Retroviral insertional mutagenesis in BXH2 and AKXD mice induces a high incidence of myeloid leukemia and B- and T-cell lymphoma, respectively. The retroviral integration sites (RISs) in these tumors thus provide powerful genetic tags for the discovery of genes involved in cancer1,2. Here we report the first large-scale use of retroviral tagging for cancer gene discovery in the post-genome era. Using high throughput inverse PCR1, we cloned and analyzed the sequences of 884 RISs from a tumor panel composed primarily of B-cell lymphomas. We then compared these sequences, and another 415 RIS sequences previously cloned from BXH2 myeloid leukemias and from a few AKXD lymphomas, against the recently assembled mouse genome sequence. These studies identified 152 loci that are targets of retroviral integration in more than one tumor (common retroviral integration sites, CISs) and therefore likely to encode a cancer gene. Thirty-six CISs encode genes that are known or predicted to be genes involved in human cancer or their homologs, whereas others encode candidate genes that have not yet been examined for a role in human cancer. Our studies demonstrate the power of retroviral tagging for cancer gene discovery in the post-genome era and indicate a largely unrecognized complexity in mouse and presumably human cancer.
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We thank D. Gilbert for help with the interspecific backcross mapping, J. Hartley for the NFS.V+ congenic tumors and S. Chattopadhyay for DNA isolation from NFS.V+ tumors. This research was supported by the National Cancer Institute (N.A.J. and N.G.C.), the National Institute of Allergy and Infectious Diseases (H.C.M.), the Japan Society for the Promotion of Science (K.A.) and the National Science Foundation (D.Q.M.).
The authors declare no competing financial interests.
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