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

Previous research has reported many EOC-associated genes. In a recent meta-analysis, Suszynska et al. [ 45 ] reported 11 cancer predisposition genes, including BRCA1 and BRCA2 , that were significantly associated with the development of EOC. Through a large-scale association analysis, they compared the frequencies of GPVs in a group of approximately 120,000 controls derived from the population-based noncancer Genome Aggregation Database (gnomAD) [ 45 ]. These statistically significant EOC-associated genes include ATM , BRIP1 , BRCA1 , BRCA2 , MSH2 , MSH6 , NBN , PALB2 , RAD51C , RAD51D , and TP53 . Liu et al. [ 30 ] also identified ATM , BRIP1 , BRCA1 , BRCA2 , MLH1 , MSH2 , MSH6 , PALB2 , RAD51C , and RAD51D as EOC-associated genes that exhibited a risk beyond that of the general population risk for EOC. By combining these lists with the clinical practice guidelines in oncology of the National Comprehensive Cancer Network (NCCN) [ 46 , 47 ], we selected ATM , BRIP1 , BRCA1 , BRCA2 , NBN , PALB2 , RAD51C , and RAD51D as key EOC-associated genes involved in the HR repair pathway ( Figure 1 ). Among these genes, we focused on the following six: ATM , BRIP1 , NBN , PALB2 , RAD51C , and RAD51D . This is because, unlike BRCA1/2 , there is still substantial debate as to whether the degree of risk of EOC in individuals with GPVs in these genes is sufficiently higher than that in the general population to warrant consideration of RRSO [ 30 ]. The unreliability of risk estimates for these genes is primarily attributed to the following factors: the GPV prevalence of candidate genes is generally low; individual ovarian cancer studies typically involve fewer cases than breast cancer studies; and most previous analyses lack a comparable control group, which hinders the interpretation of results [ 48 , 49 ]. The process by which the genome repairs DNA damage from external or internal sources is essential for preventing cell death. One of the most serious DNA alterations can be caused by DSBs, which are lethal to cells if left unchecked [ 50 ]. DSBs describe disruptions in both reading frames of the DNA and are often caused by external sources such as ionizing radiation [ 51 ]. Two main mechanisms enable cells to repair DSBs: nonhomologous end-joining (NHEJ) and HR [ 52 ] ( Figure 1 ). In response to DSBs induced by genotoxic agents in the S/G2 phase, either side of the DNA is lysed from 5′ to 3′ by MRE11. The MRE-RAD50-NBN complex (MRN) is recruited to DSBs and promotes ATM recruitment ( Figure 1 a). NHEJ causes binding proteins to attach to the open ends of DNA to stabilize and ultimately reconnect the sides of the DNA but does not consider the reading frame, which introduces errors into the DNA [ 53 , 54 ]. ATM phosphorylates and activates many downstream targets that are essential for DNA damage repair via NHEJ and HR ( Figure 1 b,c). ATM activates other kinases, such as CHEK2, and ultimately phosphorylates multiple proteins that regulate the cell cycle, resulting in cell cycle arrest. This prevents cells from dividing with residual DNA damage, passing DNA damage to daughter cells, and causing chromosomal aberrations. When the amount of DNA damage is large and exceeds the repair capacity of the cell, p53 protein and other proteins are activated to induce cell death or apoptosis. Active ATM creates a platform to recruit BRCA1, which facilitates a shift from NHEJ to HR ( Figure 1 b). While this occurs, HR repairs the unaltered reading frame. CtBP-interacting protein, in conjunction with the MRN complex, catalyzes 5′-3′ resection at DSBs to generate single-stranded DNA (ssDNA). From the open ends, a single-strand 3′ opening is created, which allows a series of proteins (e.g., RAD51/BRCA2) to begin searching for a compatible sequence with which to invade and create a D-loop. This process allows both sides to faithfully reconstruct the reading frame [ 23 ] ( Figure 1 c). BRCA1/2 each play multiple, unique roles in HR repair. For example, BRCA1 is thought to be part of a larger complex molecule that helps to survey DNA for DSB damage [ 16 ]. The role of BRCA2 is less clear, but it may play a more direct role in repair by helping the RAD51 complex attach to the repair site. Both BRCA1 and BRCA2 play important roles in a large framework of repair molecules. RAD51 is recruited by the BRCA1–PALB2–BRCA2 effector complex, resulting in their promotion of RPA removal and RAD51 loading [ 55 ]. The resulting RAD51-ssDNA filament invades the intact sister chromatid and extends the strand ( Figure 1 c), which