Recent translational research: Oncogene discovery by insertional mutagenesis gets a new boost

Oncogenic transformation of a normal cell is a multistep process that requires activation or inactivation, usually by mutagenic events, of several key genes controlling various essential cellular pathways that are involved in growth and development. An understanding of which pathways and genes are involved is essential to the development of novel therapeutic strategies. Although a large number of genes involved in breast and other cancers has been discovered, the picture is far from complete. Retroviral insertional mutagenesis (IM) in mouse models is among the most efficient tools to uncover cancer genes. The most important advantage of IM over chemical and radiation induced mutagenesis is that the mutagen is also a molecular tag, facilitating the identification of the mutated locus. Because proviral integration is essentially random with some bias for transcriptionally active domains, retroviral insertions in the same genomic locus in multiple independent tumours mark a so-called common insertion site (CIS), which is likely to contain a gene involved in tumourigenesis.IM was first described in 1981 by Hayward and coworkers [1] when those investigators, in an effort to elucidate the mechanism by which avian leukosis virus induces lymphomas, discovered that the virus targeted the cellular Myc gene. Shortly thereafter, Nusse and Varmus [2] identified Wnt1 as a frequent target of mouse mammary tumour virus (MMTV) using this approach. IM mediated by retroviruses is based on the integration of a DNA copy of retroviral RNA as a provirus into the cellular genome as part of the life cycle of the virus. The regulatory elements in the proviral long terminal repeats can then transcriptionally activate adjacent cellular genes. Proviral insertions that truncate cellular genes giving rise to dysfunctional or constitutively active proteins are also frequently found; for an extensive overview of retroviral IM, see the reports by Jonkers and Berns [3] and Mikkers and Berns [4].Altho