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Article

Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families

by
Ava Kwong
1,2,3,*,
Cecilia Yuen Sze Ho
4,
Chun Hang Au
4,
Sze Keong Tey
1 and
Edmond Shiu Kwan Ma
2,4
1
Division of Breast Surgery, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China
2
Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong SAR, China
3
Cancer Genetics Centre, Breast Surgery Centre, Surgery Centre, Hong Kong Sanatorium & Hospital, Hong Kong SAR, China
4
Division of Molecular Pathology, Department of Pathology, Hong Kong Sanatorium & Hospital, Hong Kong SAR, China
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2024, 14(8), 866; https://doi.org/10.3390/jpm14080866
Submission received: 9 July 2024 / Revised: 5 August 2024 / Accepted: 14 August 2024 / Published: 16 August 2024
(This article belongs to the Section Omics/Informatics)
Browse Figures
Versions Notes

Abstract

:
Background: RAD51C and RAD51D are crucial in homologous recombination (HR) DNA repair. The prevalence of the RAD51C and RAD51D mutations in breast cancer varies across ethnic groups. Associations of RAD51C and RAD51D germline pathogenic variants (GPVs) with breast and ovarian cancer predisposition have been recently reported and are of interest. Methods: We performed multi-gene panel sequencing to study the prevalence of RAD51C and RAD51D germline mutations among 3728 patients with hereditary breast and/or ovarian cancer (HBOC). Results: We identified 18 pathogenic RAD51C and RAD51D mutation carriers, with a mutation frequency of 0.13% (5/3728) and 0.35% (13/3728), respectively. The most common recurrent mutation was RAD51D c.270_271dupTA; p.(Lys91Ilefs*13), with a mutation frequency of 0.30% (11/3728), which was also commonly identified in Asians. Only four out of six cases (66.7%) of this common mutation tested positive for homologous recombination deficiency (HRD). Conclusions: Taking the family studies in our registry and tumor molecular pathology together, we concluded that this relatively common RAD51D variant showed incomplete penetrance in our local Chinese community. Personalized genetic counseling emphasizing family history for families with this variant, as suggested at the UK Cancer Genetics Group (UKCGG) Consensus meeting, would also be appropriate in Chinese families.

1. Introduction

RAD51 is a RecA-like DNA recombinase known to be a key element in homologous recombination (HR) and DNA repair. Five human RAD51 paralogs have been reported: RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3. Different combinations of these proteins interact to form functional complexes. The BCDX2 complex consists of RAD51B, RAD51C, RAD51D, and XRCC2, while the CX3 dimer is composed of RAD51C and XRCC3 [1,2,3,4,5]. These complexes catalyze homologous pairing between single- and double-stranded DNA and are considered to play a role in the early stages of recombination repair of DNA double-strand breaks [6,7,8]. RAD51D deficiency causes embryonic lethality in mice, revealing that RAD51D is an essential element in development [9]. RAD51C knockout mice were viable and fertile, but these mice exhibited numerous defects in HR [10]. RAD51D also plays a role in protecting telomeres against attrition and chromosome fusion [11]. Chromosomal instability in RAD51D-deficient cells results in aneuploidy, chromosome breakage, translocations, and fusion. RAD51D is also involved in the fidelity of endogenous DNA sequences. RAD51D/HR deficiency promotes chromosome instability by shifting the repair of double-strand breaks (DSBs) toward highly deleterious end-joining processes, leading to the excessive loss of large chromosome segments localized around the DSBs [12].
The BRC repeats of BRCA2 bind to RAD51C and RAD51D. These interactions are important for recruiting RAD51 to sites of DNA damage and support the DNA repair process [13]. RAD51C also interacts with other proteins involved in HR, such as PALB2 and RAD51D [13]. The association of RAD51C and RAD51D GPVs with ovarian cancer susceptibility was first proposed in 2011. Mutation carriers in breast–ovarian cancer families were associated with 3.4- to 15.8- and 6.3- to 12-fold increases in ovarian cancer risk, respectively [14]. A meta-analysis of ~29,400 ovarian cancer patients revealed RAD51D to be one of the highest-risk genes related to ovarian cancers [15]. The estimated risk associated with RAD51C and RAD51D were odd ratios of 5.2 (95% CI, 1.1 to 24) and 12 (95% CI, 1.5–90), respectively [16], and confirmed their strong association with ovarian cancer [17]. The mutation frequencies of RAD51C and RAD51D in unselected ovarian cases ranged from 0.2% to 1.1% and 0.35% to 1.1%, respectively [16,18,19,20].
Several studies have advocated for the correlation between RAD51D GPVs and breast cancer (BC) susceptibility. In 2020, Yang and colleagues emphasized the association of RAD51D GPVs with BCs. The relative risk of developing BC was 1.83 for RAD51D, while the cumulative risk of BC was 20% for RAD51D carriers [21]. The association between RAD51D GPVs and ER-negative BC and TNBC was further confirmed by two large epidemiological studies [22,23], which led to the recent conclusion that RAD51D is a moderate-risk gene with a lifetime risk of developing BC of 15–40% [24].
The mutation frequencies for RAD51C and RAD51D in unrelated breast and/or ovarian cancer in European–American patients were 0.45% and 0.26%, respectively [25]. The mutation frequencies for RAD51C and RAD51D in women with BC from a population screening program performed in the UK were both 0.07% [26]. In contrast, among a large series of unselected BC patients in the Chinese population, the mutation frequency of RAD51D was 0.38%. This observed frequency was much higher than that of Caucasian women [27]. A high RAD51D mutation rate was also noted in high-risk Korean BRCA1/2 mutation-negative BC patients, showing a mutation frequency of 1% [28].
In vitro studies have supported that the loss-of-function mutation of RAD51D was the basis for the initial response to the platinum and PARPi therapy [29]. The increased sensitivity of RAD51D-mutated cells to Olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), confirmed the opportunity for targeted treatments of cancers associated with RAD51D [14]. RAD51D’s loss-of-function mutation is an inclusion criterion for trials evaluating the effectiveness of Rucaparib in ovarian cancer [30] or prostate cancer [31], Talazoparib in HER2-negative BC [32], and Niraparib in pancreatic cancer [33]. In a phase II study on Rucaparib (ARIEL2), there were two RAD51D GPVs mutation carriers included in the trial, with both mutation carriers showing significant tumor responses to Rucaparib [34]. A case study also described a patient with ovarian carcinosarcoma with a known germline RAD51D mutation, and although the patient had already received multiple lines of therapies, she exhibited a remarkable and durable response to PARPi [35]. Moreover, in cases of high-grade epithelial ovarian carcinomas, individuals with either germline or primary somatic RAD51D truncated variants exhibited a response to PARPi. However, these cases eventually developed resistance to the PARP inhibitor due to the acquisition of a secondary RAD51D somatic mutation, which restored the original function of RAD51D [29,36].
Knowledge about RAD51C and RAD51D mutations is important for identifying individuals at increased risk of cancer for early detection and screening. It also helps to understand cancer development mechanisms, identify patients with appropriate therapies, and improve treatment outcomes. This study evaluated the prevalence of RAD51C and RAD51D genes in Chinese high-risk breast and/or ovarian cancer patients. We also focused on the characteristics of the effect of a common Asian truncated RAD51D mutant c.270_271dupTA; p.(Lys91Ilefs*13). These findings could help identify patients for risk assessment, cancer surveillance, and more focused management planning and education for RAD51C and RAD51D mutation carriers, as well as provide a hypothesis of the mechanistic role of RAD51D in carcinogenesis.

2. Methods

2.1. Participants and Selection Criteria

A total of 3728 high-risk Chinese breast and/or ovarian cancer patients fulfilling the high-risk criteria previously described [37] were recruited through the Hong Kong Hereditary Breast Cancer Family Registry from March 2007 to March 2022. This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority West Cluster. All probands and family members provided written informed consent for DNA analysis and received genetic counseling in accordance with the guidelines. Family histories were obtained from patients during genetic counseling and the questionnaire.

2.2. Multi-Gene Panel Testing by NGS

Genomic DNA from peripheral blood underwent multi-gene sequencing analysis using next-generation sequencing (NGS). Library preparation, sequencing, variant interpretation, annotation, and statistical analysis were performed as previously described [37]. All detected PGVs were further validated by conventional Sanger bi-directional DNA sequencing.

2.3. Measures of Genomic Instability by HRD

Formalin-fixed, paraffin-embedded (FFPE) breast or ovarian tumor tissue from RAD51C and RAD51D GPV-positive carriers were retrieved for tumor DNA extraction. Homologous recombination deficiency (HRD) status was measured by NGS genomic profiling of the tumor tissue, quantifying the “genomic scar” by studying the loss of heterozygosity (LOH) in a commercial laboratory (ACTHRDTM test offered by ACT Genomics, Taiwan). HRD status is defined as deleterious or suspected deleterious alterations of BRCA1 and BRCA2, and/or LOH status positive, and the threshold for LOH positivity in this study was set at a score ≥ 0.4.
The assay assessed the mutational status of 24 HRD-related genes (ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCI, FANCL, PPP2R2A, PALB2, RAD51C, RAD51D, RAD51B, RAD54L, ATR, EMSY, FANCA, FAM175A, NBN, MRE11A, RAD50, and PTEN). Moreover, the assay also included over 10,000 single-nucleotide polymorphisms (SNPs) from the Agilent OneSeq platform (Agilent, Santa Clara, CA, USA) for the detection of LOH. The panel spanned over 2.8 MB of the human genome, and the analytical performance of the ACTHRD assay has been validated by the Food and Drug Administration (FDA)-approved companion test myChoice CDx [38]. HRD status was assayed only in cases with available FFPE samples that passed the internal quality control for tumor purity.

