Whole-exome DNA sequence analysis of Brca2 and Trp53 deficient mouse mammary gland tumours

Mutations in the tumour suppressor BRCA2 predispose to breast, ovarian and a number of other human cancers. We have performed whole-exome DNA sequencing analysis of mouse mammary tumours from Blg-Cre Brca2f/f Trp53f/f animals, a model of BRCA2 deficient cancer. In this tumour panel, we identified recurrent somatic mutations in three genes; Sik1, Cd244 and Prr14l, but the reported frequently of these genes mutated in human breast cancer is low. We also used the exome DNA sequencing data to estimate DNA copy number alterations in these tumours and identified a recurrent copy number gain in Met, which has been found amplified in a number of other mouse mammary cancer models. Through comparative genomic analysis we found that the somatic mutations identified in mouse Brca2 null, Trp53 null mammary tumours do not closely mirror the mutations found in human breast cancer. However, by focusing on the genes mutated in human BRCA2 mutant breast and ovarian tumours, we identified a set of genes that are mutated in both human and mouse tumours. Finally, although Blg-Cre Brca2f/f Trp53f/f mammary tumours respond to drugs that target Brca2 deficient cells, a mutational signature found in human BRCA1/2 deficient cancers was not present in the genome of these mouse tumours.