Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Heterozygous ATM mutations do not contribute to early onset of breast cancer

Nature Genetics volume 15, pages 307–310 (1997)Cite this article

Abstract

Ataxia telangiectasia (AT) is a recessive syndrome, including cerebellar degeneration, immunologic defects and cancer predisposition1,2, attributed to mutations in the recently isolated ATM (ataxia telangiectasia, mutated) gene3. AT is diagnosed in 1/40,000 to 1/100,000 live births, with carriers calculated to comprise ∼1% of the population. Studies of AT families have suggested that female relatives presumed to be carriers have a 5 to 8-fold increased risk for developing breast cancer4,5, raising the possibility that germline ATM mutations may account for ∼5% of all breast cancer cases. The increased risk for breast cancer reported for AT family members has been most evident among younger women, leading to an age-specific relative risk model predicting that 8% of breast cancer in women under age 40 arises in AT carriers, compared with 2% of cases between 40–59 years6. To test this hypothesis, we undertook a germ-line mutational analysis of the ATM gene in a population of women with early onset of breast cancer, using a protein truncation (PTT) assay to detect chain-terminating mutations, which account for 90% of mutations identified in children with AT7–11. We detected a heterozygous ATM mutation in 2/202 (1%) controls, consistent with the frequency of AT carriers predicted from epidemiologic studies. ATM mutations were present in only 2/401 (0.5%) women with early onset of breast cancer (P = 0.6). We conclude that heterozygous ATM mutations do not confer genetic predisposition to early onset of breast cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Shiloh, Y. Ataxia-telangiectasia: closer to unraveling the mystery. Eur. J. Hum. Genet 3, 116–138 (1995).

    Article  CAS  Google Scholar 

  2. Morrell, D. Cromartie, E. & Swift, M. Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J. Natl. Cancer Inst. 77, 89–92 (1986).

    CAS  PubMed  Google Scholar 

  3. Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749–1753 (1995).

    Article  CAS  Google Scholar 

  4. Swift, M. Reitnauer, P. Morrell, D. & Chase, C. Breast and other cancers in families with ataxia-telangiectasia. New Engl. J. Med. 316, 1289–1294 (1987).

    Article  CAS  Google Scholar 

  5. Swift, M. Morrell, D. Massey, R. & Chase, C. Incidence of cancer in 161 families affected by ataxia-telangiectasia. New Engl. J. Med. 325, 1831–1836 (1991).

    Article  CAS  Google Scholar 

  6. Easton, D. Cancer risks in A-T heterozygotes. Int. J. Radiat Biol. 66, S177–182 (1994).

    Article  CAS  Google Scholar 

  7. Gilad, S. et al. Predominance of null mutations in ataxia-telangiectasia. Hum. Mol. Genet. 5, 433–439 (1996).

    Article  CAS  Google Scholar 

  8. Byrd, P. et al. Mutations revealed by sequencing the 5′ half of the gene for ataxia telangiectasia. Hum. Mol. Genet. 5, 145–149 (1996).

    Article  CAS  Google Scholar 

  9. Telatar, M. et al. Ataxia-telangiectasia: mutations in ATM cDNA detected by protein-truncation screening. Am. J. Hum. Genet. 59, 40–44 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wright, J. et al. A high frequency of distinct ATM gene mutations in ataxia-telangiectasia. Am. J. Hum. Genet. 59, 839–846 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Baumer, A. Bernthaler, U. Wolz, W. Hoehn, H. & Schindler, D. New mutations in the ataxia telangiectasia gene. Hum. Genet. 98, 246–249 (1996).

    Article  CAS  Google Scholar 

  12. Wooster, R. et al. Absence of linkage to the ataxia-telangiectasia locus in familial breast cancer. Hum. Genet. 92, 91–94 (1993).

    Article  CAS  Google Scholar 

  13. Vorechovsky, I. et al. The ATM gene and susceptibility to breast cancer: analysis of 38 breast tumors reveals no evidence for mutation. Cancer Res. 56, 2726–2732 (1996).

    CAS  PubMed  Google Scholar 

  14. Vorechovsky, I. et al. ATM mutations in cancer families. Cancer Res. 56, 4130–4133 (1996).

    CAS  PubMed  Google Scholar 

  15. FitzGerald, M. et al. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset of breast cancer. New Engl. J. Med. 334, 143–149 (1996).

    Article  CAS  Google Scholar 

  16. Pippard, E.C. Hall, A.J. Barker, D.J.P. & Bridges, B.A. Cancer in homozygotes and heterozygotes of ataxia-telangiectasia and xeroderma pigmentosum in Britain. Cancer Res. 48, 2929–2932 (1988).

    CAS  PubMed  Google Scholar 

  17. Borresen, A.L. Anderson, T.I. Treti, S. Heiberg, A. & Muller, P. Breast cancer and other cancers in Norwegian families with ataxia-telangiectasia. Genes Chrom. Cancer 2, 339–340 (1990).

    Article  CAS  Google Scholar 

  18. Athma, P. Rappaport, R. & Swift, M. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet. Cytogenet. 92, 130–134 (1996).

