DNA repair deficiencies in ovarian cancer: genomic analysis of high grade serous ovarian tumors from the NOVA study

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Catégorie Primary study
Year 2015

This article is not included in any systematic review

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Background: Ovarian cancer is characterized by a high degree of genomic instability caused by deficiencies in DNA repair. Genome wide analysis was conducted on tumors obtained from patients enrolled in the NOVA study, a phase 3 clinical trial evaluating the PARP inhibitor niraparib as a maintenance treatment in patients with platinum sensitive ovarian cancer. Homologous recombination deficiency (HRD), sequence analysis of 43 genes involved in DNA damage response and other measures of genomic instability were evaluated. Material and Methods: DNA was extracted from FFPE tumor tissue and used to create libraries that were hybridized to a custom Agilent SureSelect capture array carrying probes for 54,091 single nucleotide polymorphism sites distributed across the human genome, as well as probes targeting 43 genes involved in DNA repair, including BRCA1 and BRCA2. The captured and enriched DNA was sequenced on an Illumina HiSeq 2500 sequencer. Sequences covering SNP positions were used to generate allelic imbalance profiles. Measures of genomic instability, including determination of a HRD score (integer value of 0‐100), were calculated using allelic imbalance profiles and determination of loss of heterozygosity by ASCN. A previously identified threshold HRD score of 42 was used to define HRD positivity in the absence of a BRCA mutation. Results: The NOVA study is a Phase 3, multicenter, randomized, doubleblind, placebo‐controlled study of niraparib as maintenance in platinum sensitive ovarian cancer patients who have either gBRCAmut or a tumor with high‐grade serous histology and who have responded to their most recent chemotherapy containing a platinum agent. Approximately 1/3 of the tumor samples have been analyzed to date. Both BRCA mutational status and HRD score were obtained from 174 samples of the initial set of archival FFPE tumor samples investigated, (n = 68 gBRCAmut; and n = 106 non‐gBRCAmut). In the gBRCAmut cohort, HRD analysis of the tumor confirmed the presence of a deleterious or suspected deleterious mutation in all cases. In the non‐gBRCAmut cohort, 14 tumors had a somatic BRCA mutation (13%) and 47 tumors (44%) had a high HRD score with no evidence of a BRCA mutation, collectively indicating 57% of the patient samples assessed in this cohort had tumors defective in HR. Additional sequencing of a panel of DNA repair genes identified a heterogeneous set of potential drivers of HRD in the absence of a BRCA mutation. The remaining set of tumor samples from NOVA are being evaluated and will be discussed. Conclusions: High grade serous ovarian cancer that has demonstrated platinum sensitivity is characterized by a high degree of genomic instability. HRD testing in the clinical setting is able to identify patients with tumor BRCA mutations, in addition to BRCAwt tumors that may be sensitive to agents exploiting deficiencies in HR.
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First added on: Dec 20, 2022