33. Tumor testing of DNA repair genes in high grade serous ovarian cancer (HGSOC); a potential tool for personalized therapy

      Ovarian cancer is the leading cause of death in women with gynecological tumors. Approximately 28% of women with high-grade serous ovarian cancer (HGSOC) carry either a germline or acquired somatic variant in BRCA1 or BRCA2 resulting in deficient homologous recombination repair (HRR). HRR deficiency may also be attributed to loss-of-function variants in other HRR pathway genes. Inhibitors of poly (ADP-ribose) polymerase (PARP inhibitors) are approved for HGSOC patients as first-line maintenance therapy in the presence of a BRCA loss-of-function variant which could be expanded to other HRR pathway genes as additional clinical information becomes available. To assess the utility of a 32 gene panel test for the detection of clinically relevant variants in HGSOC tumors DNA was extracted from 50 formalin-fixed paraffin embedded (FFPE) tumors from patients who have had previous germline hereditary cancer testing. NGS libraries were generated using a custom capture EZlibrary (Roche) and sequenced on the MiSeq (Illumina). The same gene panel was used for tumor and matched blood samples. Sequencing success was determined by quality control (QC) metrics along with comparison to germline data. NGS data from tumor samples passed QC but overall coverage was lower than expected. Variant calls in the tumors were concordant with matched germline sample when coverage was sufficient. Somatic variants were identified in a subset of tumors. In addition to BRCA1 and BRCA2 loss-of-function variants several mutations were detected in other hereditary cancer genes. Some of these variants suggest HRR deficiency and may predict HGSOC that are amenable to treatment.
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