Somatic structural rearrangements in genetically engineered mouse mammary tumors

Here we present the first paired-end sequencing of tumors from genetically engineered mouse models of cancer to determine how faithfully these models recapitulate the landscape of somatic rearrangements found in human tumors. These were models of Trp53-mutated breast cancer, Brca1- and Brca2-associa...

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Bibliographic Details
Published in:	Genome biology 2010-10, Vol.11 (10), p.R100-R100
Main Authors:	Varela, Ignacio, Klijn, Christiaan, Stephens, Phillip J, Mudie, Laura J, Stebbings, Lucy, Galappaththige, Danushka, van der Gulden, Hanneke, Schut, Eva, Klarenbeek, Sjoerd, Campbell, Peter J, Wessels, Lodewyk Fa, Stratton, Michael R, Jonkers, Jos, Futreal, P Andrew, Adams, David J
Format:	Article
Language:	eng
Subjects:	Animals Animals, Genetically Modified Base Sequence BRCA1 Protein - genetics BRCA1 Protein - metabolism BRCA2 Protein - genetics BRCA2 Protein - metabolism Breast Neoplasms - genetics Cadherins - metabolism Cell Line, Tumor Female Gene Fusion Gene Rearrangement Genomic Library Humans Mice Mutation Receptors, LDL - genetics Sequence Deletion Tumor Suppressor Protein p53 - genetics Tumor Suppressor Proteins - genetics
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Summary:	Here we present the first paired-end sequencing of tumors from genetically engineered mouse models of cancer to determine how faithfully these models recapitulate the landscape of somatic rearrangements found in human tumors. These were models of Trp53-mutated breast cancer, Brca1- and Brca2-associated hereditary breast cancer, and E-cadherin (Cdh1) mutated lobular breast cancer. We show that although Brca1- and Brca2-deficient mouse mammary tumors have a defect in the homologous recombination pathway, there is no apparent difference in the type or frequency of somatic rearrangements found in these cancers when compared to other mouse mammary cancers, and tumors from all genetic backgrounds showed evidence of microhomology-mediated repair and non-homologous end-joining processes. Importantly, mouse mammary tumors were found to carry fewer structural rearrangements than human mammary cancers and expressed in-frame fusion genes. Like the fusion genes found in human mammary tumors, these were not recurrent. One mouse tumor was found to contain an internal deletion of exons of the Lrp1b gene, which led to a smaller in-frame transcript. We found internal in-frame deletions in the human ortholog of this gene in a significant number (4.2%) of human cancer cell lines. Paired-end sequencing of mouse mammary tumors revealed that they display significant heterogeneity in their profiles of somatic rearrangement but, importantly, fewer rearrangements than cognate human mammary tumors, probably because these cancers have been induced by strong driver mutations engineered into the mouse genome. Both human and mouse mammary cancers carry expressed fusion genes and conserved homozygous deletions.
ISSN:	1465-6906 1474-760X 1465-6914