Genomic DNA copy number alterations in mouse cancer models and human cancer

Abstract

The development of solid tumors is associated with the acquisition of genetic and epigenetic alterations. Although these changes may be brought about at the genomic level in a variety of ways, genomic DNA copy number aberrations are particularly frequent in solid tumors and are expected to contribute to tumor evolution by copy number induced alterations in gene expression. Mouse cancer models recapitulate genomic alterations observed in human tumors to varying degrees. Comparison of aberrations in tumor genomes in mouse models and human cancer has facilitated the identification of oncogenes and tumor suppressors, as well as polymorphic variants contributing to individual cancer susceptibility. Cancer development is associated with the acquisition of genomic and epigenetic alterations. These changes may be brought about at the genomic level in a variety of ways, including altered karyotypes, point mutations, and epigenetic mechanisms. Cytogenetic and more recently molecular and array-based analytic methods have found great variation in the numbers and types of chromosome level alterations present in human tumors (Mitelman et al. 2008). Recurrent alterations involving chromosomal copy number changes have been observed frequently, particularly in solid tumors. Reduced or enhanced expression of one or more genes mapping to such regions is expected to provide the selection for maintenance of the aberrations. Thus, recurrent chromosomal aberrations provide a route to discovery of genes or pathways that contribute to development and progression of tumors. Nevertheless, uncovering the driver genes for recurrent chromosomal aberrations remains challenging because the aberrations may span large regions of the genome and contain many genes. Here, we illustrate with examples how mouse cancer models recapitulate genomic alterations observed in human cancer, and how cross-species comparisons have facilitated the identification of oncogenes and tumor suppressors, as well as polymorphic variants contributing to individual cancer susceptibility.