Abstract
Simple SummaryGermline and somatic variant testing of the BRCA1 and BRCA2 genes are important to predict treatment response to PARP inhibitors in ovarian cancer patients. However, germline variants in other genes besides BRCA1 and BRCA2 are associated with ovarian cancer predisposition, which would be missed by a genetic testing aimed only at treatment decision. We aimed to evaluate the yield of clinically actionable germline variants using next-generation sequencing of a customized panel of 10 genes for the analysis of pathology samples of ovarian carcinomas. We identified clinically actionable germline variants in a significantly higher proportion of ovarian cancer patients when compared with genetic testing focused only on BRCA1 and BRCA2. This strategy increases the chance to make available genetic counseling, presymptomatic genetic testing, and gynecological cancer prophylaxis to female relatives who turn out to be healthy carriers of deleterious germline variants. Since the approval of PARP inhibitors for the treatment of high-grade serous ovarian cancer, in addition to cancer risk assessment, BRCA1 and BRCA2 genetic testing also has therapeutic implications (germline and somatic variants) and should be offered to these patients at diagnosis, irrespective of family history. However, variants in other genes besides BRCA1 and BRCA2 are associated with ovarian cancer predisposition, which would be missed by a genetic testing aimed only at indication for PARP inhibitor treatment. In this study, we aimed to evaluate the yield of clinically actionable germline variants using next-generation sequencing of a customized panel of 10 genes for the analysis of formalin-fixed paraffin-embedded samples from 96 ovarian carcinomas, a strategy that allows the detection of both somatic and germline variants in a single test. In addition to 13.7% of deleterious germline BRCA1/BRCA2 carriers, we identified 7.4% additional patients with pathogenic germline variants in other genes predisposing for ovarian cancer, namely RAD51C, RAD51D, and MSH6, representing 35% of all pathogenic germline variants. We conclude that the strategy of reflex gene-panel tumor testing enables the identification of clinically actionable germline variants in a significantly higher proportion of ovarian cancer patients, which may be valuable information in patients with advanced disease that have run out of approved therapeutic options. Furthermore, this approach increases the chance to make available genetic counseling, presymptomatic genetic testing, and gynecological cancer prophylaxis to female relatives who turn out to be healthy carriers of deleterious germline variants.
Highlights
Ovarian cancer (OC) is the third most common malignant disease among patients with gynecological neoplasia, being the eighth most common cancer and the eighth most common cause of cancer-related death in women [1]
Among the ten genes included in the next-generation sequencing (NGS) panel (BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, PMS2, RAD51C, RAD51D, and TP53), a total of 3457 variants was annotated and classified among the remaining 95 tumor samples
Among the variants not classified in ClinVar, two variants were nonsense, seven were frameshift variants, two were canonical +1 and −2 splice site variants, and one was an inframe variant, all of which were considered pathogenic since there is strong evidence of pathogenicity [15]
Summary
Ovarian cancer (OC) is the third most common malignant disease among patients with gynecological neoplasia, being the eighth most common cancer and the eighth most common cause of cancer-related death in women [1]. Epithelial ovarian cancer (EOC) is recognized as a heterogeneous disease mainly represented by five histological subtypes (high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous) that are characterized by distinct clinical and molecular features. Despite this knowledge, the initial standard treatment has typically been maximal effort cytoreductive surgery, with platinum-paclitaxel chemotherapy being the standard of care treatment [3,4]. The first poly(ADP-ribose) polymerase (PARP)-inhibitor (PARPi) received the approval from the European Medicines Agency (EMA) in 2014 for use as a maintenance therapy in relapsed high-grade serous ovarian cancer (HGSOC) patients with platinum-sensitivity and with BRCA1/BRCA2 somatic or germline variants [7,8]. The mechanism underlying the efficacy of PARPi is synthetic lethality, which occurs in cells with deficiency in homologous recombination (HR) repair, where
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