Acquired Promoter Methylation Loss Causes PARP Inhibitor Resistance in High-Grade Serous Ovarian Carcinoma.

In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. promoter methylation (me) 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 promoter show responses to PARPi. Both complete and heterogeneous methylation patterns were associated with gene silencing and homologous recombination deficiency (HRD). PDX models lost me following treatment with PARPi rucaparib or niraparib, where a single unmethylated copy of 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 -methylated HGSC, various patterns of me 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 me after six lines of therapy (four platinum-based), whereas another HGSC sample was found to have heterozygous me and elevated gene expression (relative to homozygous me controls) after only neoadjuvant chemotherapy.As me 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 methylation is a positive predictive biomarker for sensitivity to PARP inhibitors, whereas a single unmethylated gene copy is sufficient to confer resistance.