New genes involved in cancer identified by retroviral tagging

An Erratum to this article was published on 01 October 2002


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: CIS genes can be assigned to signaling pathways associated with hematopoietic disease.


  1. 1

    Li, J. et al. Leukaemia disease genes: large-scale cloning and pathway predictions. Nature Genet. 23, 348–353 (1999).

    CAS  Article  Google Scholar 

  2. 2

    Hansen, G.M., Skapura, D. & Justice, M.J. Genetic profile of insertion mutations in mouse leukemias and lymphomas. Genome Res. 10, 237–243 (2000).

    CAS  Article  Google Scholar 

  3. 3

    Hartley, J.W. et al. Accelerated appearance of multiple B cell lymphoma types in NFS/N mice congenic for ecotropic murine leukemia viruses. Lab. Invest. 80, 159–169 (2000).

    CAS  Article  Google Scholar 

  4. 4

    Lazo, P.A., Lee, J.S. & Tsichlis, P.N. Long-distance activation of the Myc protooncogene by provirus insertion in Mlvi-1 or Mlvi-4 in rat T-cell lymphomas. Proc. Natl Acad. Sci. USA 87, 170–173 (1990).

    CAS  Article  Google Scholar 

  5. 5

    Zeidler, R. et al. Breakpoints of Burkitt's lymphoma t(8;22) translocations map within a distance of 300 kb downstream of MYC. Genes Chromosom. Cancer 9, 282–287 (1994).

    CAS  Article  Google Scholar 

  6. 6

    Ben-David, Y., Lavigueur, A., Cheong, G.Y. & Bernstein, A. Insertional inactivation of the p53 gene during friend leukemia: a new strategy for identifying tumor suppressor genes. New Biol. 2, 1015–1023 (1990).

    CAS  PubMed  Google Scholar 

  7. 7

    Largaespada, D.A., Shaughnessy, J.D. Jr, Jenkins, N.A. & Copeland, N.G. Retroviral integration at the Evi-2 locus in BXH-2 myeloid leukemia cell lines disrupts Nf1 expression without changes in steady-state Ras-GTP levels. J. Virol. 69, 5095–5102 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Mock, B.A., Liu, L., LePaslier, D. & Huang, S. The B-lymphocyte maturation promoting transcription factor BLIMP1/PRDI-BF1 maps to D6S447 on human chromosome 6q21-q22.1 and the syntenic region of mouse chromosome 10. Genomics 37, 24–28 (1996).

    CAS  Article  Google Scholar 

  9. 9

    Cao, J. et al. Characterization of colorectal-cancer-related cDNA clones obtained by subtractive hybridization screening. J. Cancer Res. Clin. Oncol. 123, 447–451 (1997).

    CAS  Article  Google Scholar 

  10. 10

    Neri, A., Fracchiolla, N.S., Migliazza, A., Trecca, D. & Lombardi, L. The involvement of the candidate proto-oncogene NFKB2/lyt-10 in lymphoid malignancies. Leuk. Lymphoma 23, 43–48 (1996).

    CAS  Article  Google Scholar 

  11. 11

    Tomasetto, C. et al. Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11-q21.3 region of chromosome 17. Genomics 28, 367–376 (1995).

    CAS  Article  Google Scholar 

  12. 12

    Collins, C. et al. Positional cloning of ZNF217 and NABC1: genes amplified at 20q13.2 and overexpressed in breast carcinoma. Proc. Natl Acad. Sci. USA 95, 8703–8708 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Zeng, W.R. et al. Loss of heterozygosity and reduced expression of the CUTL1 gene in uterine leiomyomas. Oncogene 14, 2355–2365 (1997).

    CAS  Article  Google Scholar 

  14. 14

    Taipale, J. & Beachy, P.A. The Hedgehog and Wnt signalling pathways in cancer. Nature 411, 349–354 (2001).

    CAS  Article  Google Scholar 

  15. 15

    Nakamura, T., Largaespada, D.A., Shaughnessy, J.D. Jr., Jenkins, N.A. & Copeland, N.G. Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukaemias. Nature Genet. 12, 149–153 (1996).

    CAS  Article  Google Scholar 

  16. 16

    Lund, A.H. et al. Genome-wide retroviral insertional tagging of cancer genes in Cdkn2a-deficient mice. Nature Genet. 32, 80–85 (2002); advance online publication, 19 August 2002 (doi:10.1038/ng956).

    Article  Google Scholar 

  17. 17

    Mikkers, H. et al. High-throughput retroviral tagging to identify components of specific signaling pathways in cancer. Nature Genet. 32, 73–79 (2002); advance online publication, 19 August 2002 (doi:10.1038/ng950).

    Article  Google Scholar 

  18. 18

    Mitelman, F., Mertens, F. & Johansson, B. A breakpoint map of recurrent chromosomal rearrangements in human neoplasia. Nature Genet. 15 (Spec. No.), 417–474 (1997).

    CAS  Article  Google Scholar 

  19. 19

    Pollack, J.R. et al. Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nature Genet. 23, 41–46 (1999).

    CAS  Article  Google Scholar 

  20. 20

    Luo, G. et al. Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nature Genet. 26, 424–429 (2000).

    CAS  Article  Google Scholar 

  21. 21

    Dupuy, A.J., Fritz, S. & Largaespada, D.A. Transposition and gene disruption in the male germline of the mouse. Genesis 30, 82–88 (2001).

    CAS  Article  Google Scholar 

  22. 22

    Fischer, S.E., Wienholds, E. & Plasterk, R.H. Regulated transposition of a fish transposon in the mouse germ line. Proc. Natl Acad. Sci. USA 98, 6759–6764 (2001).

    CAS  Article  Google Scholar 

  23. 23

    Horie, K. et al. Efficient chromosomal transposition of a Tc1/mariner-like transposon Sleeping Beauty in mice. Proc. Natl Acad. Sci. USA 98, 9191–9196 (2001).

    CAS  Article  Google Scholar 

  24. 24

    Jenkins, N.A., Copeland, N.G., Taylor, B.A., Bedigian, H.G. & Lee, B.K. Ecotropic murine leukemia virus DNA content of normal and lymphomatous tissues of BXH-2 recombinant inbred mice. J. Virol. 42, 379–388 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Gilbert, D.J., Neumann, P.E., Taylor, B.A., Jenkins, N.A. & Copeland, N.G. Susceptibility of AKXD recombinant inbred mouse strains to lymphomas. J. Virol. 67, 2083–2090 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Morse, H.C. III et al. Combined histologic and molecular features reveal previously unappreciated subsets of lymphoma in AKXD recombinant inbred mice. Leuk. Res. 25, 719–733 (2001).

    CAS  Article  Google Scholar 

  27. 27

    Copeland, N.G. & Jenkins, N.A. Development and applications of a molecular genetic linkage map of the mouse genome. Trends Genet. 7, 113–118 (1991).

    CAS  Article  Google Scholar 

Download references


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.).

Author information



Corresponding author

Correspondence to Neal G Copeland.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Suzuki, T., Shen, H., Akagi, K. et al. New genes involved in cancer identified by retroviral tagging. Nat Genet 32, 166–174 (2002).

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing