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Clinicopathological features of Chinese ovarian cancer patients with double heterozygosity for cancer-predisposed genes

BMC Cancer volume 25, Article number: 1391 (2025) Cite this article

Abstract

Background

Double heterozygosity (DH) is rarely reported in hereditary ovarian cancer. The clinicopathological and pedigree features of ovarian cancer patients harboring DH of cancer-predisposed genes are not well established.

Methods

This study included ovarian cancer patients who received genetic counseling at Peking University Third Hospital between 2018 and 2024. Among patients who received genetic testing, 75 patients were found to carry germline pathogenic variants (PVs) in BRCA1. In 75 BRCA1 PV carriers, 6 unrelated patients harboring additional germline PV in cancer-predisposed genes were identified. The clinicopathological characteristics and family history of the 75 ovarian cancer patients were collected.

Results

Six patients harboring germline BRCA1 variant and a concurrent germline variant in cancer-predisposed genes were identified. Coupling with BRCA1 PV, the additional variant involved MUTYH/RECQL4, RAD51C, RECQL4, BRCA2, RAD54L, and ATM. We did not observe a difference in age at diagnosis between DH carriers (median 56 years) and single BRCA1 carriers (median 51 years). There were no significant differences in other clinicopathological profiles (stage, pathology, tumor behavior, and survival) between the two groups. All the DH patients had a family history of multiple types of cancer. The presence of ovarian cancer family history was 66.7% (4/6) in DH group and 27.5% (19/69) in single BRCA1 PV group (p = 0.125). In comparison to single BRCA1 PV carriers, a higher percentage of family history of non-ovarian or breast cancer (100% vs. 46.4%, p = 0.025) was observed in DH carriers.

Conclusions

Our study suggests that BRCA1 variant seems to drive the phenotypic expressions of ovarian cancer patients with DH. The management of these patients might be like BRCA1-mutated patients. Harboring DH may further increase the family member’s chance of acquiring cancer of various types.

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Background

Ovarian cancer is the third most common gynecologic cancer around the world, but accounts for the highest mortality rate among these malignancies [1]. Approximately 15–20% of epithelial ovarian cancer are caused by hereditary cancer predisposition, with deleterious variants in BRCA1/2 or other double-strand DNA break repair genes [2]. BRCA1 and BRCA2 have been identified as causative genes that account for 65–75% of hereditary epithelial ovarian cancer [3]. Other genes of moderate penetrance include less common variants in homologous recombination repair pathway (such as RAD51C, RAD51D, BRIP1, PALB2, BARD1) and mismatch repair genes (MLH1, MSH2, MSH6, and PSM2) [4, 5]. Given these findings, genetic testing for epithelial ovarian cancer patients with a family history ought to include BRCA1/2 and other hereditary susceptibility genes.

Since first reported in 1997, over 100 carriers of double heterozygosity (DH) of pathogenic variant (PV) in cancer-predisposed genes, particularly hereditary breast and ovarian cancer (HBOC) related genes, have been described [6]. Considering the variant frequency of cancer predisposing genes, most previous studies reported a DH of BRCA1 and BRCA2. Based on the frequency of BRCA1 and BRCA2 variant carriers, the prevalence of BRCA1/2 DH was estimated between 1/700,000 and 1/250,000 in British and Canadian populations, and ∼1/2500 among the Ashkenazi Jewish families [7, 8]. Data collected from Israeli national breast cancer cohort showed that the frequency of BRCA1/2 DH was 0.3% (22 cases) of all breast cancer cases in the Ashkenazi population [9]. Among 32,295 female BRCA1/2 variant carriers from the CIMBA (Consortium of Investigators of Modifiers of BRCA1/2) database, the prevalence of BRCA1/2 DH was identified as 0.3% (93 carriers) [10]. In non-Ashkenazi Jewish populations, the frequency of DH carriers is quite rare.

The clinicopathological features and pedigree characteristics of malignancies in patients harboring DH of cancer-predisposed genes are not well established. A few reports have studied the variants and phenotype expressions in breast cancer patients carrying DH [10,11,12,13,14,15,16]. Compared to single PV, whether DH of PV leads to a more severe clinical presentation remains controversial. In contrast to breast cancer, the consequences of DH in ovarian cancer are poorly understood. A systematic review collected 37 BRCA1/2 DH patients with epithelial ovarian cancer from 18 isolated studies and described a clinical feature that resembled those of BRCA1 variant carriers [17]. There is a paucity of studies assessing variants and clinicopathological features of Chinese ovarian cancer patients with DH of cancer-predisposed genes.

