Abstract
BackgroundHere 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.ResultsWe 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.ConclusionsPaired-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.
Highlights
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
We sought to determine whether the functional abrogation of homologous recombination (HR) would lead to differences in DNA structural rearrangements in mouse models of breast cancer
To test this we used Paired-end massively parallel sequencing (PE-MPS) to analyze four HR-deficient mouse mammary tumors derived from K14cre;Brca1flox/ flox;Trp53 flox/flox and K14cre;Brca2 flox/flox;Trp53 flox/flox conditional knock-out mice [19,20,21], and four tumors derived from K14cre;Cdh1flox/flox;Trp53 flox/flox and two K14cre;Trp53 flox/flox mice that do not carry engineered mutations in the HR machinery [19,20,21,24]
Summary
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. Analysis of structural DNA rearrangements in mouse tumors has mainly relied on inferred breakpoint analysis based on copy number changes gleaned from array-based comparative genomic hybridization (aCGH) [10]. Paired-end massively parallel sequencing (PE-MPS) can be used to overcome these inherent shortcomings, as this technique allows all sequence rearrangements to be identified at base-pair resolution, including copy number neutral changes such as inversions and translocations
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