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

Francis, Jeffrey C., Melchor, Lorenzo, Campbell, James, Kendrick, Howard, Wei, Wenbin, Armisen-Garrido, Javier, Assiotis, Ioannis, Chen, Lina, Kozarewa, Iwanka, Fenwick, Kerry, Swain, Amanda, Smalley, Matthew John ORCID: https://orcid.org/0000-0001-9540-1146, Lord, Christopher J. and Ashworth, Alan 2015. Whole exome DNA sequence analysis of Brca2 and Trp53 deficient mouse mammary gland tumours. Journal of Pathology 236 (2) , pp. 186-200. 10.1002/path.4517

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords:	Brca2; mammary gland; mouse model; exome sequencing
Publisher:	Wiley
ISSN:	0022-3417
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	11 February 2015
Last Modified:	19 Nov 2024 03:00
URI:	https://orca.cardiff.ac.uk/id/eprint/71737

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