2.4. Statistical Analysis

Fisher’s exact test was used in the study to study the relationship between clinicopathological characteristics and mutation status. The limit of significance for all analyses was defined as a p-value of < 0.05. Data analyses were performed using the statistical software R v.4.1.0.

3. Result

3.1. Patients’ Characteristics of the Cohort

Our testing cohort included 3728 patients with BC and/or ovarian cancer. The median age at diagnosis of BC and ovarian cancer was 44 and 48 years. In our cohort, 3147 (84.4%) were BC patients, 485 (13%) were ovarian cancer patients, and 96 (2.6%) were diagnosed with both breast and ovarian cancers. Among these, 3665 (98.3%) were women and 577 (17.8%) had bilateral BCs. A positive family history of BCs (first- or second-degree relatives) was seen in 1317 (35.3%), while 151 (4.1%) had a family history of ovarian cancers, with or without BCs. The majority of BCs were ductal carcinoma (2705, 72.7%), of which 658 (17.7%) were ductal carcinoma in situ (DCIS) and 359 were medullary, lobular, or mucinous carcinoma (9.6%). Detailed clinicopathological characteristics of our patient cohort are listed in Table 1.

3.2. Clinicopathological Characteristics of RAD51C/D Mutations Carriers

We identified 18 germline pathogenic RAD51C (NM_058216.3) and RAD51D (NM_002878.4) mutation carriers (RAD51C: 5; RAD51D: 13). The mutation percentages were 0.13% and 0.35%, respectively. Among these, 12 carriers were BC patients, 5 were ovarian cancer patients, and 1 had both breast and ovarian cancers. The ages of diagnosis of breast and ovarian cancers were 40.5 and 44, respectively. There was a significant association between RAD51C/D mutations and high-grade BC (p-value = 0.0059). Among ovarian cancer patients, RAD51C/D mutation carriers presented with a higher stage of ovarian cancer at diagnosis (p-value = 0.0117). However, no significant difference was seen between RAD51C/D carriers and non-carriers in the age of diagnosis, breast or ovarian cancer histology, the hormonal subtype of BC, or family history of cancers (Table 1).

3.3. RAD51C/D Mutations

We identified 18 pathogenic RAD51C/D mutation carriers. A total of five different variants were identified, two from RAD51C and three from RAD51D. Two recurrent mutation variants were seen in our study. The most common recurrent mutation was RAD51D c.270_271dupTA; p.(Lys91Ilefs*13). This mutation was identified in 11 probands: 3 patients with bilateral BCs, 6 with unilateral BC, and 2 with ovarian cancer. Less than half of the families (5/11) had a family history of breast or ovarian cancer. We performed a co-segregation test on family 014 and the mutation showed co-segregation with the phenotype on the proband’s mother with BC. Two families (007 and 010) with positive probands were cancer-free in other family members (Figure 1).
Another recurrent mutation was RAD51C c.394dupA; p.(Thr132Asnfs*23). The variant was identified in four patients: two with unilateral BC, one with ovarian cancer, and another with both bilateral breast and ovarian cancer (Table 2). This proband (004), with double primary cancers and no family history of breast or ovarian cancer, was seen in her family, but only lung and pancreas cancers in one of her sisters and her father. Family histories of breast or ovarian cancers were seen in the other three probands (Figure 1).

3.4. Homologous Recombination Deficiency (HRD)

The HRD measures the degree of genomic instability in cancer cells that arises from defects in the HR DNA repair pathway. HRD status is defined as deleterious or suspected deleterious alterations of BRCA1 and BRCA2 and/or LOH-positive status by ACT genomics. HRD in the tumors of all tested RAD51C mutation carriers were positive in their tumors, including c.394dupA; p.(Thr132Asnfs*23) mutation carriers from probands 002, 003, and 004 and c.1000_1003delinsTTTCC; p.(Glu334Phefs*14) mutation carrier from proband 005. For the RAD51D mutants, the tumors from mutation carriers of c.556C > T; p.(Arg186*) and c.801delC; p.(Trp268Glyfs*42) (probands 017 and 018) were both HRD-negative. Among the six tumors from the RAD51D c.270_271dupTA; p.(Lys91Ilefs*13) carriers, tumors from four probands (probands 007, 014, 015, and 016) were HRD-positive, while tumors from the other two (probands 012 and 013) were HRD-negative (Table 2).

