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New genes involved in cancer identified by retroviral tagging
Takeshi Suzuki1, Haifa Shen, Keiko Akagi
1Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland 21702, USA.
Abstract:
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 cancer. Here we report the first large-scale use of retroviral tagging for cancer gene discovery in the post-genome era. Using high throughput inverse PCR, 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.
Insights
Retroviral tagging identified 152 common integration sites (CISs) in mouse tumors, revealing 36 known cancer genes and novel candidates. This approach advances cancer gene discovery in the post-genome era.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Retroviral insertional mutagenesis in mice causes specific cancers (myeloid leukemia, B- and T-cell lymphoma).
- Retroviral integration sites (RISs) serve as genetic tags to identify cancer-driving genes.
- The post-genome era enables large-scale analysis of these RISs for cancer gene discovery.
Purpose of the Study:
- To conduct the first large-scale retroviral tagging study for cancer gene discovery.
- To identify common retroviral integration sites (CISs) associated with specific tumor types.
- To discover novel candidate genes involved in cancer development.
Main Methods:
- High-throughput inverse PCR was used to clone and sequence 884 RISs from a B-cell lymphoma tumor panel.
- An additional 415 RIS sequences from myeloid leukemias and lymphomas were analyzed.
- Sequences were compared against the mouse genome to identify common integration sites (CISs).
Main Results:
- 152 CISs were identified across multiple tumors, indicating potential cancer genes.
- 36 CISs encoded known or predicted human cancer genes or their homologs.
- Other CISs identified novel candidate genes not previously linked to cancer.
Conclusions:
- Retroviral tagging is a powerful tool for cancer gene discovery in the post-genome era.
- The study identified numerous novel candidate cancer genes in mice.
- Findings suggest significant complexity in mouse and human cancer etiology.