Yazaki Shu, Hori Megumi, Aiba Hisaki, Momozawa Yukihide, Yoshida Masayuki, Shiino Sho, Harano Kenichi, Yamauchi Chisako, Yamanaka Takashi, Miwa Maiko, Matsuda Koichi, Kawai Yosuke, Kobayashi-Kato Mayumi, Kitagawa Masakazu, Saito Motonobu, Nakagomi Hiroshi, Tachibana Kazunoshin, Sakamoto Ikuko, Takahashi Kazuaki, Asami Yuka, Katanoda Kota, Kuchiba Aya, Yoshida Hiroshi, Ishikawa Mitsuya, Shimoi Tastunori, Sudo Kazuki, Shimizu Chikako, Shimomura Akihiko, Murata Takeshi, Yamashita Yuji, Kogawa Takahiro, Fujiwara Saori, Saji Haruya, Kato Hisamori, Miyagi Etsuko, Iwasaki Yusuke, Aoi Tomomi, Takata Sadaaki, Ogasawara Aiko, Ohtake Tohru, Fujimori Keiya, Hirotsu Yosuke, Nagashima Minoru, Komatsu Masaaki, Hamamoto Ryuji, Hirata Makoto, Yoshida Teruhiko, Honda Takayuki, Hiranuma Kengo, Matsuda Maiko, Shimada Yoko, Sunami Kuniko, Noiri Eisei, Omae Yosuke, Matsumoto Koji, Okamoto Aikou, Omata Masao, Watanabe Takafumi, Miyagi Yohei, Murakami Yoshinori, Tokunaga Katsushi, Hasegawa Kosei, Kato Tomoyasu, Onishi Tatsuya, Yamashita Toshinari, Naito Yoichi, Suto Akihiko, Yonemori Kan, Kohno Takashi, Shiraisihi Kouya
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan; Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of International Clinical Development, National Cancer Center Hospital, Tokyo, Japan.
School of Nursing, University of Shizuoka, Shizuoka, Japan.
EBioMedicine. 2025 Jun;116:105758. doi: 10.1016/j.ebiom.2025.105758. Epub 2025 May 21.
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.
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.
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).
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.
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.
BRCA1和BRCA2的致病性变异（PVs）使个体患乳腺癌和卵巢癌的风险更高；然而，其他癌症易感基因所带来的精确风险仍不明确，尤其是在亚洲人群中。
我们对来自日本一个多中心、基于医院的登记处的7220名乳腺癌女性、2464名卵巢癌女性和4032名对照者进行了一项病例对照研究，分别涉及11个和26个与乳腺癌和卵巢癌易感性相关的基因。此外，我们对来自其他六项基于医院的研究的23193例乳腺癌和/或卵巢癌患者及31190名对照者进行了荟萃分析。
总体而言，395名（5.5%）乳腺癌患者和331名（13.4%）卵巢癌患者携带PVs。荟萃分析显示，BRCA1、BRCA2、CHEK2、PALB2和TP53的PVs与乳腺癌风险显著相关（P<0.001），而ATM、BRCA1、BRCA2、MSH6和RAD51D的PVs与卵巢癌风险显著相关（P<0.001）。在调整癌症类型和家族史后，BRCA1 DNA结合域中的PVs与诊断时较年轻的年龄相关（β=-3.79，95%CI=-7.16至-0.41；P=0.028）。
这些结果提供了有关亚洲女性乳腺癌和卵巢癌风险相关基因的信息，以及对PV携带者管理的指导。
该研究由日本医疗研究与开发机构（AMED）（JP15ck010609、19cm0106605h0003、23ama221520h0001和JP19kk0305010）、健康劳动科学研究资助（202108001B）、日本学术振兴会科研资助（JP18K16292、20H03668、23H02955、17H06162、20H03695和16H06277）以及山梨县基因组研究项目资助金资助。
