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

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.