To characterize the variants and phenotype expressions in Chinese ovarian cancer patients carrying DH of cancer-predisposed genes, we described clinicopathological and pedigree features of six patients harboring DH and compared them with those harboring a single BRCA1 variant. This work helps to establish a better understanding of ovarian cancer patients with DH in China.

Methods

Study population

We’ve established a cohort of hereditary ovarian cancer in China (NCT 06564428) [18]. This study included ovarian cancer patients who received genetic counseling at Peking University Third Hospital between 2018 and 2024. Among patients who received genetic testing, 35 patients (including proband 3, 4, 5, 6) used a 425-gene pan-cancer panel (Supplement Table), and 40 patients received whole-exon sequencing (including proband 1, 2). 75 patients were found to carry germline pathogenic variants (PVs) in BRCA1. In 75 patients with germline BRCA1 PV, 6 unrelated patients harboring additional germline PV in cancer-predisposed genes were found. Therefore, 6 patients with double heterozygosity (BRCA1 and a concurrent variant in cancer-predisposed genes) and 69 patients with a single BRCA1 variant were included in the study. This research was approved by Peking University Third Hospital Medical Science Research Ethics Committee (ethic approval No: 2024 260-01). Written consent was directly obtained from participants of the study.

Data collection

The electronic medical records and the family history of the 75 ovarian cancer patients were collected by medical professionals. Clinical data were collected on germline PVs, age at diagnosis, FIGO stage (2014), histopathology, disease laterality, surgery, chemotherapy treatment, and survival status. Variants were evaluated and interpreted following the American College of Medical Genetics and Genomics Association for Molecular Pathology guidelines 2015 (ACMG-AMP 2015) [19]. The family history of cancer was collected by certified genetic counselors during genetic counseling with the extent of the first-, second-, and third-degree relatives. A positive family history of cancer was defined as one or more first-, second-, or third-degree relatives diagnosed with cancer.

Statistical analysis

All statistical analyses were performed on SPSS ver. 27.0 software (IBM Corp., Armonk, NY). Continuous variables are presented as mean ± standard deviation (SD), and categorical variables are presented as the number and percentage of cases. The Kruskal-Wallis exact test was used to compare the continuous variables. While Fisher’s exact test and Pearson’s chi-square test were used to compare categorical variables. Values of p < 0.05 were considered statistically significant.

Results

Variant profiles and clinicopathological features of ovarian cancer patients with double heterozygosity

Based on the established cohort of hereditary ovarian cancer patients [18], 6 probands harboring a germline BRCA1 variant and a concurrent germline variant in cancer-predisposed genes were identified. The variant profiles of DH are listed in Table 1. Three patients (No. 3, 5, 6) harbored a variant in ovarian cancer cluster region (OCCR) of BRCA1 [20]. Variants in breast cancer cluster region (BCCR) of BRCA1 were observed in two patients (No. 1, 2). Coupling with BRCA1 PVs, the second heterozygous variant involved MUTYH, RAD51C, RECQL4, RAD54L, and ATM. Notably, patient 1 harbored three concurrent germline PVs in BRCA1, MUTYH, and RECQL4. Patient 4 carried DH in BRCA1 and BRCA2.

Table 1 Variant profiles of ovarian cancer patients with double heterozygosity of cancer-predisposed genes
Full size table

The main clinicalpathological characteristics of ovarian cancer patients with DH are shown in Table 2. The median age of ovarian cancer diagnosis was 56 years, ranging from 49 to 69 years. All 6 patients with DH were HGSOC (High-Grade Serous Ovarian Carcinoma) histotype. Five patients (83.3%) with DH presented with bilateral masses. All patients received cytoreduction surgery and 5 patients achieved R0 resection. Five patients received poly (ADP-ribose) polymerase (PARP) inhibitor treatment. One patient (No. 2) relapsed during follow-up.

