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

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 IdeOsamu 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

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19 Citations (Scopus)

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.

Original language	English
Article number	25
Journal	npj Breast Cancer
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/s41523-020-0163-1
Publication status	Published - Dec 1 2020
Externally published	Yes

ASJC Scopus subject areas

Oncology
Radiology Nuclear Medicine and imaging
Pharmacology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41523-020-0163-1

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Kaneyasu, T., Mori, S., Yamauchi, H., Ohsumi, S., Ohno, S., Aoki, D., Baba, S., Kawano, J., Miki, Y., Matsumoto, N., Nagasaki, M., Yoshida, R., Akashi-Tanaka, S., Iwase, T., Kitagawa, D., Masuda, K., Hirasawa, A., Arai, M., Takei, J., ... Nakamura, S. (2020). Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome. npj Breast Cancer, 6(1), Article 25. https://doi.org/10.1038/s41523-020-0163-1

Kaneyasu, T, Mori, S, Yamauchi, H, Ohsumi, S, Ohno, S, Aoki, D, Baba, S, Kawano, J, Miki, Y, Matsumoto, N, Nagasaki, M, Yoshida, R, Akashi-Tanaka, S, Iwase, T, Kitagawa, D, Masuda, K, Hirasawa, A, Arai, M, Takei, J, Ide, Y, Gotoh, O, Yaguchi, N, Nishi, M, Kaneko, K, Matsuyama, Y, Okawa, M, Suzuki, M, Nezu, A, Yokoyama, S, Amino, S, Inuzuka, M, Noda, T & Nakamura, S 2020, 'Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome', npj Breast Cancer, vol. 6, no. 1, 25. https://doi.org/10.1038/s41523-020-0163-1

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

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.",

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

note = "Funding Information: The authors thank Norio Tanaka, Kazuma Kiyotani, Yasuo Uemura, Koichiro Inaki, Noriomi Matsumura, Mayuka Nakatake, and Futoshi Akiyama for helpful discussions. The authors also thank Megumi Nakai, Rika Nishiko, Junko Kanayama, Ryoichi Minai, and Kumiko Sakurai for technical assistance, Noriko Ishikawa, Kana Hayashi, and Minako Hoshida for administrative assistance, and Rebecca Jackson for editing a draft of this manuscript. This study was performed as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT) (2014 and 2015) and AMED P-CREATE under the grant numbers of JP16cm0106503 and JP17cm0106503 (2016 and 2017). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41523-020-0163-1",

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T1 - Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome

AU - Kaneyasu, Tomoko

AU - Mori, Seiichi

AU - Yamauchi, Hideko

AU - Ohsumi, Shozo

AU - Ohno, Shinji

AU - Aoki, Daisuke

AU - Baba, Shinichi

AU - Kawano, Junko

AU - Miki, Yoshio

AU - Matsumoto, Naomichi

AU - Nagasaki, Masao

AU - Yoshida, Reiko

AU - Akashi-Tanaka, Sadako

AU - Iwase, Takuji

AU - Kitagawa, Dai

AU - Masuda, Kenta

AU - Hirasawa, Akira

AU - Arai, Masami

AU - Takei, Junko

AU - Ide, Yoshimi

AU - Gotoh, Osamu

AU - Yaguchi, Noriko

AU - Nishi, Mitsuyo

AU - Kaneko, Keika

AU - Matsuyama, Yumi

AU - Okawa, Megumi

AU - Suzuki, Misato

AU - Nezu, Aya

AU - Yokoyama, Shiro

AU - Amino, Sayuri

AU - Inuzuka, Mayuko

AU - Noda, Tetsuo

AU - Nakamura, Seigo

N1 - Funding Information: The authors thank Norio Tanaka, Kazuma Kiyotani, Yasuo Uemura, Koichiro Inaki, Noriomi Matsumura, Mayuka Nakatake, and Futoshi Akiyama for helpful discussions. The authors also thank Megumi Nakai, Rika Nishiko, Junko Kanayama, Ryoichi Minai, and Kumiko Sakurai for technical assistance, Noriko Ishikawa, Kana Hayashi, and Minako Hoshida for administrative assistance, and Rebecca Jackson for editing a draft of this manuscript. This study was performed as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT) (2014 and 2015) and AMED P-CREATE under the grant numbers of JP16cm0106503 and JP17cm0106503 (2016 and 2017). Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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

Abstract

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