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Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history

  1. Sharon N. Teraoka Ph.D.1,†,
  2. Kathleen E. Malone Ph.D.2,3,†,
  3. David R. Doody M.S.2,
  4. Nicola M. Suter Ph.D.4,
  5. Elaine A. Ostrander Ph.D.4,
  6. Janet R. Daling Ph.D.2,3,
  7. Patrick Concannon Ph.D.1,5,‡,*

Article first published online: 9 AUG 2001

DOI: 10.1002/1097-0142(20010801)92:3<479::AID-CNCR1346>3.0.CO;2-G

Issue

Cancer

Cancer

Volume 92, Issue 3, pages 479–487, 1 August 2001

Additional Information

How to Cite

Teraoka, S. N., Malone, K. E., Doody, D. R., Suter, N. M., Ostrander, E. A., Daling, J. R. and Concannon, P. (2001), Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer, 92: 479–487. doi: 10.1002/1097-0142(20010801)92:3<479::AID-CNCR1346>3.0.CO;2-G

Author Information

  1. 1

    Molecular Genetics Program, Virginia Mason Research Center, Seattle, Washington

  2. 2

    Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington

  3. 3

    Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, Washington

  4. 4

    Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington

  5. 5

    Department of Immunology, University of Washington School of Medicine, Seattle, Washington

  1. †

    Sharon N. Teraoka, Ph.D. and Kathleen E. Malone, Ph.D. contributed equally to this article.

  2. ‡

    Fax: (206) 625-7213

*Molecular Genetics Program, Virginia Mason Research Center, 1201 Ninth Avenue, Seattle, WA 98101-2795

Publication History

  1. Issue published online: 9 AUG 2001
  2. Article first published online: 9 AUG 2001
  3. Manuscript Revised: 19 APR 2001
  4. Manuscript Received: 20 DEC 2000

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Keywords:

  • breast carcinoma;
  • ataxia-telangiectasia;
  • missense mutations;
  • DNA double-strand break repair

Mutations in the ATM gene, specifically those predicted to result in amino acid substitutions, were significantly increased in breast carcinoma cases selected for positive family history.

Abstract

BACKGROUND

An increased incidence of breast carcinoma has been reported among relatives of individuals who are affected with the rare recessive disorder, ataxia-telangiectasia (A-T), and who are heterozygous for mutations in the ataxia-telangiectasia mutated (ATM) gene. However, most studies of breast carcinoma cases from the general population have failed to find a higher incidence of ATM mutations in cases when compared with controls.

METHODS

Genomic DNA samples from 258 individuals were screened for mutations of all types in each of the 62 coding exons of the ATM gene; 142 of these were from breast carcinoma cases with a first-degree family history or early age at diagnosis, 35 were from cases selected for the presence of either known disease-related mutations (n = 25) or missense alterations of unknown consequences (n = 10) in BRCA1 or BRCA2, and 81 were from matched controls.

RESULTS

A total of 12 individuals with ATM mutations were identified, 11 among 142 breast carcinoma cases (7.7%; 95% CI, 3.9–13.4%) and 1 among 81 controls (1.2%; 95% CI, 0.0–6.7%) (P = 0.06). All mutations detected were of the missense type; none were predicted to truncate the ATM protein. Among cases, mutations were found exclusively in patients with a family history of breast carcinoma (12.1%; 95% CI, 6.2–20.6%) (P = 0.02). Similar frequencies of ATM mutations were found in 35 additional cases selected for the presence of BRCA1 or BRCA2 mutations when compared with cases overall.

CONCLUSIONS

ATM mutations, specifically missense mutations, are more common in breast carcinoma cases selected for first-degree family history and early age at diagnosis. Cancer 2001;92:479–87. © 2001 American Cancer Society.

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