is followed by further restoration and ligation of double strands. The multifunctional enzyme Poly ADP ribose polymerase (PARP) plays an important role in DNA damage repair and genome stability. Among the 18 members of the PARP family, PARP-1 is the most important and plays dominant roles in DNA repair pathways. Activated PARP-1 plays an important role in DNA base excision repair (BER) [ 57 ]. When PARP-1 fails to function, oxidized bases accumulate. The replication fork stops at the site of the damaged DNA, eventually resulting in DSBs. In normal cells which are proficient at HR (HR proficiency, HPR), both BER and HR are available for the repair of damaged DNA ( Figure 2 a). Meanwhile, in cells with HR deficiency (HRD), HR is nonfunctional and leads to carcinogenesis ( Figure 2 b). When PARP-1 is inhibited by PARP inhibitor, cancer cells with HRD are unable to repair DNA damage by HR and BER, leading to cell death (synthetic lethality, Figure 2 c). PARP-1 is also involved in the regulation of nucleotide excision repair (NER), classical NHEJ (cNHEJ), alternative NHEJ (aNHEJ), microhomology-mediated end-joining (MMEJ), HR, MMR, and maintenance of replication fork stability [ 58 ]. For example, PARP-1 recruits DSB repair enzymes MRE11 and NBS1 for modulating DSB repair [ 59 ]. PARP inhibitors are the first clinically approved anti-cancer agents which specifically targeted the DNA damage response in BRCA1/2 -mutated cancers [ 60 ]. In advanced-stage EOC patients with the BRCA1/2 GPVs, maintenance therapy with a PARP inhibitor (olaparib) resulted in a 70% lower risk of disease progression or death (SOLO1 clinical trial) [ 55 ]. The phase III OlympiAD trial showed that olaparib had better efficacy than standard chemotherapy for HER2-negative breast cancer patients with the BRCA1/2 GPVs [ 61 ]. Their indication has been gradually extended to prostate and pancreatic cancer patients with BRCA1/2 GPVs [ 56 ]. More recently, the effect of PARP inhibitors was also validated in HR-deficient cancers without BRCA 1/2 GPVs, suggesting widespread use of PARP inhibitors for cancers caused by GPVs in other HR pathway genes [ 62 , 63 ].

The ATM gene encodes a protein kinase with pleiotropic functions belonging to the superfamily of phosphatidylinositol 3-kinase-related protein kinases at the peak of a cascade responding to DSBs [ 64 ]. In DSB repair, the HR repair pathway is largely restricted to the S and G2 phases of the cell cycle, when an intact sister chromatid is available as a template, whereas NHEJ can be active in any cell cycle [ 65 ] ( Figure 1 b). ATM, which is recruited and activated by the MRN protein complex that recognizes the free DNA ends of DSBs, phosphorylates many important proteins, e.g., BRCA1, p53, AKT, and CHEK2 proteins, thereby mediating the DNA damage response, promoting cell cycle arrest, or inducing apoptosis. In addition to playing a key role in HR, ATM also orchestrates DSB repair by preventing the toxic error-prone NHEJ pathway [ 66 , 67 ]. ATM GPV heterozygous carriers have an increased risk for several types of cancers, including breast, ovarian, and pancreatic cancers [ 46 , 68 ]. However, the carriers of biallelic ATM GPVs are affected by ataxia–telangiectasia (AT, OMIM #208900), which is a rare autosomal recessive syndrome characterized by progressive cerebellar ataxia, cutaneous telangiectasias, increased risk of developing hematologic and solid tumors, and immunodeficiency [ 66 , 68 , 69 ]. A recent meta-analysis [ 45 ] reported the prevalence of ATM GPVs in patients with EOC to be 0.6767% (26/3842 cases) and showed a significant association between ATM GPVs and EOC (odds ratio (OR) = 1.977, 95% confidence interval (CI) = 1.330–2.939) ( Table 1 ). Another population-based cohort study reported that the prevalence of ATM GPVs was 0.57–0.64% [ 18 , 69 ]. The absolute lifetime risk of EOC estimated by the NCCN clinical practice guidelines in oncology is <3% [ 26 , 46 ]. For heterozygote ATM GPV carriers, there is insufficient evidence available to recommend RRSO, although a large EOC study reported strong evidence for an approximately two-fold increased risk of developing EOC compared with noncarriers [ 46 ]. Therefore, RRSO should be considered according to the family history of the patient ( Table 1 ) [ 46 ]. The detection of heterozygous ATM GPVs should not lead to a recommendation to avoid radiation therapy at this time [ 46 ]. Furthermore, the NCCN clinical practice guidelines in oncology recommend counseling for ATM GPV carriers because of the risk of autosomal recessive inheritance in their offspring [ 46 ].

