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Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer

Nature Genetics volume 32, pages 185–190 (2002)Cite this article

Abstract

Ataxia-telangiectasia is characterized by radiosensitivity, genome instability and predisposition to cancer1,2. Heterozygous carriers of ATM, the gene defective in ataxia-telangiectasia, have a higher than normal risk of developing breast and other cancers3,4,5,6. We demonstrate here that Atm 'knock-in' (Atm-ΔSRI) heterozygous mice harboring an in-frame deletion corresponding to the human 7636del9 mutation show an increased susceptibility to developing tumors. In contrast, no tumors are observed in Atm knockout (Atm+/−) heterozygous mice. In parallel, we report the appearance of tumors in 6 humans from 12 families who are heterozygous for the 7636del9 mutation. Expression of ATM cDNA containing the 7636del9 mutation had a dominant-negative effect in control cells, inhibiting radiation-induced ATM kinase activity in vivo and in vitro. This reduces the survival of these cells after radiation exposure and enhances the level of radiation-induced chromosomal aberrations. These results show for the first time that mouse carriers of a mutated Atm that are capable of expressing Atm have a higher risk of cancer. This finding provides further support for cancer predisposition in human ataxia-telangiectasia carriers.

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Figure 1: Atm-ΔSRI heterozygous mice are susceptible to developing a variety of tumors.
Figure 2: Expression of wildtype and mutant Atm.
Figure 3: Effect of ionizing radiation on survival and ATM kinase activity in human and mouse cells.
Figure 4: Effect of radiation on ATM kinase activity in control (C3ABR) lymphoblastoid cells transfected with full-length ATM cDNA (pMAT1) or 7636del9 mutant from (pΔSRI).

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Acknowledgements

We thank the Australian National Health and Medical Research Council, the Ataxia-Telangiectasia Research Foundation (Los Angeles) and the Ataxia-Telangiectasia Children's Project (Florida) for support. Thanks to A. Farrell for technical support and T. Laing for typing the manuscript. P.J.M. acknowledges support from the NIH and the American Lebanese and Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital. M.S. acknowledges support from the NIH.

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Authors and Affiliations

  1. Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, 4029, Australia

    Kevin Spring, Farida Ahangari, Shaun P. Scott, David M. Purdie, Philip C. Chen, Jonathan Ramsay & Martin F. Lavin

  2. Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne, Victoria, Australia

    Paul Waring

  3. Alexandra House, 201 Wickham Terrace, Brisbane, Australia

    Kevin Hourigan

  4. Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Peter J. McKinnon

  5. Department of Biological Sciences, Pace University, Pleasantville, New York, USA

    Michael Swift

  6. Department of Surgery, Clinical Sciences Building, Royal Brisbane Hospital, Herston, 4029, Australia

    Martin F. Lavin

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Correspondence to Martin F. Lavin.

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Spring, K., Ahangari, F., Scott, S. et al. Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nat Genet 32, 185–190 (2002). https://doi.org/10.1038/ng958

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