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. 2020 Sep 30;12(10):2834.
doi: 10.3390/cancers12102834.

Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/ BRCA2

Ana Barbosa  1 , Pedro Pinto  1 , Ana Peixoto  1   2 , Joana Guerra  1 , Carla Pinto  1   2 , Catarina Santos  1   2 , Manuela Pinheiro  1 , Carla Escudeiro  1 , Carla Bartosch  3 , João Silva  1   2 , Manuel R Teixeira  1   2   4
Affiliations

Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/ BRCA2

Ana Barbosa et al. Cancers (Basel). .

Abstract

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.

Keywords: clinically actionable alterations; genetic predisposition; multi-gene panel; next generation sequencing; ovarian cancer; tumor testing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Spectrum of germline variants (pathogenic and variants of uncertain significance (VUS)).
Figure 2
Figure 2
Pedigrees of patients with the RAD51C c.709C>T germline variant: (a) OC16 and (b) OC31. The index patients are indicated by an arrow.
Figure 2
Figure 2
Pedigrees of patients with the RAD51C c.709C>T germline variant: (a) OC16 and (b) OC31. The index patients are indicated by an arrow.
Figure 3
Figure 3
Pedigrees of patients with RAD51D c.748del germline variant. Family of patient OC54 (a) and OC17, OC30, and OC55 (b). The index patient is indicated by an arrow. Plus (+) and minus (−) signals indicate a positive and a negative result for germline genetic testing, respectively.
Figure 4
Figure 4
Pedigree of patient OC24 with the likely pathogenic MSH6 c.3848_3862del germline variant. The index patient is indicated by an arrow.
See this image and copyright information in PMC

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