The protein encoded by BRIP1 is a member of the RecQ DEAH helicase family and part of the Fanconi anemia group. The BRIP1 protein interacts with the BRCT repeats at the carboxyl-terminus of BRCA1 ( Figure 1 b). The bound complex is important for normal DSB repair by HR. BRIP1 is also physiologically essential for maintaining genomic integrity, removing proteins bound to DNA, stabilizing replication forks, and unwinding substitutive DNA structures along with RPA [ 70 ]. GPVs in BRIP1 are the second most common pathogenic variant found in patients with EOC after those in BRCA1/2 , with a frequency of approximately 1% of EOC cases ( Table 1 ) [ 17 , 45 ]. In a recent meta-analysis [ 46 ], BRIP1 GPVs were significantly associated with EOC (OR = 4.878, 95% CI = 3.729–6.380). Another population-based cohort study reported that the prevalence of BRIP1 GPVs was 0.92–1.36% [ 18 , 71 ]. A larger meta-analysis using approximately 29,400 EOC cases from 63 studies and approximately 116,000 controls from the gnomAD database reported that the prevalence of BRIP1 GPVs in patients with EOC was 0.8891% (200/22,494 cases) and that BRIP1 was significantly associated with EOC (OR = 4.94, 95%CI = 4.07–6.00) [ 49 ]. The NCCN clinical practice guidelines in oncology estimate that the absolute lifetime risk of EOC for individuals with BRIP1 GPVs is >10% [ 46 ]. For BRIP1 GPV carriers, the NCCN clinical practice guidelines in oncology recommend that RRSO should be considered from age 45 to 50 years or earlier based on a specific family history of early-onset EOC [ 45 , 46 , 72 ] ( Table 1 ). Although the lifetime risk of EOC in BRIP1 GPV carriers seems to be sufficient to justify considering RRSO, there is currently no evidence to make a firm recommendation on the optimal age for this procedure. Reportedly, the median age at diagnosis for BRIP1 GPV carriers with EOC is 65 years old [ 72 ]. Moreover, the age at which to begin consultation for surgery may change as more evidence is collected. Furthermore, because BRIP1 was originally identified in research on Fanconi anemia (FANCJ; OMIM #609054) [ 73 ], the NCCN clinical practice guidelines in oncology recommend counseling BRIP1 GPV carriers about the risk of autosomal recessive conditions in their offspring [ 46 ].

NBN encodes the protein NBN or nibrin, one of the components of the MRN protein complex, which is essential for DSB repair, DNA recombination, maintenance of telomere integrity, cell cycle checkpoint regulation, and meiosis ( Figure 1 a) [ 74 ]. The MRN protein complex is composed of two heterodimers of RAD50 and MRE11, as well as a single NBN, and possesses single-strand endonuclease activity and double-strand-specific 3′-5′ exonuclease activity provided by MRE11. In DSB repair, RAD50 is required to bind DNA ends and hold them in close proximity [ 75 ]. NBN modulates DNA damage signal sensing by recruiting ATM, ATR, and DNA-dependent protein kinase catalytic subunits to the sites of DNA damage and activating their functions [ 76 ]. NBN can also recruit MRE11 and RAD50 to the proximity of DSBs via its interaction with the histone H2AX [ 77 ]. NBN also functions in telomere length maintenance by generating the 3′ overhang which serves as a primer for telomerase-dependent telomere elongation [ 78 ]. GPVs at the homozygous or compound heterozygous status within NBN are responsible for Nijmegen breakage syndrome (NBS; OMIM #251260), a rare autosomal recessive disorder characterized by microcephaly, growth retardation, humoral and cellular immunodeficiency, radiosensitivity, and cancer predisposition. By the age of 20 years, more than 40% of patients with NBS develop a malignant disease, primarily of lymphoid origin [ 79 ]. As NBN has an essential function in the DNA repair pathway, several case–control studies have investigated its status as an EOC susceptibility gene. However, most studies have provided insufficient evidence of a significant association with the risk of developing EOC [ 42 , 46 ]. In a recent meta-analysis [ 45 ], the reported prevalence of NBN GPVs in patients with EOC was 0.2837% (20/7050 EOC cases), and NBN GPVs were significantly associated with EOC (OR = 2.166, 95% CI = 1.346–3.488) ( Table 1 ). Another population-based cohort study including 6,001 patients with EOC reported a prevalence of NBN GPVs of 0.35% [ 71 ]. According to the NCCN clinical practice guidelines in oncology, the absolute lifetime risk of EOC in NBN GPV carriers is relatively low (<3%); however, the evidence strength is limited, and insufficient data are available [ 46 ]. According to the NCCN clinical practice guidelines in oncology, there is currently insufficient evidence to recommend RRSO in NBN GPV carriers at this time [ 46 ]. Medical management for EOC risk should be considered based on family history [ 46 ]. Because the NBN gene is associated with the development of NBS, the NCCN clinical practice guidelines in oncology recommend counseling NBN GPV carriers about the risk of autosomal recessive conditions in their offspring [ 46 ].

