Abstract
Germline mutations in the tumour suppressor BRCA2 predispose to breast, ovarian and a number of other human cancers. Brca2-deficient mouse models are used for preclinical studies but the pattern of genomic alterations in these tumours has not yet been described in detail. 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 human cancer. We also used the 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 other mouse mammary cancer models. Through a comparative genomic analysis, we identified several mouse Blg-Cre Brca2f/f Trp53f/f mammary tumour somatic mutations in genes that are also mutated in human cancer, but few of these genes have been found frequently mutated in human breast cancer. A more detailed analysis of these somatic mutations revealed a set of genes that are mutated in human BRCA2 mutant breast and ovarian tumours and that are also mutated in mouse Brca2-null, Trp53-null mammary tumours. Finally, a DNA deletion surrounded by microhomology signature found in human BRCA1/2-deficient cancers was not common in the genome of these mouse tumours. Although a useful model, there are some differences in the genomic landscape of tumours arising in Blg-Cre Brca2f/f Trp53f/f mice compared to human BRCA-mutated breast cancers. Therefore, this needs to be taken into account in the use of this model.
Original language | English |
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Pages (from-to) | 186-200 |
Number of pages | 15 |
Journal | Journal of Pathology |
Volume | 236 |
Issue number | 2 |
Early online date | 18 Feb 2015 |
DOIs | |
Publication status | Published - Jun 2015 |
Keywords
- Animals
- Antigens, CD
- Breast Neoplasms
- Chromosomal Proteins, Non-Histone
- DNA Copy Number Variations
- DNA, Neoplasm
- Disease Models, Animal
- Female
- Gene Knockout Techniques
- Genes, BRCA2
- Germ-Line Mutation
- Humans
- Mammary Neoplasms, Experimental
- Mice, Transgenic
- Mutation, Missense
- Ovarian Neoplasms
- Protein-Serine-Threonine Kinases
- Receptors, Immunologic
- Sequence Analysis, DNA
- Tumor Suppressor Protein p53
- Brca2
- mammary gland
- mouse model
- exome sequencing