BRCA Mutations and Fertility Preservation

Abstract

Hereditary cancers mostly affect the adolescent and young adult population (AYA) at reproductive age. Mutations in BReast CAncer (BRCA) genes are responsible for the majority of cases of hereditary breast and ovarian cancer. BRCA1 and BRCA2 act as tumor suppressor genes as they are key regulators of DNA repair through homologous recombination. Evidence of the accumulation of DNA double-strand break has been reported in aging oocytes, while BRCA expression decreases, leading to the hypothesis that BRCA mutation may impact fertility. Moreover, patients exposed to anticancer treatments are at higher risk of fertility-related issues, and BRCA mutations could exacerbate the treatment-induced depletion of the ovarian reserve. In this review, we summarized the functions of both genes and reported the current knowledge on the impact of BRCA mutations on ovarian ageing, premature ovarian insufficiency, female fertility preservation strategies and insights about male infertility. Altogether, this review provides relevant up-to-date information on the impact of BRCA1/2 mutations on fertility. Notably, BRCA-mutated patients should be adequately counselled for fertility preservation strategies, considering their higher sensitivity to chemotherapy gonadotoxic effects.

Keywords: BRCA; DNA damage; breast cancer; chemotherapy; fertility preservation; ovarian aging.

Figure 1

BRCA1 and BRCA2 structure. BReast CAncer 1 (BRCA1) is an 1863 amino acids (aa) protein constituted of a Really Interesting New Gene (RING) domain, a serin cluster domain (SCD) and two BRCA1 C-Terminal (BRCT) domains. Its localization is supported by one nuclear export sequence (NES) and two nuclear localization sequences (NLSs). It interacts with BRCA1-associated RING domain protein 1 (BARD1) through its RING finger motifs, RAD50, RAD51, Partner and Localizer of BRCA2 (PALB2) through a coiled coil domain within SCD and various phosphorylated proteins involved in DNA repair by homologous recombination through its BRCT domains. BRCA2 is a 3418 aa protein composed of a Transcriptional Activation Domain (TAD), eight BRC motifs and a DNA binding domain (DBD) composed of one helical domain (HD) and three oligonucleotide-binding folds (OB1-3). Its nuclear localization is supported by three NLSs. Its phosphorylation is supported by various kinases such as cyclin-dependent kinase 1 (CDK1), polo-like kinase 1 (PLK1) and checkpoint kinases 1 and 2 (CHK1/2). BRCA2 mainly binds to PALB2 and RAD51. Pathogenic founder variants are harbored in both genes (185delAG, 5382insC and 6174delT) and more specifically present in breast cancer cluster regions (BCCR) and ovarian cluster regions (OCCR). BRCA2 also harbors a prostate cancer cluster region (PCCR).

Figure 2

DNA repair through homologous recombination. When DNA double strand breaks (DSBs) occur, the MRN complex (MRE11, RAD50 and NBS1) and ataxia-telangiectasia mutated (ATM) are recruited to the DSB site. ATM then phosphorylates (phosphorylation represented by red circles) H2A histone family member X (γ-H2AX). This signal triggers the recruitment of Mediator of DNA damage Checkpoint Protein 1 (MDC1) and its phosphorylation by ATM. H2AX is then ubiquitylated (ubiquitylation represented by blue circles) by E3-ubiquitin ligases, such as RING Finger proteins 8 and 168 (RNF8 and RNF168), and BReast CAncer 1 (BRCA1) and p53-binding protein 1 (53BP1) are recruited to DSB site. Cells in S/G2 phase form BRCA1-C complex [BRCA1, MRN complex and C-terminal binding protein 1 Interacting Protein (CtIP)] that removes 53BP1 from DSB sites and BRCA1-A complex [BRCA1, ABRAXAS (blue), RAP80 (pink)] that maintains the DNA damage response (DDR). In parallel, BRCA1-C complex initiates end resection with its endonuclease and exonuclease activity (represented by red crosses). The resulting single strand DNA is stabilized by Replication Protein A (RPA). End resection is further supported by exonuclease 1 (EXO1) and DNA2, and RPA is replaced by RAD51 due to BReast CAncer 2 (BRCA2) which is recruited to DSB sites by its interaction with BRCA1 and Partner and Localizer of BRCA2 (PALB2). BRCA2 also interacts with DSS1 to facilitate the switch RPA/RAD51. Strand invasion is the last step of HR, resulting in two homologous chromatids.