PALB2 was originally identified as the gene encoding protein immunoprecipitated with the BRCA2 protein. PALB2 colocalizes with BRCA2 in nuclear foci; promotes the stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated degradation; and enables the HR repair of DSBs and the maintenance of G2/M checkpoint functions ( Figure 1 b) [ 80 , 81 ]. Although the previous NCCN clinical practice guidelines in oncology described “ovarian cancer risk and management” for PALB2 GPVs as insufficient evidence (ver1.2022), the latest version (ver2.2022) has been updated to state that the evidence is strong [ 46 ]. A recent meta-analysis reported that the prevalence of PALB2 GPVs in patients with EOC was 0.4226% (30/7099 EOC cases), and that PALB2 GPVs were significantly associated with EOC (OR = 2.134, 95% CI = 1.420–3.207) ( Table 1 ) [ 45 ]. However, the relationship between PALB2 GPVs and EOC susceptibility is debated and exhibits low statistical significance. Another population-based cohort study reported that the prevalence of PALB2 GPVs was 0.40–0.62% [ 18 , 71 ]. A recent international study of 524 families with PALB2 GPVs estimated the relative and cumulative risks using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family [ 82 ]. This study demonstrated that the estimated risk of female PALB2 GPV carriers developing EOC by the age of 80 was 5%. Based on this result, the NCCN clinical practice guidelines in oncology estimate an absolute lifetime risk of EOC in heterozygote PALB2 GPV carriers of 3–5%, with strong evidence [ 46 ]. Although ACMG guidance showed that PALB2 GPV carriers had a small to moderate risk for EOC [ 83 ], the clinical benefit of RRSO was not sufficiently proven to reduce morbidity and mortality. For all PALB2 GPV carriers, there is insufficient evidence available to recommend RRSO. Therefore, RRSO should be considered based on family history for EOC ( Table 1 ) [ 46 ]. As PALB2 is a Fanconi anemia gene (FANCN; OMIM #610832), the NCCN clinical practice guidelines in oncology recommend counseling PALB2 GPV carriers about the risk of autosomal recessive conditions in their offspring [ 46 ].

