Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome

Tomoko Kaneyasu; Seiichi Mori; Hideko Yamauchi; Shozo Ohsumi; Shinji Ohno; Daisuke Aoki; Shinichi Baba; Junko Kawano; Yoshio Miki; Naomichi Matsumoto; Masao Nagasaki; Reiko Yoshida; Sadako Akashi-Tanaka; Takuji Iwase; Dai Kitagawa; Kenta Masuda; Akira Hirasawa; Masami Arai; Junko Takei; Yoshimi Ide; Osamu Gotoh; Noriko Yaguchi; Mitsuyo Nishi; Keika Kaneko; Yumi Matsuyama; Megumi Okawa; Misato Suzuki; Aya Nezu; Shiro Yokoyama; Sayuri Amino; Mayuko Inuzuka; Tetsuo Noda; Seigo Nakamura

doi:10.1038/s41523-020-0163-1

Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome

NPJ Breast Cancer. 2020 Jun 12:6:25. doi: 10.1038/s41523-020-0163-1. eCollection 2020.

Authors

Tomoko Kaneyasu^#¹, Seiichi Mori^#¹, Hideko Yamauchi², Shozo Ohsumi³, Shinji Ohno⁴, Daisuke Aoki⁵, Shinichi Baba⁶, Junko Kawano⁶, Yoshio Miki¹, Naomichi Matsumoto⁷, Masao Nagasaki⁸, Reiko Yoshida⁹, Sadako Akashi-Tanaka¹⁰, Takuji Iwase⁴, Dai Kitagawa⁴, Kenta Masuda⁵, Akira Hirasawa⁵, Masami Arai⁹, Junko Takei², Yoshimi Ide¹⁰, Osamu Gotoh¹, Noriko Yaguchi¹, Mitsuyo Nishi⁶, Keika Kaneko³, Yumi Matsuyama³, Megumi Okawa², Misato Suzuki², Aya Nezu⁴, Shiro Yokoyama¹⁰, Sayuri Amino¹, Mayuko Inuzuka¹⁰, Tetsuo Noda¹¹, Seigo Nakamura¹⁰

Affiliations

¹ Project for Development of Innovative Research on Cancer Therapeutics, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku Tokyo, Japan.
² Department of Breast Surgical Oncology, St. Luke's International Hospital, 10-1 Akashi-cho, Chuo-ku Tokyo, Japan.
³ National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama, Ehime Japan.
⁴ Breast Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku Tokyo, Japan.
⁵ Department of Obstetrics & Gynecology, Keio University School of Medicine, 35 Shinano-cho, Shinjuku-ku Tokyo, Japan.
⁶ Sagara Hospital, 3-31 Matsubara-cho, Kagoshima, Japan.
⁷ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku Yokohama, Japan.
⁸ Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi Japan.
⁹ Department of Clinical Genetic Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku Tokyo, Japan.
¹⁰ Division of Breast Surgical Oncology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku Tokyo, Japan.
¹¹ Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku Tokyo, Japan.

^# Contributed equally.

Abstract

Panel sequencing of susceptibility genes for hereditary breast and ovarian cancer (HBOC) syndrome has uncovered numerous germline variants; however, their pathogenic relevance and ethnic diversity remain unclear. Here, we examined the prevalence of germline variants among 568 Japanese patients with BRCA1/2-wildtype HBOC syndrome and a strong family history. Pathogenic or likely pathogenic variants were identified on 12 causal genes for 37 cases (6.5%), with recurrence for 4 SNVs/indels and 1 CNV. Comparisons with non-cancer east-Asian populations and European familial breast cancer cohorts revealed significant enrichment of PALB2, BARD1, and BLM mutations. Younger onset was associated with but not predictive of these mutations. Significant somatic loss-of-function alterations were confirmed on the wildtype alleles of genes with germline mutations, including PALB2 additional somatic truncations. This study highlights Japanese-associated germline mutations among patients with BRCA1/2 wildtype HBOC syndrome and a strong family history, and provides evidence for the medical care of this high-risk population.

Keywords: Breast cancer; Surgical oncology.