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

Jeffrey C Francis, Lorenzo Melchor, James Campbell, Howard Kendrick, Wenbin Wei, Javier Armisen-Garrido, Ioannis Assiotis, Lina Chen, Iwanka Kozarewa, Kerry Fenwick, Amanda Swain, Matthew J Smalley, Christopher J. Lord, Alan Ashworth

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


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 languageEnglish
Pages (from-to)186-200
Number of pages15
JournalJournal of Pathology
Issue number2
Early online date18 Feb 2015
Publication statusPublished - Jun 2015


  • 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


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