4. Discussion

The RAD51C and RAD51D genes encode members of the RAD51 protein family that are involved in HR-mediated repair of double-strand DNA breaks (DSBs) [6,7,8] and telomere maintenance [11], leading to the maintenance of genomic stability. HR defects have been extensively associated with the malignant transformation of cells and tumor progression in multiple cancer types [40,41]. HR-related genes (BRCA1, BRCA2, PALB2, RAD51C, and RAD51D) play crucial roles in DNA repair via HR. Thus, GPVs in these genes have been described in the etiology of HBOC syndrome [14,20,21]. Individuals who carry RAD51C or RAD51D mutations have a significantly higher risk of developing breast or ovarian cancers than the general population [22,23,24].
Studies on unselected breast or ovarian cancer cohorts in different populations showed that mutation frequencies of RAD51C and RAD51D in BC patients ranged from 0.07% to 0.2% and 0.07% to 0.48%, respectively [22,26,42,43]. A mutation frequency of 0.38% in RAD51D was identified in Chinese unselected BC cohorts [27]. Mutation frequencies of RAD51C and RAD51D for unselected ovarian cancer patients ranged from 0.2% to 1.1% and 0.35% to 1.1%, respectively [16,18,19,20]. In a Korean study on BRCA1/2 mutation-negative high-risk BC patients, 7 out of 700 (1%) carried a GPV in RAD51D, while no mutation was identified in RAD51C. African–American women and Greek patients associated with hereditary risk showed mutation frequencies of 0.18% and 0.6% in RAD51C and 0.16% and 0.3% in RAD51D [44,45]. TNBC patients in mixed populations have mutation frequencies of the RAD51C and RAD51D genes of 0.26% to 0.33% and 0.38% to 0.48%, respectively [46,47]. Chinese TNBC patients have a 2.77% (9/325) RAD51D mutation frequency [48], which was much higher than that in summation of a mixed population. In our local high-risk Chinese breast and ovarian cancer cohort, RAD51C and RAD51D mutation percentages were 0.13% and 0.35%. A recent study confirmed that RAD51D mutation carriers were more likely to develop TNBC than non-carriers (34.5% versus 13.3%, p-value = 0.003) [27]. A similar observation was noted in our local population. Four out of ten (40% versus 13.9%, p-value = 0.1197) of our RAD51D mutation carriers in our cohort with BCs were TNBC. However, the p-value was not significant because of the small sample size.
In the literature, 290 individuals have been reported to carry RAD51D GPVs, with 63 unique mutations (Supplementary Table S1), 80 of whom were Asian (27.6%). Similar to our current study, the frameshift variant, RAD51D c.270_271dupTA; p.(Lys91Ilefs*13), was the most frequent PGV and was seen in 62 individuals (21.4%). At least 55 out of 62 (88.7%) of them were Asian. In this study, including Chinese only, we reported 11 out of the 55. In a large Chinese cohort of ovarian cancer patients, RAD51D GPVs were detected in 1.7% (13/781), and this variant was found in seven patients and accounted for 53.8% of all RAD51D pathogenic variants [49]. A study on Chinese TNBC patients identified 2.77% (9/325) RAD51D GPVs, where eight of the patients harbor this same mutation variant [48]. In the Genome Aggregation Database (gnomAD), this variant was also observed in 14/18394 (0.076%) in an East Asian population but not in other populations. The second common RAD51D mutation variant was a single-nucleotide variant, c.620C > T; p.(Ser207Leu). This variant has been reported in 44 individuals. The majority are from French Canadian or Italian populations (38/44). Comments on ClinVar for this variant were conflicting, with opinions ranging between pathogenic, likely pathogenic, and variant of uncertain significance. However, this mutation was not seen in our cohort. The third most common RAD51D mutation variant was a nonsense variant, c.556C > T; p.(Arg186*), which was also observed once in our Hong Kong Chinese cohort. This variant was also reported in 22 individuals in other populations (Supplementary Table S1). This variant has been reported with phenotype segregation across four members in a family [50]. In this current study, we also reported a novel variant, c.801delC; p.(Trp268Glyfs*42).
The high mutation frequency of RAD51D c.270_271dupTA; p.(Lys91Ilefs*13) was seen especially in the Asian population but not in Caucasians, both in random unselected studies and in high-risk BC cohorts. The germline duplication of this mutation resulted in a frameshift change and led to an early termination of the protein and loss of function for RAD51D. However, in view of the high mutation frequency of this variant, it might be presented as a polymorphism or a founder variant in the Asian population. We further characterized this mutation by assaying the degree of genomic instability in cancer tissues from these families caused by defects in the HR DNA repair pathway. Four out of six tumors with the frameshift variant RAD51D c.270_271dupTA; p.(Lys91Ilefs*13) were HRD-positive, indicating that the tumor cells with this variant have a high tendency to fail to repair DNA double-strand breaks by the HR DNA repair pathway. Their genomes subsequently have higher incidents of being unstable, leaving “scars” in the genomes that are easily detected. The immunohistochemical analysis performed on tumor sections from patients carrying this specific germline RAD51D c.270_271dupTA; p.(Lys91Ilefs*13) mutation revealed low expression of RAD51D [29]. This finding supports the assertion that this mutation can lead to nonsense-mediated decay, resulting in reduced levels of the RAD51D protein [29]. RAD51D is also critical for efficient HR and is required for RAD51 recruitment at DNA damage sites [39]. RAD51 and γ-H2AX foci formation assays were conducted using a mutated clone of RAD51D c.270_271dupTA; p.(Lys91Ilefs*13) on various cell lines. These assays demonstrated a deficiency in homologous recombination (HR) repair. Such a defect was restored in an in vitro environment after the induction of a secondary mutation that specifically corrected the open reading frame caused by c.270_271dupTA. This secondary mutation eliminated the frame-shift effect caused by the two-base pair duplication [29].