RAD51C and RAD51D encode the RAD51 paralog proteins, RAD51C and RAD51D, which are structurally similar to the RAD51 recombinase. The Rad51 paralogs associate with one another in two distinct complexes: RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2) and RAD51C-XRCC3 (CX3) [ 56 ]. The RAD51 paralogs participate in the assembly and stabilization of the ssDNA/RAD51 filament and the HR intermediates. They are also involved in the process downstream of the homology search. A recent meta-analysis [ 45 ] reported that the prevalence of RAD51C and RAD51D GPVs in patients with EOC was 0.5539% (21/3791 EOC cases) and 0.5832 (19/3258 EOC cases), respectively, and that RAD51C and RAD51D were significantly associated with EOC (OR = 4.241, 95% CI = 2.562–7.022, and OR = 7.276, 95% CI = 4.028–13.140, respectively) ( Table 1 ). Another population-based cohort study reported that the prevalence of RAD51C and RAD51D GPVs was 0.57% and 0.57%, respectively [ 18 ]. In a larger meta-analysis using 29,400 EOC cases and 116,000 controls from the noncancer gnomAD database, the prevalence of RAD51C and RAD51D GPVs with EOC was 0.6260% (149/23,802 cases) and 0.4125% (94/22,787 cases), respectively, and RAD51C and RAD51D were significantly associated with EOC (OR = 5.59, 95%CI = 4.42–7.07 and OR = 6.94, 95%CI = 5.10–9.44, respectively) [ 48 ]. A recent study including 6,178 and 6,690 families with known RAD51C and RAD51D GPVs, respectively, estimated the relative and cumulative risks using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family [ 84 ]. According to the results of this relatively large case–control study, the cumulative risk of developing EOC by the age of 80 years was 11% and 13% for RAD51C and RAD51D GPV carriers, respectively. Thus, the NCCN clinical practice guidelines in oncology estimate the absolute lifetime risk of EOC in heterozygote RAD51C/RAD51D GPV carriers as >10% [ 46 ]. For RAD51C/RAD51D GPV carriers, the NCCN clinical practice guidelines in oncology recommend considering RRSO from age 45 to 50 years or earlier based on a specific family history of early-onset EOC [ 46 , 72 ]. Although the lifetime risk of EOC in RAD51C/RAD51D GPV carriers seems to be sufficient to justify considering RRSO, there is insufficient evidence to make a firm recommendation regarding the optimal age for this procedure. Reportedly, the median age at diagnosis for RAD51C/RAD51D GPV carriers with EOC is 62 and 57 years old [ 72 ]. Therefore, the age at which to begin consultation for surgery may change as more evidence is accumulated. As RAD51C is a Fanconi anemia gene (FANCO; OMIM # 613390), the NCCN clinical practice guidelines in oncology recommend counseling RAD51C GPV carriers about the risk of autosomal recessive conditions in their offspring [ 46 ]. RAD51C - [ 85 ] and RAD51D -deficient [ 86 ] cells, or those expressing pathogenic variants in these genes [ 86 , 87 ], have been shown to render sensitivity to PARP inhibitors, such as olaparib, which is the first PARP inhibitor to be approved for EOC treatment [ 62 , 63 , 88 , 89 , 90 ]. However, it remains unclear whether identifying RAD51C/RAD51D GPVs in patients with EOC is useful for identifying patients that might benefit from treatment with protocols using PARP inhibitors [ 50 ].

In 2020, ovarian cancer ranked as the eighth most common cancer in women, with an estimate of almost 320,000 new cases worldwide [ 1 ]. More than 70% of cases are diagnosed at advanced stages [ 2 , 3 ], partly because of the delayed onset of disease-specific symptoms and the absence of effective screening tools, which result in high mortality rates despite initial treatment [ 4 ]. Approximately 90% of ovarian cancers are epithelial ovarian cancers (EOCs), which can be further classified into five major histological subtypes with different risk factors and molecular characteristics: high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous carcinomas [ 5 , 6 ]. Although the pathogenesis of EOC is not well characterized, several risk factors for developing EOC have been identified, including both acquired environmental and genetic factors. Environmental factors include older age, early menarche or late menopause, smoking, and being overweight or obese [ 6 , 7 , 8 ]. Moreover, the widespread use of oral contraceptive pills, other reproductive factors such as higher parity (more children), and breastfeeding have been reported as protective factors against EOC [ 6 , 8 , 9 ]. Chronic inflammation can directly cause DNA damage related to cancer initiation and progression [ 10 , 11 ]. Thus, proinflammatory conditions such as pelvic inflammatory disease [ 12 , 13 , 14 ] and endometriosis [ 15 , 16 ] are also associated with a risk of developing EOC. Furthermore, up to 20% of EOC cases, particularly high-grade serous carcinomas, may be caused by germline pathogenic variants (GPVs) in various cancer predisposition genes [ 17 , 18 ]. A smaller proportion of other ovarian cancer subtypes are also likely to be related to GPVs in EOC predisposition genes. Some research suggests that oxidative stress during the menstrual cycle may play a role in ovarian tumorigenesis [ 19 ]. Moreover, the regulation of hormones, especially estrogen, appears to increase double-strand breaks (DSBs), which may explain tissue specificity [ 20 , 21 , 22 ]. The known EOC predisposition genes predominantly