Open Access
Research article | Published: 03 May 2024

High Frequency of BRCA2 c.5576_5579del Carriers in Kakogawa, Japan

NAKAMURA HARUNA 1 2
, 
MIZUMOTO SACHIKO 2
, 
TANINO HIROKAZU 3
, 
NIWA YUI 4 5
, 
OGINO MITSUTOSHI 1
, 
SAKODA YOKO 1
, 
TSUCHIYA KAZUHIKO 1
, 
KONO SEISHI 6
, 
KONISHI MUNEHARU 7
, 
UENO SAYAKA 8
  &  
KUNIHISA TOMONARI 2

1Department of Breast Surgery, Kakogawa Central City Hospital, Kakogawa, Japan

2Division of Breast and Endocrine Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan

3Department of Thoracic and Cardiovascular Surgery, Wakayama Medical University, Wakayama, Japan

4Department of Clinical Genetics, Kobe University Hospital, Kobe, Japan

5Department of Medical Genetics, Nara Prefecture General Medical Center, Nara, Japan

6Department of Breast Surgery, Hyogo Prefectural Harima-Himeji General Medical Center, Himeji, Japan

7Department of Surgery, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan

8Department of Genomic Medicine, School of Medicine, Fujita Health University, Toyoake, Japan

Cancer Diagnosis & Prognosis May-June; 4(3): 309-314 DOI: 10.21873/cdp.10325
Received 20 February 2024 | Revised 03 December 2024 | Accepted 19 March 2024
Corresponding author
Haruna Nakamura, Division of Breast and Endocrine Surgery, Graduate School of Medicine, Kobe University, 7- 5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, Japan. Tel: +81 783825111, Fax: +81 783826275, email: kitaharu2010kara2016@gmail.com

Abstract

Background/Aim: Certain germline pathogenic variants (PVs), known as founder mutations, have been frequently observed in specific regions and ethnic groups. In Japan, several pathogenic variants of BRCA1/2 have been identified as founder mutations, with their distribution varying across different regions. This retrospective study aimed to further investigate the detailed distribution and correlation between genotype and clinical features among breast cancer patients. Patients and Methods: This study was conducted at Kobe University Hospital and three collaborating institutions. It included breast cancer patients who underwent BRCA1/2 genetic testing between July 1, 2018, and March 31, 2021, and were found to have germline PVs. Clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2 c.5576_5579del and those with other PVs. Additionally, the detection rate of BRCA2 c.5576_5579del was compared with that observed in a previous report. Results: A total of 38 breast cancer patients were included; PVs in BRCA1 and BRCA2 were detected in 12 and 26 patients, respectively, 12 of whom were BRCA2 c.5576_5579del carriers. BRCA2 c.5576_5579del carriers were more likely to develop triple negative breast cancers among all BRCA2 PV carriers. BRCA2 c.5576_5579del accounted for 30.8% of the PVs detected, with a particularly high frequency of 72.7% at Kakogawa Central City Hospital. Conclusion: BRCA2 c.5576_5579del was detected with a particularly high frequency in Hyogo Prefecture, especially in Kakogawa city. In the future, a survey of the distribution of the BRCA2 c.5576_5579del carriers may provide more clarity regarding their localization.
Keywords: breast cancer, hereditary breast and ovarian cancer, Japan, BRCA2 c5576_5579del, founder mutation

It has been reported that approximately 300,000 women in the United States were diagnosed with breast cancer in 2023, making it the most common of all cancers (1). Breast cancer prevalence is not limited to the United States; it is also widespread in Asia, where the number of breast cancer patients is increasing (1,2). Of these, hereditary breast and ovarian cancer (HBOC) patients with pathogenic variants (PVs), mainly in the BRCA1 and BRCA2, are especially known to have an elevated cumulative lifetime risk of breast and ovarian cancer, with a higher incidence at younger ages (3-5). Phenotypic characteristics of breast cancer in BRCA1 PV carriers have been reported to be different from those in BRCA2 PV carriers (6): BRCA1 PV carriers are more likely to develop estrogen receptor (ER) negative, progesterone receptor (PgR) negative, and human epidermal growth factor receptor 2 (HER2) negative breast cancer (triple negative breast cancer), whereas BRCA2 PV carriers are more likely to develop ER positive, HER2 negative breast cancer (luminal type breast cancer). To date, various BRCA1/2 germline variants have been reported and information on the variants has been accumulated in public disease databases. Some variants have been observed with high frequency in certain regions and races and are called founder mutations (7). Founder mutations in BRCA1/2 have been reported in Ashkenazi Jewish (8-11) and Europeans (12-14), whereas there are still few reports in Asian countries (15,16).