The real-world assessment of genomic scars in clinical tumor samples has been performed using the HRD (homologous recombination deficiency) assay. In a study conducted on Chinese ovarian cancer patients, a correlation was observed between the RAD51D mutation and the HRD score determined by their in-house-developed HRD assay [51]. However, we did not observe similar findings in our study. Among the tumors with the RAD51D mutation from c.270_271dupTA; p.(Lys91Ilefs13) cases, only four out of six showed a positive result for HRD, while all tumors with other RAD51D mutations exhibited a negative result for HRD. Notably, in cases of the c.270_271dupTA; p.(Lys91Ilefs13) mutation, only 67% of tumors with this variant displayed positive HRD, while the remaining 33% were negative. Furthermore, only three out of four HRD-positive cases displayed a heterozygous deletion in RAD51D, resulting in copy number loss. These observations suggest that this truncated variant still retains a certain degree of recruiting ability to form the DNA repair complex at the site of DNA damage. Deleterious mutations in the RAD51D gene tend to cluster in the C-terminal region (residues 77 to 328), which affects binding to RAD51C and likely impairs double-strand DNA break repair [16]. Tumors from the other two patients with RAD51D pathogenic variants, c.556C > T; p.(Arg186*) and c.801delC; p.(Trp268Glyfs*42), harboring longer RAD51D gene products, were also negative for HRD.
Studying the family pedigrees from these c.270_271dupTA; p.(Lys91Ilefs*13) carriers (Figure 1), Family 014 showed phenotype segregation with her mother with BC. Four out of eleven families had family histories of breast or ovarian cancer in their first- to third-degree relatives. A study found that in RAD51D carriers with two first-degree relatives affected with BC, lifetime risks increased to 40% [14] while the risk was 20% [21] for those with no significant cancer family history. One case was reported to carry two deleterious mutations in cis (G217X and Q219X) in RAD51D genes. She had no family history of breast and ovarian cancer in her first-degree relatives but had personal ovarian cancer at a late age [16].
Regarding sensitivity to PARPi, four c.270_271dupTA; p.(Lys91Ilefs*13) mutation carriers with recurring peritoneal or ovarian cancer patients received PARPi for secondary maintenance treatment. Two of them discontinued the treatment because of progressive disease after 8.1 and 33.5 months [49]. c.270_271dupTA; p.(Lys91Ilefs*13) mutation carriers with high-grade ovarian cancer with metastasis also demonstrated a good response to PARPi for 15 months before the gain of secondary somatic RAD51D mutation [52]. Considering real-world evidence, the RAD51D c.270_271dupTA; p.(Lys91Ilefs*13) mutation variant demonstrated incomplete penetrance, at least within our local Chinese population.
This study has demonstrated the complex functional interactions between BRCA2, FANCD2, RAD18, and RAD51 [53] in facilitating the repair of replication-associated DSB. RAD18 interacted directly with RAD51C but weakly with RAD51D [54], which may explain the incomplete penetrance of this RAD51D mutation variant. However, the mutation status of RAD18 and FANCD2 was not determined as these two genes were not classified as HBOC-related genes and were not included in the gene panel.
Despite being classified as pathogenic or likely pathogenic by 12 submitters in ClinVar, it showed variability in its penetrance. To further estimate the lifetime breast cancer (BC) risk from the age of 20, we utilized the CanRisk breast and ovarian cancer model [54]. This allowed us to predict the risk for cancer-free female siblings within the 18 RAD51C/D carrier families with unknown genetic makeup (refer to Table 2). Among the RAD51C carriers, 20% (1/5) of families were identified as having a high risk of developing BC, while 3 out of 5 families had a moderate risk based on the NICE guidelines [55]. For RAD51D mutation carriers, 30.8% (4/13) of their family members have a high lifetime breast cancer risk compared to the average population, while 46% (6/13) of their siblings were in the moderate-risk category. When we focused on the RAD51D c.270_271dupTA; p.(Lys91Ilefs*13) families, 36.3% (4/11) showed a high risk and 45.5% (5/11) were of moderate risk, with only 2 families having risk similar to the general populations. These family members have a lifetime risk of BC spanning from high to moderate to population risk, even when the same mutation variant runs in their families. The application of the CanRisk model provided further evidence for the incomplete penetrance of this particular mutation.
Recent UK consensus recommendations state that breast surveillance in carriers of GPVs in RAD51C and RAD51D should be based on an individual risk assessment. Under NICE guidelines on familial BC, for mutation carriers with a lifetime BC risk of 17%–30%, moderate-risk surveillance should be offered (annual mammograms from 40–49 years) followed by standard population screening (mammography every 3 years from age 50). Patients with a lifetime risk of BC between 30% and 40% (high risk) should undergo annual mammography until the age of 59 years [55]. Current National Comprehensive Cancer Network (NCCN) guidelines v2024.2 recommended that carriers of GPVs of RAD51C and RAD51D have annual mammograms and breast MRIs with contrast starting at age 40. These women should consider risk-reducing salpingo-oophorectomy (RRSO) from the age of 45 to 50. Due to the incomplete penetrance of RAD51D pathogenic variants, especially in the Chinese population, providing surveillance to all RAD51D pathogenic variant carriers and their family members would be a wasteful use of resources. We propose a more individualized approach to breast cancer surveillance for this population.

