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

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.

Authors

Institutions

Publication Details

Journal
npj Breast Cancer
Published
2025-11-28
DOI
https://doi.org/10.1038/s41523-025-00848-2
Primary Topic
BRCA gene mutations in cancer
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Takeshi Murata, Kenichi Harano, Takashi Yamanaka, Yosuke Hirotsu et al.
npj Breast Cancer
BRCA gene mutations in cancer
article

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

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

Abstract

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.

npj Breast CancerVol. 11(1)
Fukushima Medical University (JP), University of Shizuoka (JP), Kanagawa Prefectural Hospital Organization (JP), Tokyo Institute of Psychiatry (JP), National Center for Global Health and Medicine (JP), BioBank Japan (JP), National Center of Neurology and Psychiatry (JP), National Cerebral and Cardiovascular Center (JP), RIKEN Center for Advanced Intelligence Project (JP), National Center For Child Health and Development (JP), The Cancer Institute Hospital (JP), National Cancer Center Hospital East (JP), RIKEN Center for Integrative Medical Sciences (JP), Tokyo National Hospital (JP), National Center for Geriatrics and Gerontology (JP), Yamanashi Prefectural Central Hospital (JP), Japanese Foundation For Cancer Research (JP), Kanagawa Cancer Center, National Cancer Research Institute (GB), The University of Tokyo (JP), Nippon Medical School (JP), Teikyo University (JP)
Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, RIKEN
Openalex Percentile: Top 61%
BRCA gene mutations in cancer
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.