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.

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.

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