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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 J ; Lord, Christopher J ; Ashworth, Alan

The Journal of pathology, 2015-06, Vol.236 (2), p.186-200 [Periódico revisado por pares]

Chichester, UK: John Wiley & Sons, Ltd

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  • Título:
    Whole-exome DNA sequence analysis of Brca2- and Trp53-deficient mouse mammary gland tumours
  • Autor: 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 J ; Lord, Christopher J ; Ashworth, Alan
  • Assuntos: Animals ; Antigens, CD - genetics ; Brca2 ; Breast Neoplasms - genetics ; Chromosomal Proteins, Non-Histone - genetics ; Disease Models, Animal ; DNA Copy Number Variations - genetics ; DNA, Neoplasm - genetics ; exome sequencing ; Female ; Gene Knockout Techniques ; Genes, BRCA2 - physiology ; Germ-Line Mutation - genetics ; Humans ; mammary gland ; Mammary Neoplasms, Experimental - genetics ; Mice, Transgenic ; mouse model ; Mutation, Missense - genetics ; Ovarian Neoplasms - genetics ; Protein Serine-Threonine Kinases - genetics ; Receptors, Immunologic - genetics ; Sequence Analysis, DNA ; Signaling Lymphocytic Activation Molecule Family ; Tumor Suppressor Protein p53 - deficiency
  • É parte de: The Journal of pathology, 2015-06, Vol.236 (2), p.186-200
  • Notas: AppendixS1. Supplementary materials and methodsFigureS1. Schematic of the workflow to exon sequence Blg-Cre Brca2f/f Trp53f/f mammary tumours. Spleen and mammary tumour was dissected from mutant Blg-Cre Brca2f/f Trp53f/f animals and genomic DNA was isolated. DNA exon sequencing was performed using Illumina technology, followed by BWA alignment, variant calling and somatic tumour mutation determinationFigureS2. Blg-Cre Brca2f/f Trp53f/f mammary tumours have a candidate gain on chromosome 6: (left panels) Met exons 3-7 DNA sequence reads displayed in the Broad Institute IGV show an increase in tumour reads compared to the matched spleen; (right panels) the tumour DNA sequence read copy number gain break point, indicated by a black arrow; spleen and tumour reads from each animal are indicatedTableS1. Histopathalogical features of Blg-Cre Brca2f/f Trp53f/f mammary tumours used in this studyTableS2. Quantity and coverage of sequencing dataTableS3. Median depth of sequence in Blg-Cre Brca2f/f Trp53f/f mammary tumours of the most recurrently mutated genes in human breast cancersTableS4. Log2(RPKM + 1) values for Brca2 and Trp53 DNA sequenceTableS5. Unfiltered somatic mutations identified in individual Blg-Cre Brca2f/f Trp53f/f mammary tumoursTableS6. Filtered somatic mutations identified in Blg-Cre Brca2f/f Trp53f/f mammary tumoursTableS7. Number and types of de novo mutations detected in each mouse tumourTableS8. Number and types of de novo mutations detected in each histological typeTableS9. Somatic mutations predicted to alter protein sequence identified in Blg-Cre Brca2f/f Trp53f/f mammary tumoursTableS10. Sanger sequenced mutationsTableS11. CONTRA identified DNA target region alterationsTableS12. CoNIFER identified DNA copy number alterationsTableS13. Genes with copy number alteration detected by CONTRA and CoNIFERTableS14. TCGA and ICGC BRCA2 mutant breast tumoursTableS15. TCGA and ICGC BRCA2 mutant breast cancer somatic mutationsTableS16. TCGA BRCA2 mutant ovarian tumoursTableS17. TCGA BRCA2 mutant ovarian cancer somatic mutationsTableS18. Genes mutated in Blg-Cre Brca2f/f Trp53f/f mammary tumours and human BRCA2 mutant and BRCA2;TP53 mutant breast tumoursTableS19. Genes mutated in Blg-Cre Brca2f/f Trp53f/f mammary tumours and human BRCA2 mutant and BRCA2;TP53 mutant ovarian tumours
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  • Descrição: 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. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
  • Editor: Chichester, UK: John Wiley & Sons, Ltd
  • Idioma: Inglês
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