Table 2 Clinicalpathological characteristics of ovarian cancer patients with double heterozygosity
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Family history of ovarian cancer patients with double heterozygosity

An overview of family history of DH carriers is listed in Table 3. All the DH patients had a family history of cancer. Four patients (66.7%) had a family history of ovarian cancer. Three patients (50.0%) had a family history of breast cancer. Five of six patients (83.3%) had a family history of ovarian or breast cancer. In family 3, an uncommon cancer, cholangiocarcinoma, occurred.

Table 3 Family history of ovarian cancer patients carrying double heterozygosity
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The pedigrees of six ovarian cancer patients harboring DH are presented in Fig. 1. The types of cancer included ovarian cancer, breast cancer, colorectal cancer, lymphoma, gastric cancer, gallbladder cancer, renal cancer, liver cancer, and esophageal cancer. The detected PVs were further validated in family members via Sanger sequencing. Carrier of PV was indicated in the pedigree.

Fig. 1
figure 1

Pedigrees of ovarian cancer patients with double heterozygosity of cancer-predisposed genes. The proband is indicated by the arrow. Age at diagnosis is indicated next to the cancer site. Age at death is indicated after “d.” Square: male, Circle: female, Black filled symbols: patients diagnosed with cancer, Diagonal line: deceased patients. Abbreviations: Mut, mutant; OVCA, Ovarian cancer; BRCA, Breast cancer; READ, Rectum adenocarcinoma; STAD, Stomach adenocarcinoma; CHOL, Cholangiocarcinoma; RCC, Renal cell carcinoma; ESCA, Esophageal carcinoma

Full size image

Clinicalpathological characteristics of DH carriers compared with single BRCA1 PV carriers

The comparisons of clinicalpathological characteristics between ovarian patients carrying DH and single BRCA1 PV are presented in Table 4. There was no significant difference in median age at diagnosis between DH group (56 years) and single BRCA1 PV group (51 years). No significant differences were observed in other clinicopathological profiles including pathological type, FIGO stage, disease laterality, ascites, residual disease, response to treatment, and survival status. These results indicated that DH carriers did not show more optimistic or downhill clinical manifestations than BRCA1 single PV carriers.

Table 4 Clinicalpathological characteristics of DH carriers compared with BRCA1 single PV carriers
Full size table

Family history of DH carriers compared with single BRCA1 PV carriers

Family history of cancer was compared between DH carriers and single BRCA1 PV carriers (Table 5). The presence of ovarian cancer family history was 66.7% (4/6) in DH group and 27.5% (19/69) in single BRCA1 PV group. Family history of breast cancer was observed in 50.0% (3/6) of DH group and 33.3% (23/69) of single BRCA1 PV group. The percentage of ovarian cancer or breast cancer family history was 83.3% (5/6) in DH group and 47.8% (33/69) in single BRCA1 PV group. Although higher percentages were observed, these differences were not statistically significant. Since all six DH patients had a family history of cancer, other types of cancer were compared between the two groups. In comparison to single BRCA1 PV carriers, a higher percentage of family history of non-ovarian or breast cancer (100% vs. 46.4%, p = 0.025) was observed in DH carriers.

Table 5 Family history of DH carriers compared with BRCA1 single PV carriers
Full size table

Discussion

In current study, we summarized the clinicopathological and pedigree characteristics of ovarian cancer patients harboring DH of cancer-predisposed genes. The profiles of DH carriers were compared to those of single BRCA1 variant carriers. Our study was hitherto the first report of Chinese ovarian cancer patients with DH of cancer-predisposed genes.

DH in cancer is rarely reported, particularly in non-Ashkenazi Jewish populations. BRCA1/2 DH in breast cancers is relatively more frequently reported, and emerging evidence suggests that clinical and pathological differences may exist [12,13,14,15,16]. However, the effect of two ovarian cancer predisposing variants on disease phenotypes remains unclear. So far, only one systematic review compared the clinicopathological parameters of BRCA1/2 DH (37 cases) to single BRCA1 or BRCA2 carriers in epithelial ovarian cancer patients [17]. The median age at diagnosis of DH was 51.9 years, similar to BRCA1 carriers (49.7 years) and younger than BRCA2 carriers (58.1 years). The DH patients presented a lower 5-year survival rate (60%) than BRCA2 carriers (76%), but not compared to BRCA1 carriers (51%). Compared to carriers of a single BRCA1 variant, BRCA1/2 DH does not seem to lead to a more severe phenotype.