5. Conclusions

This study showed that some of these variants might partially retain their functions from a clinical perspective and molecular pathology perspective. We would, therefore, agree with the recommendation of the UK consensus meeting of a more conservative approach to breast surveillance. Managing RAD51C and RAD51D carriers should be based on an individual risk assessment and stratified by the level of lifetime BC risk [51]. The genetic counselor should consider offering management advice tailored to the individual family history. This approach is particularly important in incomplete-penetrance genes, such as RAD51D, in hereditary breast and/or ovarian cancer syndrome.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jpm14080866/s1, Table S1: Pathogenic RAD51D mutations being reported. References [56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90] are cited in supplementary materials.

Author Contributions

The study was designed by A.K., C.H.A., and E.S.K.M. A.K. designed and coordinated prospective data collection for the Hong Kong Hereditary Breast Cancer Family Registry. C.Y.S.H. retrieved and collected data for this particular study, interpreted the results, and drafted the manuscript. A.K., C.Y.S.H., C.H.A., S.K.T., and E.S.K.M. reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the Ellen Li Charitable Foundation, the Kerry Kuok Foundation, the Health and Medical Research Fund (03143406), Seed Fund for Basic Tesearch, The University of Hong Kong (201811159150), the Asian Fund for Cancer Research, and the Hong Kong Hereditary Breast Cancer Family Registry.

Institutional Review Board Statement

The study was performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants recruited in this study. This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority West Cluster and respective authorities of other contributing hospitals in Hong Kong. The reference numbers and dates of approval are listed: UW 06-274 T/1299 (HKW Cluster), 7/8/2006; HKEC-2006-156 (HKE Cluster), 5/12/2006; KW/EX/06-088 (KWC Cluster), 21/12/2006; KC/KE 06-0135/ER-1 (KWC/E Cluster), 1/11/2006; CRE-2007.423 (NTE Cluster), 4/12/2007; NTWC/CREC/473/06 (NTW Cluster), 20/10/2006; RC-2006-01 (HKSH), 15/8/2006; SPH16/REC0001 (SPH), 21/9/2016.

Informed Consent Statement

Not applicable.

