# Mutational profiles of spontaneous and radiation-related mammary carcinomas in a rat model of Brca1 haploinsufficiency

## TL;DR

This study examines how BRCA1 haploinsufficiency influences the development of breast cancer in rats, finding that it reduces the need for driver mutations.

## Contribution

The study reveals that Brca1 haploinsufficiency enables carcinogenesis without typical driver mutations.

## Key findings

- Brca1L63X/+ rats had higher mammary carcinoma incidence than wild-type rats after radiation.
- Radiation-associated carcinomas in Brca1L63X/+ rats had fewer cancer-driver mutations than in wild-type rats.
- Some carcinomas in Brca1L63X/+ rats lacked detectable driver mutations from SNVs, InDels, or CNVs.

## 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.

The online version contains supplementary material available at 10.1038/s41598-026-41240-9.