In addition to BRCA1/2 DH, other DHs in cancer-predisposed genes have been reported less frequently [21, 22]. Our study reported six ovarian cancer patients harboring germline BRCA1 variant and concurrent germline variant in cancer-predisposed genes (MUTYH/RECQL4, RAD51C, RECQL4, BRCA2, RAD54L, and ATM), in which the allele frequencies of pathogenic variants within the general Chinese population remain incompletely characterized, posing challenges for contextualizing our findings. Current data indicate low baseline frequencies: ATM variants occur in approximately 1.4% of Chinese HBOC high-risk patients [23] and 0.35-1% in non-Chinese populations [24, 25], while heterozygous MUTYH variants are estimated at 1–2% in Western cohorts [26]. For RECQL4 and RAD54L, population data are notably scarce, though both are inferred to be rare, and germline variants lack reliable evidence for hereditary ovarian cancer pathogenicity, unlike established genes (BRCA1/2, RAD51C, MUTYH, ATM). RECQL4 evidence is largely confined to breast cancer susceptibility [27, 28] and adverse ovarian cancer prognostic impacts [29], similarly RAD54L lacks robust clinical validation. Until prospective studies validate functional impacts and penetrance estimates, these genes should be considered investigational in ovarian cancer contexts. Crucially, the combined probability of concomitant heterozygous pathogenic variants in BRCA1/2 and any two of these genes calculated from extant frequency estimates is statistically negligible. This improbability substantiates that general population allele frequencies cannot adequately explain the observed co-occurring carriers in our cohort, suggesting potential biological or clinical selection mechanisms underlying their presentation.

On the subject of phenotype alteration, we did not observe a difference in age at diagnosis between DH carriers and single BRCA1 carriers. Besides, there were no significant differences in other clinicopathological profiles (stage, pathology, tumor behavior) between the two groups. These results indicate that the presence of additional variants of cancer-predisposed genes in BRCA1-mutated patients does not lead to a severe disease phenotype. BRCA1 plays a central role in pathways involving DNA damage sensing and DNA damage repair [30]. One possible explanation is that since DNA damage repair response is already altered by BRCA1 dysfunction, an additional variant in the same pathway may not cause evident effects [21]. Whereas BRCA1 variants dominantly confer 40% lifetime ovarian cancer risk, how double heterozygosity involving BRCA variants modulates penetrance is unclear. Among co-occurring variants, ATM (Odds Ratio 1.5–2.5 [31, 32]) and RAD51C (Odds Ratio 5 [33]) show established penetrance in ovarian cancer, and biallelic MUTYH variant carriers held 17-fold increased risk of ovarian cancer [34]. Critically, systemic evidence is lacking on whether these variants modify penetrance in BRCA1 carriers, though double heterozygosity may predispose to earlier onset/multiple primaries [15, 22].

Considering the hereditary risks for first-degree relatives and other family members, the genetic counseling associated with DH carriers is also a matter of discussion. In current study, all the DH patients had a family history of multiple types of cancer. Four patients (66.7%) had a family history of ovarian cancer. Three patients (50.0%) had a family history of breast cancer. In addition to female ovarian or breast cancer, other cancer types included colorectal cancer, lymphoma, gastric cancer, gallbladder cancer, renal cancer, liver cancer, and esophageal cancer. In comparison to single BRCA1 carriers, a higher percentage of family history of non-ovarian or breast cancer (100% vs. 46.4%) was observed in DH carriers. The observed higher prevalence of cancers in families of DH probands may be attributed to two non-exclusive factors: increased penetrance associated with the individual pathogenic variants themselves, and/or the potential for combined effects arising from the co-occurrence of variants in these cancer susceptibility genes. These results indicate that harboring DH of cancer-predisposed genes may further increase the family member’s chance of acquiring cancer of various types.

According to a review of BRCA1/2 DH cases, approximately one-fourth of the patients had a family history of cancer on both sides [11]. The increased risk of cancer in DH carriers is not limited to female breast and ovarian cancer but also involves various types of cancer [35,36,37]. Recently, Wen et al. reported a higher percentage of family history of breast cancer in Chinese breast cancer patients with BRCA1/2 DH than in patients with single BRCA1 PV [14]. Kwong et al. observed a greater family history of ovarian cancer in Chinese breast cancer patients with DH variants than single variant carriers [15]. Our reports on the family history of DH patients were in line with previous literatures.

