Tumor Testing for Somatic and Germline BRCA1/BRCA2 Variants in Ovarian Cancer Patients in the Context of Strong Founder Effects.

Ana Peixoto,Deolinda Pereira,Pedro Pinto,Almerinda Petiz,Carla Pinto,Catarina Santos,Miguel Henriques Abreu,Joana Guerra,Carla Escudeiro,Rui Santos,Manuela Pinheiro,Alfredo Gouveia,João Silva,Rita Canário,Ana Barbosa,Carla Bartosch,Manuel R Teixeira,Susana Sousa

doi:10.3389/fonc.2020.01318

Abstract

Deleterious variants in the BRCA1/BRCA2 genes and homologous recombination deficiency (HRD) status are considered strong predictors of response to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). The introduction of PARPi in clinical practice for the treatment of patients with advanced ovarian cancer imposed changes in the molecular diagnosis of BRCA1/BRCA2 variants. BRCA1/BRCA2 tumor testing by next-generation sequencing (NGS) can detect simultaneously both somatic and germline variants, allowing the identification of more patients with higher likelihood of benefiting from PARPi. Our main goal was to determine the frequency of somatic and germline BRCA1/BRCA2 variants in a series of non-mucinous OC, and to define the best strategy to be implemented in a routine diagnostic setting for the screening of germline/somatic variants in these genes, including the BRCA2 c.156_157insAlu Portuguese founder variant. We observed a frequency of 19.3% of deleterious variants, 13.3% germline, and 5.9% somatic. A higher prevalence of pathogenic variants was observed in patients diagnosed with high-grade serous ovarian cancer (23.2%). Considering the frequencies of the c.3331_3334del and the c.2037delinsCC BRCA1 variants observed in this study (73% of all BRCA1 pathogenic germline variants identified) and the limitations of NGS to detect the BRCA2 c.156_157insAlu variant, it might be cost-effective to test for these founder variants with a specific test prior to tumor screening of the entire coding regions of BRCA1 and BRCA2 by NGS in patients of Portuguese ancestry.

Highlights

Pathogenic germline variants in the breast cancer susceptibility genes BRCA1 and BRCA2 increase the risk for the development of ovarian cancer (OC) in carriers
PARPi blocks the base excision repair (BER) pathway, which is involved in the repair of DNA singlestrand breaks, leading to the formation of DSBs that cannot be accurately repaired in homologous recombination (HR)-deficient cells and to cell death. [4, 6]
It became important to evaluate whether a tumor-testing-first strategy would be the most costeffective option, allowing for the simultaneous detection of both germline and somatic BRCA1/BRCA2 variants

Summary

Introduction

Pathogenic germline variants in the breast cancer susceptibility genes BRCA1 and BRCA2 increase the risk for the development of ovarian cancer (OC) in carriers. The PARPi olaparib (Lynparza) was the first-in-class agent to gain approval for treatment in OC by the European Medicines Agency (EMA) for use as maintenance therapy of patients with platinumsensitive relapsed, BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer and by the U.S Food and Drug Administration (FDA) as monotherapy for patients with germline BRCA mutations, who have received three or more prior lines of chemotherapy [8]. The regulatory approvals of FDA and EMA differed, as the latter considered HGSOC patients with somatic BRCA1/BRCA2 mutations as eligible for PARPi therapy. Since BRCA1/BRCA2 tumor testing can detect simultaneously both somatic and germline variants, with the exception of some variants like rearrangements, a higher number of patients who may benefit from PARPi can be identified at a faster turnaround time and at a lower cost [9]

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