    Article  CAS  Google Scholar 

  19. Cunliffe, P.N. Mann, J.R. Cameron, A.H. Roberts, K.D. & Ward, H.W.C. Radiosensitivity in ataxia-telangiectasia. Br. J. Radiol. 48, 374–376 (1975).

    Article  Google Scholar 

  20. Taylor, A.M.R. et al. Ataxia-telangiectasia: a human mutation with abnormal radiation sensitivity. Nature 258, 427–429 (1975).

    Article  CAS  Google Scholar 

  21. Houldsworth, J. & Lavin, M. Effect of ionizing radiation on DNA synthesis in ataxia telangiectasia cells. Nucleic Acid Res. 8, 3709–3720 (1980).

    Article  CAS  Google Scholar 

  22. Cole, J. et al. Comparative human cellular radiosensitivity. II The survival following gamma-irradiation of unstimulated (G°) T lymphocytes, T lymphocyte lines, lymphoblastoid cell lines and fibroblasts from normal donors, from ataxia-telangiectasia patients, and from ataxia-telangiectasia heterozygotes. Int. J. Radiat Biol. 54, 929–943 (1988).

    Article  CAS  Google Scholar 

  23. Beamish, H. & Lavin, M. Radiosensitivity in ataxia-telangiectasia. Anomalies in radiation-induced cell cycle delay. Int. J. Radiat. Biol. 6, 175–184 (1994).

    Article  Google Scholar 

  24. Thacker, J. Cellular radiosensitivity in ataxia-telangiectasia. Int. J. Radiat. Biol. 66, 587–596 (1994).

    Article  Google Scholar 

  25. West, C. Elyan, S. Berry, P. Cowan, R. & Scott, D. A comparison of the radiosensitivity of lymphocytes from normal donors, cancer patients, individuals with ataxia-telangiectasia (A-T) and A-T heterozygotes. Int. J. Radiat. Biol. 68, 197–203 (1995).

    Article  CAS  Google Scholar 

  26. Jorgensen, T.J. & Shiloh, Y. The ATM gene and the radiobiology of ataxia-telangiectasia. Int. J. Radiat. Biol. 69, 57–537 (1996).

    Article  Google Scholar 

  27. Kastan, M. et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71, 587–597 (1992).

    Article  CAS  Google Scholar 

  28. Khanna, K. & Lavin, M. Ionizing radiation and UV induction of p53 protein by different pathways in ataxia-telangiectasia cells. Oncogene 8, 3307–3312 (1993).

    CAS  PubMed  Google Scholar 

  29. Xu, Y. & Baltimore, D. Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev. 10, 2401–2410 (1996).

    Article  CAS  Google Scholar 

  30. Savitsky, K. et al. The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. Hum. Mol. Genet. 4, 2025–2032 (1995).

    Article  CAS  Google Scholar 

  31. Greenwell, P. et al. TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene. Cell 82, 823–829 (1995).

    Article  CAS  Google Scholar 

  32. Morrow, D. Tagle, D. Shiloh, Y. Collins, F. & Hieter, P. TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1. Cell 82, 831–840 (1995).

    Article  CAS  Google Scholar 

  33. Paulovich, A. & Hartwell, L. A checkpoint regulates the rate of progression through S phase in S. cerevisiae in response to DNA damage. Cell 82, 841–847 (1995).

    Article  CAS  Google Scholar 

  34. Hartley, K. et al. DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product. Cell 82, 849–856 (1995).

    Article  CAS  Google Scholar 

  35. Hari, K. et al. The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene. Cell 82, 815–821 (1995).

    Article  CAS  Google Scholar 

  36. Zakian, V. ATM-related genes; what do they tell us about functions of the human gene? Cell 82, 685–687 (1995).

    Article  CAS  Google Scholar 

  37. Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996).

    Article  CAS  Google Scholar 

  38. Xu, Y. et al. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10, 2411–2422 (1996).

    Article  CAS  Google Scholar 

  39. Ramsay, J. Birrell, G. & Lavin, M. Breast cancer and radiotherapy in ataxia-telangiectasia heterozygote. Lancet 347, 1627 (1996).

    Article  CAS  Google Scholar 

  40. Stine, G.J. Population genetics, in The new human genetics, (ed. Kevin Kane) 393–396 (Wm. C. Brown, Dubuque, Iowa, 1989).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Cancer Risk Analysis, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts, 02129, USA

    Michael G. FitzGerald, James M. Bean, Sanjay R. Hegde, Hilal Unsal, Deborah J. MacDonald, D. Paul Harkin, Kurt J. Isselbacher & Daniel A. Haber

  2. Department of Biostatistics, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts, 02129, USA

    Dianne M. Finkelstein

Authors
  1. Michael G. FitzGerald
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James M. Bean
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sanjay R. Hegde
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hilal Unsal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Deborah J. MacDonald
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D. Paul Harkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dianne M. Finkelstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kurt J. Isselbacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daniel A. Haber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel A. Haber.

Rights and permissions

Reprints and permissions

About this article

Cite this article

FitzGerald, M., Bean, J., Hegde, S. et al. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 15, 307–310 (1997). https://doi.org/10.1038/ng0397-307

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0397-307

This article is cited by

Search

Advanced search

Quick links

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