Impact of germline variants on breast and ovarian cancer risk in Japanese women: an original cohort study and meta-analysisResearch in context

Impact of germline variants on breast and ovarian cancer risk in Japanese women: an original cohort study and meta-analysisResearch in context

Summary: Background: Pathogenic variants (PVs) of BRCA1 and BRCA2 predispose individuals to a higher risk of breast and ovarian cancer; however, the precise risks posed by other cancer susceptibility genes remain unclear, particularly in Asian populations. Methods: We executed a case–control study...

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Main Authors: Shu Yazaki, Megumi Hori, Hisaki Aiba, Yukihide Momozawa, Masayuki Yoshida, Sho Shiino, Kenichi Harano, Chisako Yamauchi, Takashi Yamanaka, Maiko Miwa, Koichi Matsuda, Yosuke Kawai, Mayumi Kobayashi-Kato, Masakazu Kitagawa, Motonobu Saito, Hiroshi Nakagomi, Kazunoshin Tachibana, Ikuko Sakamoto, Kazuaki Takahashi, Yuka Asami, Kota Katanoda, Aya Kuchiba, Hiroshi Yoshida, Mitsuya Ishikawa, Tastunori Shimoi, Kazuki Sudo, Chikako Shimizu, Akihiko Shimomura, Takeshi Murata, Yuji Yamashita, Takahiro Kogawa, Saori Fujiwara, Haruya Saji, Hisamori Kato, Etsuko Miyagi, Yusuke Iwasaki, Tomomi Aoi, Sadaaki Takata, Aiko Ogasawara, Tohru Ohtake, Keiya Fujimori, Yosuke Hirotsu, Minoru Nagashima, Masaaki Komatsu, Ryuji Hamamoto, Makoto Hirata, Teruhiko Yoshida, Takayuki Honda, Kengo Hiranuma, Maiko Matsuda, Yoko Shimada, Kuniko Sunami, Eisei Noiri, Yosuke Omae, Koji Matsumoto, Aikou Okamoto, Masao Omata, Takafumi Watanabe, Yohei Miyagi, Yoshinori Murakami, Katsushi Tokunaga, Kosei Hasegawa, Tomoyasu Kato, Tatsuya Onishi, Toshinari Yamashita, Yoichi Naito, Akihiko Suto, Kan Yonemori, Takashi Kohno, Kouya Shiraisihi
Format: Article
Language:English
Published: Elsevier 2025-06-01
Series:EBioMedicine
Subjects:
Breast cancer
Ovarian cancer
Cancer predisposition genes
Cumulative cancer risk
Online Access:http://www.sciencedirect.com/science/article/pii/S2352396425002026
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Summary:Summary: Background: Pathogenic variants (PVs) of BRCA1 and BRCA2 predispose individuals to a higher risk of breast and ovarian cancer; however, the precise risks posed by other cancer susceptibility genes remain unclear, particularly in Asian populations. Methods: We executed a case–control study of 11 and 26 genes associated with breast and ovarian cancer susceptibility, respectively, in 7220 women with breast cancer, 2464 women with ovarian cancer, and 4032 controls from a multicentre, hospital-based registry in Japan. Furthermore, we conducted a meta-analysis of 23,193 patients with breast and/or ovarian cancer and 31,190 controls from six other hospital-based studies. Findings: Overall, 395 (5.5%) patients with breast cancer and 331 (13.4%) patients with ovarian cancer harboured PVs. Meta-analyses revealed that PVs of BRCA1, BRCA2, CHEK2, PALB2, and TP53 were associated significantly with breast cancer risk (P < 0.001), while PVs of ATM, BRCA1, BRCA2, MSH6, and RAD51D were associated significantly with ovarian cancer risk (P < 0.001). PVs in the BRCA1 DNA-binding domain were associated with a younger age at diagnosis after adjusting for cancer type and family history (β = −3.79, 95% CI = −7.16 to −0.41; P = 0.028). Interpretation: These results provide information about genes associated with breast and ovarian cancer risk in Asian women, as well as guidance for management of PV carriers. Funding: The study was funded by AMED (JP15ck010609, 19cm0106605h0003, 23ama221520h0001, and JP19kk0305010), by a Health Labour Sciences Research Grant (202108001B), by JSPS KAKENHI (JP18K16292, 20H03668, 23H02955, 17H06162, 20H03695, and 16H06277), and by a Grant-in-Aid for the Genome Research Project from Yamanashi Prefecture.
ISSN:2352-3964

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