One origin of founder mutations in Japan

Abstract Background: Some germline pathogenic variants (PVs) have been observed with high frequency in certain regions and races and are called founder mutations. Founder mutations in BRCA1/2 genes have rarely been reported in Japan. At Kakogawa Central City Hospital, BRCA2 c.5576_5579del accounted for approximately 70% of PVs detected by BRCA1/2 genetic testing. 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. Breast cancer patients with germline PVs detected by BRCA1/2 genetic testing between July 1, 2018 and March 31, 2021 were included. The clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2c.5576_5579del and those of other PVs. The detection rate of BRCA2c.5576_5579del was also compared with that observed in a previous report. Results: A total of 38 breast cancer patients were included; 14 of them underwent testing for companion diagnosis to poly ADP-ribose polymerase inhibitor treatment and 24 underwent testing for diagnosis of hereditary breast and ovarian cancer. PVs in BRCA1 andBRCA2 were detected in 12 and 26 patients, respectively, 12 of whom were BRCA2c.5576_5579del carriers. There were no clinicopathological differences between BRCA2PV carriers and BRCA2 c.5576_5579del carriers. BRCA2c.5576_5579del accounted for 30.8% of the PVs detected, with a particularly high frequency of 72.7% at Kakogawa Central City Hospital. Conclusion: Our study revealed a strong founder effect for BRCA2 c.5576_5579del in breast cancer patients 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.