title: Whole-exome DNA sequence analysis of Brca2- and Trp53-deficient mouse mammary gland tumours.
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 Brca2(f/f) Trp53(f/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 Brca2(f/f) Trp53(f/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 Brca2(f/f) Trp53(f/f) mice compared to human BRCA-mutated breast cancers. Therefore, this needs to be taken into account in the use of this model.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.|The CRUK Gene Function Laboratory, Institute of Cancer Research, London, UK.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Francis
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Melchor
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.|The CRUK Gene Function Laboratory, Institute of Cancer Research, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Campbell
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.|The CRUK Gene Function Laboratory, Institute of Cancer Research, London, UK.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wei
authors.affiliation: Tumour Profiling Unit, Institute of Cancer Research, London, UK.
authors.forename: Javier
authors.initials: J
authors.lastname: Armisen-Garrido
authors.affiliation: Tumour Profiling Unit, Institute of Cancer Research, London, UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Assiotis
authors.affiliation: Tumour Profiling Unit, Institute of Cancer Research, London, UK.
authors.forename: Lina
authors.initials: L
authors.lastname: Chen
authors.affiliation: Tumour Profiling Unit, Institute of Cancer Research, London, UK.
authors.forename: Iwanka
authors.initials: I
authors.lastname: Kozarewa
authors.affiliation: Tumour Profiling Unit, Institute of Cancer Research, London, UK.
authors.forename: Kerry
authors.initials: K
authors.lastname: Fenwick
authors.affiliation: Tumour Profiling Unit, Institute of Cancer Research, London, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Swain
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Smalley
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.|The CRUK Gene Function Laboratory, Institute of Cancer Research, London, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.|The CRUK Gene Function Laboratory, Institute of Cancer Research, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D055786:Gene Knockout Techniques; D024522:Genes, BRCA2 / Q000502:physiology*; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics; D017422:Sequence Analysis, DNA; D000071176:Signaling Lymphocytic Activation Molecule Family; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
chemical_list: D015703:Antigens, CD; C490007:Cd244a protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D004273:DNA, Neoplasm; C000594006:PRR14 protein, human; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; C495376:Sik1 protein, mouse
keywords: Brca2; exome sequencing; mammary gland; mouse model