Data Availability Statement

The dataset supporting the conclusions of this article is included within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

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Jpm 14 00866 g001aJpm 14 00866 g001bJpm 14 00866 g001c
Figure 1. Pedigree of RAD51C and RAD51D mutation carriers.
Figure 1. Pedigree of RAD51C and RAD51D mutation carriers.
Jpm 14 00866 g001aJpm 14 00866 g001bJpm 14 00866 g001c
Table 1. Clinicopathological characteristics of our patient cohort.
Table 1. Clinicopathological characteristics of our patient cohort.
RAD51C/D+NegativeTotalp-Value
N=18N=3710N=3728
Pathogenic Mutation
RAD51C+527.8%
RAD51D+1372.2%
Gender
F18100.0%364798.3%366598.3%1
M00.0%631.7%631.7%
Cancer Type
Breast Cancer1266.7%313584.5%314784.4%0.0761
Ovarian Cancers527.8%48012.9%48513.0%
Breast & Ovarian Cancer15.6%952.6%962.6%
Dx Age (Breast Cancer)
Median
(Range)		41
(29–72)		 44
(18–95)		 44
(18–95)		 0.4050
<45861.5%171653.1%172453.2%0.5903
≥45538.5%151446.9%151946.8%
Dx Age (Ovarian Cancer)
Median
(Range)		45.5
(36–61)		 48
(9–79)		 48
(9–79)		 0.8800
<45350.0%19934.6%20234.8%0.4238
≥45350.0%37665.4%37965.2%
Bilateral Breast Cancer
Y538.5%57217.7%57717.8%0.0648
N861.5%265882.3%266682.2%
Family History (1st & 2nd Degree)
Breast CA738.9%131035.3%131735.3%0.8064
Ovarian CA211.1%1494.0%1514.1%0.1636
Characteristics of Breast CancerN=18N=3779N=3797
Histology
Ductal1794.4%268872.6%270572.7%0.1404
In-situ15.6%65717.7%65817.7%
Others00.0%3599.7%3599.6%
NS0 75 75
Grade
1318.8%50219.2%50519.2%0.0059
2212.5%122646.9%122846.7%
31168.8%88633.9%89734.1%
Stage
015.6%69119.3%69219.2%0.0508
1527.8%130536.4%131036.3%
2738.9%105629.4%106329.5%
3211.1%40811.4%41011.4%
4316.7%1283.6%1313.6%
NS0 191 191
T
T0211.1%72620.4%72820.3%0.1819
T1738.9%170047.7%170747.6%
T2738.9%99728.0%100428.0%
T315.6%952.7%962.7%
T415.6%481.3%491.4%
NS0 213 213
N
N01164.7%244568.6%245668.5%0.2180
N1423.5%72820.4%73220.4%
N200.0%2607.3%2607.3%
N3211.8%1333.7%1353.8%
NS1 213 214
ER
Pos1164.7%258375.4%259475.4%0.3945
Neg635.3%84124.6%84724.6%
NS1 355 356
PR
Pos850.0%217864.3%218664.3%0.2955
Neg850.0%120735.7%121535.7%
NS2 394 396
Her2
Pos212.5%77224.0%77424.0%0.6037
Equivocal16.3%2588.0%2598.0%
Neg1381.3%218067.9%219368.0%
NS2 569 571
TNBC
Yes531.3%40113.9%40614.0%0.0611
No1168.8%248586.1%249686.0%
Characteristics of Ovarian CancerN=6N=575N=581
Site of Cancer
Ovarian583.3%50388.1%50888.0%0.2093
Fallopian Tube00.0%111.9%111.9%
Peritoneal00.0%295.1%295.0%
Uterus00.0%193.3%193.3%
Mixed116.7%91.6%101.7%
NS0 4
Histology
Epithelial5100.0%51396.1%51896.1%1
Germ Cell00.0%71.3%71.3%
Stromal00.0%50.9%50.9%
Others00.0%10.2%10.2%
Mixed00.0%81.5%81.5%
NS1 41 42
Epithelial Subtype
Serous5100%16030.7%16531.2%0.1008
Mucinous00%5410.4%5410.3%
Endometrioid00%17533.6%17533.3%
Clear cell00%10219.6%10219.4%
Mixed00%193.6%193.6%
Others00%112.1%112.1%
Grade
000.0%122.3%122.3%0.3903
100.0%6512.7%6512.6%
200.0%13927.1%13926.9%
35100.0%28856.3%29356.7%
Mixed00.0%81.6%81.5%
NS1 63 64
Stage
100.0%26751.4%26750.9%0.0117
2116.7%6913.3%7013.3%
3350.0%13926.8%14227.0%
4233.3%448.5%468.8%
NS0 56 56
Table 2. RAD51C and RAD51D mutation variants identified in breast and ovarian cancer patients.
Table 2. RAD51C and RAD51D mutation variants identified in breast and ovarian cancer patients.
GeneMutation VariantsProbandsDxPersonal CancerHRD Status *
