Abstract
Female carriers of a heterozygous germline mutation in BRCA1/2 have a high risk of breast cancer. Although recent research has suggested that genomic instability via BRCA1/2 haploinsufficiency contributes to the early phase of BRCA-associated carcinogenesis, insights into the role of BRCA haploinsufficiency in carcinogenesis are lacking. We previously reported that the Brca1L63X/+ rat, a model of Brca1 haploinsufficiency carcinogenesis, exhibits a significantly higher incidence of mammary carcinomas than wild-type rats exposed to ionizing radiation; notably, the carcinomas retained a wild-type Brca1 allele. To explore the mutation spectrum underlying Brca1 haploinsufficiency, we performed whole-exome sequencing of spontaneous and radiation-associated mammary carcinomas in wild-type and Brca1L63X/+ rats. Mammary tumors from wild-type and Brca1L63X/+ rats did not differ significantly regarding the number of somatic single-nucleotide variants (SNVs), small insertions/deletions (InDels), or frequency of copy-number variants (CNVs). The radiation-associated carcinomas of Brca1L63X/+ rats had significantly fewer identifiable cancer-driver mutations induced by SNVs and InDels than those of wild-type rats; moreover, irradiated Brca1L63X/+ rats tended to have more carcinomas with no detectable cancer-driver mutations via SNVs, InDels or CNVs. Thus, Brca1 haploinsufficiency contributes to breast carcinogenesis by bypassing the generation of cancer-driver mutations that would otherwise occur via accumulation of nonsynonymous mutations and CNVs.
Data availability
The DNA sequences generated and analyzed during the current study are available in the DNA Data Bank of Japan (DDBJ) under accession number PRJDB35787. Other data used in this study are available from the corresponding author upon reasonable request.
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Acknowledgements
We thank Masami Ootawara, Misuzu Fujita, Mari Ogawa, Hitomi Seo, Hitomi Moriyama, Jo Kubota, Ken-ichi Kudo, Daisuke Iizuka, Yi Shang, Takahiro Hamoya, Hiromi Yanagihara, and the staff at the Department of Radiation Effects Research and the Laboratory Animal and Bioresource Sciences Section of QST for technical support.
Funding
Declaration. The study was supported by the Japan Society for the Promotion of Science (JSPS), Grant Numbers JP21H03601 and JP25H01188 to T.I., JP21H04932 and JP24H00764 to S.K. and K.D. Y.N. was supported by JSPS fellowship (Grant Number JP25KJ2002).
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Y.N., D.K., S.K. and T.I. wrote the main manuscript text. Y.N. prepared all figures and tables and performed formal analysis. Y.N., K.D., A.I., S.K., Y.N-Y., K.N., M.T. and M.N. performed the experiments. M.T., K.I. and T.I. supervised Y.N. on this project. T.M. provided the rat model used in this study. T.I. conceptualized and managed the study. All authors reviewed the manuscript.
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Protocols for animal studies were approved by the Institutional Animal Care and Use Committee of the National Institutes for Quantum Science and Technology (approval numbers 07-1016, 14-1021 and 16-1034).
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Nakamura, Y., Daino, K., Ishikawa, A. et al. Mutational profiles of spontaneous and radiation-related mammary carcinomas in a rat model of Brca1 haploinsufficiency. Sci Rep (2026). https://doi.org/10.1038/s41598-026-41240-9
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DOI: https://doi.org/10.1038/s41598-026-41240-9