In Japan, owing to the development of the HBOC Consortium (4,17), several PVs have been reported to exhibit founder effects, including BRCA1 c.188T>A (p.Leu63*) (4,5,17,18), BRCA2 c.5576_5579del (p.Ile1859fs), BRCA2 c.6952C>T (p.Arg2318*) (4,5,18). Among them, BRCA2 c.5576_5579del has a higher carrier frequency in the Kinki region including Hyogo Prefecture than in other regions (5) Therefore, we conducted a retrospective observational study to investigate its distribution in Hyogo Prefecture.

Patients and Methods

This study was conducted at Kobe University Hospital and three collaborating institutions: Kakogawa Central City Hospital, Hyogo Prefectural Harima-Himeji General Medical Center, and Hyogo Prefectural Nishinomiya Hospital. Breast cancer patients with germline PVs detected by BRCA1/2 genetic testing between July 1, 2018, and March 31, 2021 were included. BRCA1/2 genetic testing was performed for companion diagnostic purpose to determine Olaparib, a poly (adenosine diphosphate ribose) polymerase inhibitor, dosing for patients with unresectable or metastatic breast cancer or for diagnosis of HBOC in patients with early breast cancer. Patients with early breast cancer had to meet at least one of the following criteria for public health care in Japan; (i) breast cancer diagnosed before age 45, (ii) triple negative breast cancer diagnosed before age 60, (iii) two or more primary breast cancers, (iv) family history of breast or ovarian cancer in the third degree, (v) male breast cancer, (vi) history of the ovarian, fallopian tube, or peritoneal cancer. Before BRCA1/2 genetic testing, patients received an explanation about the genetic testing and its implications at each institute, then a 7 ml blood sample was collected from those who requested testing. Blood samples were anonymized and sent to Myriad Genetics (Salt Lake City, UT, USA) via SRL (Fukuoka, Japan). The results of the genetic testing were returned to each institute and disclosed to the patients. In this study, variants reported as ‘Positive for a deleterious mutation’ or ‘Positive for a suspected deleterious mutation’ were defined as PVs.

The information collected from medical records included: age at breast cancer onset, sex, history of other cancers, breast cancer subtype (status of ER, PgR, and HER2), details of detected PVs, and family history of breast, ovarian, peritoneal, and fallopian tube cancer. The clinical characteristics such as breast cancer subtypes were evaluated between carriers of BRCA2 c.5576_5579del and those of other BRCA1/2 PVs. We did not perform a rigorous statistical analysis because of the very small sample size. The detection rate of BRCA2 c.5576_5579del in the BRCA1/2 genetic testing at each institution was compared with that in the previous report (4).

All patients were aged 20 years or older. All eligible patients were informed about the testing results and subsequently informed about associated cancer risks and recommended medical management options, including risk-reducing surgery.

This study was approved by the ethics committee of Kobe University and all collaborating institutions. Informed consent was obtained in the form of opt-out.

Results

A total of 38 breast cancer patients were included in this study. Their clinical characteristics are shown in Table I. Among them, 14 patients underwent BRCA1/2 genetic testing for companion diagnostic purposes for Olaparib and 24 patients underwent testing for the diagnosis of HBOC. All 24 patients met the criteria for BRCA1/2 genetic testing in public health care: 13 were diagnosed with breast cancer under the age of 45 years, 5 were diagnosed with triple negative breast cancer under the age of 60, five were diagnosed with multiple primary breast cancer, one had a personal history of ovarian cancer, and one was a male breast cancer patient. Regarding family history, 18 and 6 of the 24 patients had a family history of breast and ovarian cancer among third-degree relatives, respectively.

PVs in BRCA1 and BRCA2 were detected in 12 and 26 of the 38 patients, respectively. The most frequently detected PVs in BRCA1 was BRCA1 c.4357+2T>G, which was detected in two patients. BRCA1 c.188T>A, which is common in Japanese, was not observed in this study. The most frequently detected PV in BRCA2 was BRCA2 c.5576_5579del, in 12 patients. The second most common PV in BRCA2 were BRCA2 c.6952C>T (p.Arg2318*) and BRCA2 c.9382C>T (p.Arg3128*), with 2 each. To investigate the impact of PVs in each gene on the clinical features of breast cancer, we compared the clinicopathological characteristics between the patients with PVs in BRCA1 and those with PVs in BRCA2 (Table II). BRCA1 PV carriers were more likely to be diagnosed with triple negative breast cancer and to have a family history of ovarian cancer. BRCA2 PV carriers were diagnosed with breast cancer at a higher age than BRCA1 PV carriers and were more likely to have a family history of prostate or pancreatic cancer. Triple negative breast cancer tended to be more common in BRCA2 c.5576_5579del carriers compared to all BRCA2 PV carriers (21.4% vs. 9.4%).

The carrier frequency was compared among the four participating hospitals, as shown in Figure 1. We also compared the observed frequency with that of Japanese patients reported by Yoshimura et al. (4). BRCA2 c.5576_5579del accounted for 30.8% of the PVs detected in this study, and it was detected with a particularly high frequency of 72.7% at Kakogawa Central City Hospital.