belong to two different DNA repair pathways [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Most EOC predisposition genes, including BRCA1 and BRCA2 , are involved in part of the homologous recombination (HR) repair pathway, which governs the error-free DNA repair mechanism. Conversely, the mismatch repair (MMR) genes, such as MLH1 , MSH2 , MSH6 , and PMS 2 , are involved in the MMR pathway, which handles erroneous misincorporations, insertions, and deletions of nucleotides. GPVs in genes encoding proteins important for the HR repair pathway increase the risk of high-grade serous carcinoma, whereas GPVs in MMR genes increase the risk of endometriosis-associated EOC, such as endometrioid and clear cell carcinomas [ 26 , 30 ]. In addition, a number of common variants associated with EOC susceptibility have been identified by genome-wide association studies [ 31 , 32 ]. Thus, the ability to accurately estimate ovarian cancer risk using genetic information from the patient may have crucial implications for EOC management in individuals. Several screening tools have been proposed for EOC, such as serial transvaginal ultrasound and serum cancer antigen 125 (CA-125); however, there are no effective secondary prevention strategies for reducing mortality in EOC [ 3 ]. Therefore, the only strategy shown to reduce EOC mortality in women with a high risk of developing EOC is primary prevention, such as risk-reducing salpingo-oophorectomy (RRSO) and chemoprevention. For example, in BRCA1 - and BRCA2 -associated hereditary breast and ovarian cancer syndromes (HBOC), RRSO decreases the incidence of EOC and reduces mortality [ 32 , 33 , 34 , 35 ], whereas the potential benefits and dangers of oral contraceptive pills, a type of chemoprophylaxis for EOC, remain unclear [ 36 ]. In contrast to the high-penetrance BRCA1 or BRCA2 ( BRCA1/2 ) gene, there is still substantial controversy regarding the degree of conferred risks for EOC in individuals with other EOC predisposition genes and whether those risks are sufficiently elevated above the general population to warrant consideration of RRSO [ 37 , 38 ]. Additionally, RRSO has potential negative aspects with regard to women’s health, such as cardiovascular events and osteoporosis. Even though RRSO prevents EOC, there is concern that cardiovascular events caused by RRSO-induced ovarian dysfunction may worsen life expectancy and reduce the quality of life due to menopausal symptoms. For this reason, several clinical trials are currently being conducted to demonstrate the risk-reducing effects of prior risk-reducing salpingectomy (RRS) [ 38 , 39 , 40 , 41 ]. Because most EOC-associated genes are involved in one of two DNA repair pathways [ 42 ], a fundamental understanding of disease drivers in these pathways will allow us to accurately estimate the genetic risk of developing EOC and select appropriate prevention and treatment strategies for hereditary EOC. Syndromic diseases such as Lynch syndrome, Li–Fraumeni syndrome, Cowden syndrome/PTEN hamartoma tumor syndrome (PHTS), Peutz–Jeghers syndrome, DICER1 syndrome, and rhabdoid tumor predisposition syndrome—which are caused by GPVs in MMR genes, TP53 , PTEN , STK11 , DICER1 , and SMARCB1 / SMARCA4 , respectively, and may also predispose to EOC [ 24 , 43 , 44 ]—can be characterized separately as syndromes. In this review, therefore, we mainly focused on candidate EOC predisposition genes involved in the HR repair pathway ( Figure 1 ), summarized their molecular mechanisms of cancer predisposition, and discussed the clinical management of individuals carrying GPVs in each of these genes.

Compared to other cancers, EOC includes a relatively high percentage of hereditary tumors. Approximately 50% of patients with hereditary EOC harbor GPVs in the BRCA1/2 genes contributing to the HR repair pathway. Moreover, other genes participating in the HR repair pathway, such as ATM , BRIP1, NBN , PALB2 , and RAD51C/D , are also known as predisposition genes related to hereditary EOC with moderate penetrance. This review has outlined the current knowledge of these moderate-risk genes for EOC involved in the HR repair pathway. In addition to the molecular functions of these EOC-associated genes, we discussed the recommended clinical strategies for preventing EOC in individuals carrying GPVs in these genes. This review can improve our ability to estimate the genetic risk of developing EOC and select appropriate preventive and treatment strategies for hereditary EOC. However, there are still some issues limiting the effective medical management for EOC based on individual genetic analysis. First, the penetrance of hereditary tumors is not 100%, and the significance of detecting moderate-risk genes for medical management remains unclear [ 91 ]. Second, further data registration is important because the GPV frequency prevalence of each cancer predisposition gene varies among populations. Third, understanding the relationship between genotype and phenotype may be extremely useful in a clinical setting. However, if the results are not properly interpreted and explained, there is a risk of inappropriate treatment. Fourth, along with the education of clinicians, it is crucial to ensure collaboration among clinicians, researchers, and companies that provide genetic testing for providing medical care based on genetic information.