCER RESEARCH
Volume 81, Issue 18, Pages 4709-4722Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-0774
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Funding
- National Health and Medical Research Council (NHMRC Australia) [1062702, APP1139071]
- Stafford Fox Medical Research Foundation
- Cancer Council Victoria (Sir Edward Dunlop Fellowship in Cancer Research)
- Victorian Cancer Agency (Clinical Fellowships) [CRF10-20, CRF16014, ECRF19003]
- Herman Trust, University of Melbourne
- NIH [2P50CA083636, P50 CA136393, F30 CA213737, T32 GM072474]
- Wendy Feuer Ovarian Cancer Research Fund
- Bev Gray Ovarian Cancer Scholarship (PhD Top-Up Scholarship)
- Research Training Program Scholarship (PhD Scholarship)
- Victorian Government Operational and Infrastructure Support Program
- Mayo Foundation for Education and Research
- Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Cancer Research Grant
- Ovarian Cancer Australia
- Peter MacCallum Foundation
- U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]
- Cancer Council Victoria, Queensland Cancer Fund
- Cancer Council New South Wales
- Cancer Council South Australia
- Cancer Council Tasmania
- Cancer Foundation of Western Australia [191, 211, 182]
- National Health and Medical Research Council of Australia (NHMRC) [ID199600, ID400413, ID400281]
- National Health and Medical Research Council of Australia [1062702] Funding Source: NHMRC
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This study revealed that methylation patterns in the RAD51C promoter are closely associated with sensitivity to PARP inhibitors, with complete or heterogeneous methylation affecting drug resistance development. Additionally, genomic profiling showed that resistance to PARPi can be acquired independently in genetically distinct lineages.
In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene RAD51C are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. RAD51C promoter methylation (meRAD51C) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved. In this study, three HGSC patient-derived xenograft (PDX) models with methylation at most or all examined CpG sites in the RAD51C promoter show responses to PARPi. Both complete and heterogeneous methylation patterns were associated with RAD51C gene silencing and homologous recombination deficiency (HRD). PDX models lost meRAD51C following treatment with PARPi rucaparib or niraparib, where a single unmethylated copy of RAD51C was sufficient to drive PARPi resistance. Genomic copy number profiling of one of the PDX models using SNP arrays revealed that this resistance was acquired independently in two genetically distinct lineages. In a cohort of 12 patients with RAD51C-methylated HGSC, various patterns of meRAD51C were associated with genomic scarring, indicative of HRD history, but exhibited no clear correlations with clinical outcome. Differences in methylation stability under treatment pressure were also observed between patients, where one HGSC was found to maintain meRAD51C after six lines of therapy (four platinum-based), whereas another HGSC sample was found to have heterozygous meRAD51C and elevated RAD51C gene expression (relative to homozygous meRAD51C controls) after only neoadjuvant chemotherapy. As meRAD51C loss in a single gene copy was sufficient to cause PARPi resistance in PDX, methylation zygosity should be carefully assessed in previously treated patients when considering PARPi therapy. Significance: Homozygous RAD51C methylation is a positive predictive biomarker for sensitivity to PARP inhibitors, whereas a single unmethylated gene copy is sufficient to confer resistance.
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