Discussion

Here, we have reported a surprisingly high detection rate of BRCA2 c.5576_5579del carriers among breast cancer patients at Kakogawa Central City Hospital. Globally, BRCA2 c.5576_5579del is most frequently reported in Asia (15,16), especially in Japan (4,5,15,18), Korea (15,19,20) and China (21). BRCA2 c.5576_5579del has been reported as a Japanese founder mutation; however, in these previous reports, BRCA2 c.5576_5579del accounts only for approximately 10% of breast cancer patients diagnosed as BRCA1/2 PV carriers (4,5). Geographically, there were fewer BRCA2 c.5576_5579del carriers in areas west of Kakogawa, and more in areas east of Kakogawa. It is difficult to confirm that this PV originated in Kakogawa without investigating the family trees, but BRCA2 c.5576_5579del carriers were found in a large proportion of the PVs in Kakogawa. BRCA1 c.188T>A carriers, common in Japanese, were not detected in this study. In previous studies, BRCA1 c.188T>A carriers were relatively rare in the Kinki region (5). Since this study involved a small number of carriers, we consider this result reasonable, along with the small number of BRCA2 c.6952C>T carriers, the second most common BRCA2 PV in Japan.

There have been very few reports of the phenotypic characteristics according to the genotype of BRCA2. BRCA2 PV carriers are more likely to develop luminal type breast cancer than triple negative breast cancer, with the proportion of triple negative breast cancer patients reported to be approximately 14% (6). However, the present study shows a higher incidence of triple negative breast cancer in BRCA2 PV carriers than in the previous study of BRCA2 phenotypes. There is also a report that BRCA2 c.5576_5579del is involved in the development of ovarian cancer at a younger age, although the number of cases is small (22). This suggests that BRCA2 c.5576_5579del carriers may have similar clinical features to BRCA1 carriers. However, these studies were limited to Hyogo Prefecture, and genetic traits other than BRCA1/2 variants in that district may be also responsible.

The strength of this study is that it is one of the few reports of BRCA1/2 variants in Japan. In addition, BRCA2 c.5576_5579del carriers were found at the Kakogawa Central City Hospital at an unprecedentedly high frequency of 72.7% of all BRCA1/2 PV carriers. However, this study has several limitations. The number of patients was small, and the study was conducted in a limited number of hospitals in Hyogo Prefecture. Also, no family tree was created in this study, and no information was collected on birthplace or place of residence of the patients. It is necessary to collect such information from a larger number of cases to demonstrate the founder effect of BRCA2 c.5576_5579del in Kakogawa.

Decades ago, it was considered nearly taboo to talk about genetic diseases in Japan. In recent years, as various benefits of recognizing one’s own genetic information have become better known, genetic testing and genetic research have become more prevalent in Japan. In the future, BRCA1/2 variants will be studied more widely and in larger numbers, and the distribution and the characteristics of the variants will be more precisely elucidated.

Conclusion

BRCA2 c.5576_5579del accounted for 30.8% of the BRCA1/2 PVs detected in this study conducted in the Hyogo Prefecture, Japan. It was detected with a particularly high frequency of 72.7% in Kakogawa. Future investigation of the distribution of the BRCA2 c.5576_5579del carriers may clarify their localization.

Conflicts of Interest

Sachiko Mizumoto, Hirokazu Tanino and Tomonari Kunihisa received a research grant from Ono Pharmaceutical Co. Ltd. Tomonari Kunihisa is a lecturer in an endowed chair founded by Hyogo Prefecture. The other Authors declare no conflicts of interest in relation to this study.

Authors’ Contributions

Conceptualization, H.N. (lead), S.M. (supporting), H.T. (supporting), T.K. (Supporting); data curation, H.N., S.M., H.T., Y.N., M.O., Y.S., K.T., S.K., M.K.; formal analysis, H.N., S.M., H.T., Y.N., S.U., T.K.; investigation, H.N., S.M., H.T., Y.N., M.O., Y.S., K.T., S.K., M.K., T.K.; methodology, H.N., S.M., H.T.; project administration, H.N., S.M., H.T., T.K.; resources, H.N., S.M., H.T., Y.N., M.O., Y.S., K.T., S.K., M.K., T.K.; supervision, H.T., M.O., S.U., T.K.; validation, H.N., S.M., H.T., S.U.; visualization, H.N., S.M., H.T.; writing – original draft, H.N. (lead), S.M. (supporting), H.T. (supporting); writing – review & editing, S.M., H.T., Y.N., M.O., Y.S., K.T., S.K., M.K., S.U., T.K.

Acknowledgements

The Authors thank all patients and medical staff who participated in this study.

Funding

This study was not funded.

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