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Abe, A.;  Imoto, I.;  Ueki, A.;  Nomura, H.;  Kanao, H. Moderate-Risk Genes for Hereditary Ovarian Cancers. Encyclopedia. Available online: https://encyclopedia.pub/entry/36654 (accessed on 20 April 2024).
Abe A,  Imoto I,  Ueki A,  Nomura H,  Kanao H. Moderate-Risk Genes for Hereditary Ovarian Cancers. Encyclopedia. Available at: https://encyclopedia.pub/entry/36654. Accessed April 20, 2024.
Abe, Akiko, Issei Imoto, Arisa Ueki, Hidetaka Nomura, Hiroyuki Kanao. "Moderate-Risk Genes for Hereditary Ovarian Cancers" Encyclopedia, https://encyclopedia.pub/entry/36654 (accessed April 20, 2024).
Abe, A.,  Imoto, I.,  Ueki, A.,  Nomura, H., & Kanao, H. (2022, November 26). Moderate-Risk Genes for Hereditary Ovarian Cancers. In Encyclopedia. https://encyclopedia.pub/entry/36654
Abe, Akiko, et al. "Moderate-Risk Genes for Hereditary Ovarian Cancers." Encyclopedia. Web. 26 November, 2022.
Moderate-Risk Genes for Hereditary Ovarian Cancers
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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. 

epithelial ovarian cancer germline pathogenic variant hereditary tumor

1. ATM (Ataxia–Telangiectasia Mutated) Gene

1.1. Molecular Function in the Response to DSBs

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 [1]. 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 [2] (Figure 1b). 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 [3][4]. ATM GPV heterozygous carriers have an increased risk for several types of cancers, including breast, ovarian, and pancreatic cancers [5][6]. 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 [3][6][7].

1.2. Prevalence and Risk of Developing EOC

A recent meta-analysis [8] 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% [7][9]. The absolute lifetime risk of EOC estimated by the NCCN clinical practice guidelines in oncology is <3% [5][10].
Table 1. Frequency of germline pathogenic variants in patients with epithelial ovarian cancers (EOC), relative and absolute risks for EOC, and risk reduction for EOC in each predisposition gene.
Gene Suszynska et al. [8] NCCN Guidelines [5][11]
Frequency of GPV in EOC Patients (%) Relative Risk for EOC Absolute Risk for EOC Evidence for Association Management for Risk Reduction
OR (95% CI) p-Value
BRCA1 8.607 35.26
(29.56–42.05)
<0.0001 39–58% very strong RRSO recommended for patients aged 35–40 yrs
BRCA2 4.520 11.91
(9.87–14.39)
<0.0001 13–29% very strong RRSO recommended for patients aged 40–45 yrs
BRIP1 1.057 4.88
(3.73–6.38)
<0.0001 >10% strong RRSO considered for patients aged 45–50 yrs
CHEK2 0.703 0.43
(0.29–0.63)
<0.0001 not established not established not established
ATM 0.677 1.98
(1.33–2.94)
0.001 <3% insufficient manage based on family history
RAD51C 0.554 4.24
(2.56–7.02)
<0.0001 >10% strong RRSO considered for patients aged 45–50 yrs
RAD51D 0.583 7.28
(4.03–13.14)
<0.0001 >10% strong RRSO considered for patients aged 45–50 yrs
MSH6 0.444 4.08
(2.43–6.85)
<0.0001 <13% insufficient, mixed -
PALB2 0.423 2.13
(1.42–3.21)
0.0003 3–5% insufficient manage based on family history
TP53 0.294 5.05
(2.41–10.58)
<0.0001 not established not established not established
NBN 0.284 2.17
(1.35–3.49)
0.0020 insufficient data limited manage based on family history
MSH2 0.238 3.98
(1.18–8.69)
0.0007 >10% strong RRSO should be individualized after childbearing
PMS2 0.183 0.71
(0.29–1.72)
0.5633 <3% limited -
MLH1 0.104 1.44
(0.53–3.91)
0.6815 >10% strong RRSO should be individualized after childbearing
BARD1 0.142 1.41
(0.69–2.89)
0.4706 not established not established not established
PTEN 0.063 5.47
(1.26–23.82)
0.0799 not established not established not established
CI, confidence interval; EOC, epithelial ovarian cancer; GPV, germline pathogenic variant; OR, odds ratio; RRSO, risk-reducing salpingo-oophorectomy; yrs, years. Genes in boldface indicate those described in this research.

1.3. Medical Management for the Prevention of EOC

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 [5]. Therefore, RRSO should be considered according to the family history of the patient (Table 1) [5]. The detection of heterozygous ATM GPVs should not lead to a recommendation to avoid radiation therapy at this time [5]. 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 [5].

2. BRIP1 (BRCA1 Interacting Helicase 1) Gene

2.1. Molecular Function in the Response to DSBs

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 1b). 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 [12].

2.2. Prevalence and Risk of Developing EOC

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) [8][13]. In a recent meta-analysis [5], 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% [9][14]. 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) [15]. The NCCN clinical practice guidelines in oncology estimate that the absolute lifetime risk of EOC for individuals with BRIP1 GPVs is >10% [5].

2.3. Medical Management for the Prevention of EOC

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 [5][8][16] (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 [16]. 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) [17], the NCCN clinical practice guidelines in oncology recommend counseling BRIP1 GPV carriers about the risk of autosomal recessive conditions in their offspring [5].

3. NBN (Nibrin) Gene

3.1. Molecular Function in the Response to DSBs

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 1a) [18]. 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 [19]. 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 [20]. NBN can also recruit MRE11 and RAD50 to the proximity of DSBs via its interaction with the histone H2AX [21]. NBN also functions in telomere length maintenance by generating the 3′ overhang which serves as a primer for telomerase-dependent telomere elongation [22].
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 [23].

3.2. Prevalence and Risk of Developing EOC

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 [5][24]. In a recent meta-analysis [8], 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% [14]. 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 [5].

3.3. Medical Management for the Prevention of EOC

According to the NCCN clinical practice guidelines in oncology, there is currently insufficient evidence to recommend RRSO in NBN GPV carriers at this time [5]. Medical management for EOC risk should be considered based on family history [5]. 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 [5].

4. PALB2 (Partner and Localizer of BRCA2) Gene

4.1. Molecular Function in the Response to DSBs

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 1b) [25][26].

4.2. Prevalence and Risk of Developing EOC

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 [5]. 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) [8]. 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% [9][14].
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 [27]. This research 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 [5].

4.3. Medical Management for the Prevention of EOC

Although ACMG guidance showed that PALB2 GPV carriers had a small to moderate risk for EOC [28], 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) [5]. 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 [5].

5. RAD51C/RAD51D Gene

5.1. Molecular Function in the Response to DSBs

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) [29]. 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.

5.2. Prevalence and Risk of Developing EOC

A recent meta-analysis [8] 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 [9]. 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) [30].
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 [31]. 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% [5].

5.3. Medical Management for the Prevention of EOC

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 [5][16]. 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 [16]. 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 [5].
RAD51C- [32] and RAD51D-deficient [33] cells, or those expressing pathogenic variants in these genes [33][34], have been shown to render sensitivity to PARP inhibitors, such as olaparib, which is the first PARP inhibitor to be approved for EOC treatment [35][36][37][38][39]. 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 [40].

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