Scholarlink

<p>Only 15% of young-onset breast cancers have identifiable hereditary germline pathogenic variants (PVs) in an established breast cancer susceptibility gene. However, it is believed that a significant proportion of these breast cancers have additional monogenic or rare risk variants that require identification. To uncover novel cancer susceptibility genes, we performed germline whole-exome/genome sequencing of samples from 564 patients with young-onset breast cancer (aged &lt;40 years), as well as samples from 4032 female controls. The identified candidate variants were further genotyped in 6,967 independent breast cancer cases across all age groups. We identified two PVs that were significantly associated with the risk of hormone receptor-negative young-onset breast cancer: <i>POLH</i> p.K589T (OR = 3.65, 95% confidence interval [CI] = 1.28–10.4, <i>P</i> = 0.0095) and <i>RAD51</i> p.M1fs (OR = 2.15, 95% CI = 1.15–4.02, <i>P</i> = 0.014). When <i>BRCA1/2</i> PV carriers were excluded from the analysis, only <i>RAD51</i> p.M1fs retained a significant association. Whole-genome sequencing of tumor samples carrying these germline risk variants revealed that they harbored mutational signatures indicative of a deficiency of homologous recombination. These findings suggest that hereditary <i>POLH</i> p.K589T and <i>RAD51</i> p.M1fs are candidate variants associated with an increased risk of hormone receptor-negative breast cancer.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Germline variants of the POLH and RAD51 genes are candidate variants associated with risk of hormone receptor-negative young-onset breast cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月28日

查看全文
  • Shu Yazaki,
  • Rui Kitadai,
  • Yukihide Momozawa,
  • Teruhiko Yoshida,
  • Takashi Yamanaka,
  • Sho Shiino,
  • Chisako Yamauchi,
  • Kenichi Harano,
  • Motonobu Saito,
  • Yosuke Hirotsu,
  • Hisaki Aiba,
  • Ryuji Hamamoto,
  • Chikako Shimizu,
  • Akihiko Shimomura,
  • Tatsunori Shimoi,
  • Kazuki Sudo,
  • Masayuki Yoshida,
  • Kuniko Sunami,
  • Yuichi Shiraishi,
  • Aya Kuchiba,
  • Megumi Hori,
  • Kota Katanoda,
  • Sadaaki Takata,
  • Ayumi Ogawa,
  • Masahiro Torasawa,
  • Akifumi Mochizuki,
  • Yoko Shimada,
  • Kengo Hiranuma,
  • Erisa Fujii,
  • Makoto Hirata,
  • Yuji Yamashita,
  • Takahiro Kogawa,
  • Takeshi Murata,
  • Saori Fujiwara,
  • Yohei Miyagi,
  • Hiroshi Nakagomi,
  • Kazunoshin Tachibana,
  • Koichi Matsuda,
  • Yoshinori Murakami,
  • Katsushi Tokunaga,
  • Yosuke Kawai,
  • Hatsue Ishibashi-Ueda,
  • Tsutomu Tomita,
  • Michio Noguchi,
  • Ayako Takahashi,
  • Yu-ichi Goto,
  • Sumiko Yoshida,
  • Kotaro Hattori,
  • Ryo Matsumura,
  • Aritoshi Iida,
  • Yutaka Maruoka,
  • Hiroyuki Gatanaga,
  • Masaya Sugiyama,
  • Satoshi Suzuki,
  • Kengo Miyo,
  • Yoichi Matsubara,
  • Akihiro Umezawa,
  • Kenichiro Hata,
  • Tadashi Kaname,
  • Kouichi Ozaki,
  • Haruhiko Tokuda,
  • Hiroshi Watanabe,
  • Shumpei Niida,
  • Eisei Noiri,
  • Koji Kitajima,
  • Yosuke Omae,
  • Reiko Miyahara,
  • Hideyuki Shimanuki,
  • Yosuke Kawai,
  • Biobank Japan Project,
  • Masao Omata,
  • Tohru Ohtake,
  • Akihiko Suto,
  • Tatsuya Onishi,
  • Yoichi Naito,
  • Toshinari Yamashita,
  • Kan Yonemori,
  • Takashi Kohno,
  • Kouya Shiraishi

摘要

Only 15% of young-onset breast cancers have identifiable hereditary germline pathogenic variants (PVs) in an established breast cancer susceptibility gene. However, it is believed that a significant proportion of these breast cancers have additional monogenic or rare risk variants that require identification. To uncover novel cancer susceptibility genes, we performed germline whole-exome/genome sequencing of samples from 564 patients with young-onset breast cancer (aged <40 years), as well as samples from 4032 female controls. The identified candidate variants were further genotyped in 6,967 independent breast cancer cases across all age groups. We identified two PVs that were significantly associated with the risk of hormone receptor-negative young-onset breast cancer: POLH p.K589T (OR = 3.65, 95% confidence interval [CI] = 1.28–10.4, P = 0.0095) and RAD51 p.M1fs (OR = 2.15, 95% CI = 1.15–4.02, P = 0.014). When BRCA1/2 PV carriers were excluded from the analysis, only RAD51 p.M1fs retained a significant association. Whole-genome sequencing of tumor samples carrying these germline risk variants revealed that they harbored mutational signatures indicative of a deficiency of homologous recombination. These findings suggest that hereditary POLH p.K589T and RAD51 p.M1fs are candidate variants associated with an increased risk of hormone receptor-negative breast cancer.