© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 3, 205-215,
February 6, 2002
© 2002 Oxford University Press
ARTICLE |
Dominant Negative ATM Mutations in Breast Cancer Families
Affiliations of authors: G. Chenevix-Trench, A. B. Spurdle, M. Gatei, H. Kelly, A. Marsh, X. Chen, K. Donn, D. Nyholt, K. K. Khanna, Queensland Institute of Medical Research, Brisbane, Australia; M. Cummings, Department of Pathology, University of Queensland Medical School, Australia; M. A. Jenkins, J. L. Hopper, The University of Melbourne, Centre for Genetic Epidemiology, Carlton, Victoria, Australia; C. Scott (Department of Hematology and Medical Oncology), J. Sambrook (Research Division), Peter MacCallum Cancer Institute, Victoria; G. M. Pupo, G. J. Mann, Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, Australia; T. Dörk (Department of Biochemistry and Tumor Biology, Clinic of Obstetrics and Gynecology), R. Bendix (Department of Radiation Oncology), Medical School Hannover, Germany; J. Kirk, Familial Cancer Service, Westmead Hospital, Westmead, New South Wales, Australia; K. Tucker, Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, New South Wales; M. R. E. McCredie, Cancer Epidemiology Research Unit, New South Wales Cancer Council, Sydney, Australia, and Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand.
Correspondence to: Georgia Chenevix-Trench, Ph.D., Queensland Institute of Medical Research, c/o RBH Post Office, Brisbane, Queensland 4029, Australia (e-mail: georgiaT{at}qimr.edu.au).
Background: The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10–6T
G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case–control series of breast cancer families and multiple-case breast cancer families. Methods: Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10–6TG ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided. Results: In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10–6TG mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative. Conclusion: At least two ATM mutations are associated with a sufficiently high risk of breast cancer to be found in multiple-case breast cancer families. Full mutation analysis of the ATM gene in such families could help clarify the role of ATM in breast cancer susceptibility.
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