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Whole-exome DNA sequence analysis of Brca2- and Trp53-deficient mouse mammary gland tumours
Jeffrey C Francis1,2, Lorenzo Melchor1, James Campbell1,2
1The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
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.
Insights
Genomic analysis of BRCA2-deficient mouse mammary tumors reveals similarities and differences compared to human cancers. This informs the use of mouse models for BRCA2-mutant cancer research.
Area of Science:
- Genomics
- Cancer Biology
- Translational Research
Background:
- Germline mutations in BRCA2 increase predisposition to various human cancers, including breast and ovarian.
- BRCA2-deficient mouse models are crucial for preclinical studies of these cancers.
- Detailed genomic characterization of these mouse models is essential for their effective use.
Purpose of the Study:
- To comprehensively analyze the genomic alterations in mouse mammary tumors from Blg-Cre Brca2(f/f) Trp53(f/f) animals.
- To compare the genomic landscape of these mouse tumors with human BRCA-mutated cancers.
- To identify conserved and divergent mutational patterns for improved preclinical modeling.
Main Methods:
- Whole-exome DNA sequencing of mouse mammary tumors.
- Estimation of DNA copy number alterations.
- Comparative genomic analysis with human cancer mutation data.
Main Results:
- Identified a recurrent copy number gain in the Met gene.
- Found somatic mutations in genes also mutated in human cancers, though frequency varied.
- Discovered a subset of genes mutated in both mouse and human BRCA2-mutant tumors.
- Observed a lower prevalence of microhomology-associated deletions compared to human BRCA1/2-deficient cancers.
Conclusions:
- The Blg-Cre Brca2(f/f) Trp53(f/f) mouse model exhibits a distinct genomic landscape compared to human BRCA-mutated breast cancers.
- While valuable, the differences must be considered when utilizing this model for preclinical research.
- Further comparative genomic studies are needed to refine the application of mouse models in BRCA2-deficient cancer research.
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