Moderate-Risk Genes for Hereditary Ovarian Cancers Involved in the Homologous Recombination Repair Pathway

Abstract

Approximately 20% of cases of epithelial ovarian cancer (EOC) are hereditary, sharing many causative genes with breast cancer. The lower frequency of EOC compared to breast cancer makes it challenging to estimate absolute or relative risk and verify the efficacy of risk-reducing surgery in individuals harboring germline pathogenic variants (GPV) in EOC predisposition genes, particularly those with relatively low penetrance. Here, we review the molecular features and hereditary tumor risk associated with several moderate-penetrance genes in EOC that are involved in the homologous recombination repair pathway, i.e., ATM, BRIP1, NBN, PALB2, and RAD51C/D. Understanding the molecular mechanisms underlying the expression and function of these genes may elucidate trends in the development and progression of hereditary tumors, including EOC. A fundamental understanding of the genes driving EOC can help us accurately estimate the genetic risk of developing EOC and select appropriate prevention and treatment strategies for hereditary EOC. Therefore, we summarize the functions of the candidate predisposition genes for EOC and discuss the clinical management of individuals carrying GPV in these genes.

Keywords: epithelial ovarian cancer; germline pathogenic variant; hereditary tumor; homologous recombination repair pathway; moderate risk.

Figure 1

Schematic of DNA double-strand break (DSB) repair by homologous recombination (HR) and key molecules: MRE-RAD50-NBN (MRN) protein complex, ATM, BARD, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, and RAD51C/D. The free DNA ends produced by DSBs are recognized by the MRN protein complex (a). The MRN protein complex recruits and activates ATM, which in turn phosphorylates and activates many downstream targets essential for DNA damage repair via nonhomologous end-joining (NHEJ) and HR (b,c). The replication protein A (RPA) is recruited by the BRCA1–PALB2–BRCA2 effector complex and is loaded on a long 3′ single-stranded DNA (ssDNA) tail to form RAD51–ssDNA nucleofilament. BRCA2 mediates displacement of RPA with RAD51. PALB2-BRCA2 enhances D-loop formation, which is followed by HR repair. The RAD51 paralogs associated in protein complexes (RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2) and RAD51C-XRCC3 (CX3)) participate in the assembly and stabilization of the ssDNA/RAD51 filament and the HR intermediates as well as in the steps downstream of the homology search (not represented) [56].

Figure 2

In normal cells which are proficient in homologous recombination (HRP), both base excision repair (BER) and HR are available for the repair of damaged DNA via poly (ADP-ribose) polymerase (PARP) and proteins encoded by HR deficiency (HRD)-related genes, respectively (a). In cells with HRD, HR is nonfunctional and leads to carcinogenesis (b). When PARP is inhibited by PARP inhibitor, cancer cells with HRD are unable to repair DNA damage by HR and BER, resulting in cell death (synthetic lethality) (c).