The main limitation of this study is the relatively small sample size and single-center nature. The small number of patients is insufficient to analyze different treatment strategies (platinum-based chemotherapy or PARP inhibitor) and patient response. Additionally, it remains unclear from which parental side the DH was inherited because of limited genetic tests on family members. Additionally, genetic data from relatives provides insufficient definitive evidence that non-BRCA1 variants confer increased cancer risk, with no additional affected carriers identified. These results should be validated in a larger cohort.

Taken together, these findings contribute to a better understanding of clinicopathological and pedigree features of ovarian cancer patients carrying DH of cancer-predisposed genes. Our study suggests that BRCA1 variant seems to drive the phenotypic expressions of ovarian cancer patients with DH. The management of these patients might be like BRCA1-mutated patients.

When there is a positive family history on both sides, or when the family history contains various types of cancer, genetic testing for ovarian cancer patients should contain BRCA1/2 and other cancer-predisposed genes. Furthermore, a thorough family investigation and genetic counselling are necessary for relatives after identification of a proband harboring DH of cancer-predisposed genes.

Data availability

Core datasets used and analyzed during this study are available in the figure and tables in the main text. Detailed data will be made available on reasonable request.

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Acknowledgements

We express our thanks to all individuals who participated in the study. We thank Dr. Zhang Rong, Dr. Dong Jingmei, Dr. Wu Xiaoqing, Dr. Zhao Kuaile, Dr. Lu Qing, Dr. Wang Jing, and Dr. Zhang Lei for their assistance with data collection.

Funding

This work was supported by the National Natural Science Foundation of China (82372888, 82303662, 82102769), Ningxia Key Research and Development Program (2023BEG01001), Clinical Cohort Construction Program of Peking University Third Hospital (BYSYDL2023010), Key Clinical Projects of Peking University Third Hospital (BYSYZD2021006), Peking University-Golden Resource “Tengyun Clinical Research Program” (TY2025002), China Postdoctoral Science Foundation (2023M730121), Peking University Clinical Scientist Training Program (BMU2024PYJH008), and National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital, BYSYSZKF2023031).

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  1. Yikun Jin and Wenyan Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China

    Yikun Jin, Manqi Wu, Yiming Fan, Tongxia Wang, Cuiyu Huang, Tong Gao, Yuan Li, Qiyu Liu & Hongyan Guo

  2. Department of Gynecology, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, China

    Wenyan Wang

  3. Department of Pathology, School of Basic Medical Sciences, Third Hospital, Peking University Health Science Center, Beijing, 100191, China

    Yan Liu

  4. National Clinical Research Center for Obstetrics and Gynecology, (Peking University Third Hospital), Beijing, 100191, China

    Hongyan Guo

  5. Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, 100191, China

    Hongyan Guo

  6. Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China

    Hongyan Guo

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  1. Yikun Jin
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Contributions

Yikun Jin: Data curation, Formal analysis, Writing - original draft. Wenyan Wang: Data curation, Investigation. Manqi Wu: Investigation. Yiming Fan: Investigation. Tongxia Wang: Investigation. Cuiyu Huang: Investigation. Tong Gao: Investigation. Yan Liu: Methodology. Yuan Li: Conceptualization, Funding acquisition. Qiyu Liu: Conceptualization, Funding acquisition, Writing - original draft, Writing - review & editing. Hongyan Guo: Funding acquisition, Resources, Supervision.

Corresponding authors

Correspondence to Yuan Li or Qiyu Liu.

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Ethics approval and consent to participate

Written informed consent was obtained from patients and their families in this study in accordance with the Declaration of Helsinki. This study was approved by Peking University Third Hospital Medical Science Research Ethics Committee (No. 2024 260-01). Participants gave informed consent for data to be published anonymously given that the information linked to them would not be released from any researcher.

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Jin, Y., Wang, W., Wu, M. et al. Clinicopathological features of Chinese ovarian cancer patients with double heterozygosity for cancer-predisposed genes. BMC Cancer 25, 1391 (2025). https://doi.org/10.1186/s12885-025-14835-0

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  • DOI: https://doi.org/10.1186/s12885-025-14835-0

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BMC Cancer

ISSN: 1471-2407