(LOH Score)		Breast HistologyOvarian HistologyBreast Cancer Risk for FM #Other Germline Mutations
HistoERPRHER2GradeHistoLifetime Risk from Age 20Risk at Ages 40 and 50
RAD51Cc.394dupA; p.Thr132Asnfs*2300143Breast^ QC failedDuctalPosPosNeg----26.4% (M)4.8% (M)BRCA2 VUS
c.2405A > G; p.(Asn802Ser)
00261OvarianPos (0.46)--------HighSerous23.8% (M)4.1% (M)--
00347BreastPos (0.49)DuctalPosPosPos----32.1% (H)6.7% (M)--
00447
72
74		Ovarian
Breast
Breast		Pos (0.35)DCIS
IDC		Pos
Pos		NA
Pos		NA
Neg		HighSerous21.4% (M)2.4% (P)(Somatic) BRCA1 heterozygous deletion exons 4–6
c.1000_1003delinsTTTCC; p.Glu334Phefs*1400544OvarianPos (0.4)--------HighSerous16.6% (P)2.4% (P)BRCA1 VUS
c.5068A > C; p.(Lys1690Gln)
RAD51Dc.270_271dupTA; p.Lys91Ilefs*1300641
50		Breast
Breast		^ SNP frequency aberrantDuctal
Ductal		Neg
Neg		Neg
Neg		Neg
Neg		----29.1% (M)5.8% (M)--
00733BreastPos (0.66)DuctalNegNegNeg----25.2% (M)4.7% (M)--
00833
37		Breast
Breast		^ SNP frequency aberrantDuctal
Ductal		Pos
Pos		Pos
Pos		Neg
Pos		----32.8% (H)7% (M)--
00949Breast^ SNP frequency aberrant DuctalNegNegNeg----23.5% (M)4.2% (M)--
01059Ovarian^ SNP frequency aberrant --------HighSerous13.8% (P)1.8% (P)BRCA1 VUS
c.2347A > G; p.(Ile783Val)BARD1 VUS
c.539A > G; p.(Tyr180Cys)
01130Breast^ Not DoneDuctalPosNegNeg----25.2% (M)4.7% (M)--
01236OvarianNeg (0.34)--------HighSerous15.5% (P)2.2% (M)--
01358BreastNeg (0.017)DuctalPosPosNeg----21.2% (M)3.8% (M)MSH2 VUS
c.1121A > G; p.(Gln374Arg)
RAD51D VUS
c.932T > A; p.(Ile311Asn)
01429BreastPos (0.58)DuctalNegNegNeg----32.2% (H)6.8% (M)BRCA2 VUS
c.2239G>A; p.(Glu747Lys)
01540BreastPos (0.48)DuctalPosNegNeg----32% (H)6.7% (M)--
01656
64		Breast
Breast		Pos (0.67)Ductal
Ductal		Neg
Pos		Neg
Pos		Pos
Neg		----31.8% (H)6.1% (M)BRCA1 VUS
c.5068A > C; p.(Lys1690Gln)
c.556C > T; p.Arg186*01743OvarianNeg (0.36)--------HighSerous14.1% (P)1.7% (P)BRCA2 VUS
c.2744C > G; p.(Thr915Ser)
c.801delC; p.Trp268Glyfs*4201838
38		Breast
Breast		Neg (0.28)Ductal
DCIS		Pos
--		Pos
--		Neg
--		----25.4% (M)4.7% (M)--
^ Tissue not available, DNA quality QC failed, or SNP frequency aberrant. * The homologous recombination deficiency (HRD) status is defined as deleterious or suspected deleterious alterations of BRCA1 and BRCA2, and/or LOH-positive status. The threshold for LOH-positive status is set at a score ≥ 0.4. # Breast cancer risk for cancer-free family members (proband’s siblings) was estimated by CanRisk [39]. Lifetime risk from age 20: Population (P) (less than 17%); Moderate (M) (17–30%); High (H) (>=30%); Lifetime risk from age 20: Population (P) (less than 17%); Moderate (M) (17–30%); High (H) (>=30%).
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Kwong, A.; Ho, C.Y.S.; Au, C.H.; Tey, S.K.; Ma, E.S.K. Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families. J. Pers. Med. 2024, 14, 866. https://doi.org/10.3390/jpm14080866

AMA Style

Kwong A, Ho CYS, Au CH, Tey SK, Ma ESK. Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families. Journal of Personalized Medicine. 2024; 14(8):866. https://doi.org/10.3390/jpm14080866

Chicago/Turabian Style

Kwong, Ava, Cecilia Yuen Sze Ho, Chun Hang Au, Sze Keong Tey, and Edmond Shiu Kwan Ma. 2024. "Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families" Journal of Personalized Medicine 14, no. 8: 866. https://doi.org/10.3390/jpm14080866

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