Dominant negative ATM mutations in breast cancer families

Chenevix-Trench, G., Spurdle, A. B., Gatei, M., Kelly, H., Marsh, A., Chen, X., Donn, K., Cummings, M., Nyholt, D.R., Jenkins, M. A., Scott, C., Pupo, G. M., Dork, T., Bendix, R., Kirk, J., Tucker, K., McCredie, M. R., Hopper, J. L., Sambrook, J., Mann, G. J., & Khanna, K. K. (2002) Dominant negative ATM mutations in breast cancer families. Journal of the National Cancer Institute, 94(3), pp. 205-215.

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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.


Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G 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.


In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10-6T-->G 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.


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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ID Code: 92175
Item Type: Journal Article
Refereed: No
Additional Information: Chenevix-Trench, Georgia
Spurdle, Amanda B
Gatei, Magtouf
Kelly, Helena
Marsh, Anna
Chen, Xiaoqing
Donn, Karen
Cummings, Margaret
Nyholt, Dale
Jenkins, Mark A
Scott, Clare
Pupo, Gulietta M
Dork, Thilo
Bendix, Regina
Kirk, Judy
Tucker, Katherine
McCredie, Margaret R E
Hopper, John L
Sambrook, Joseph
Mann, Graham J
Khanna, Kum Kum
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
2002/02/07 10:00
J Natl Cancer Inst. 2002 Feb 6;94(3):205-15.
Keywords: Ataxia Telangiectasia Mutated Proteins, Blotting, Western, Breast Neoplasms/*genetics/pathology, Cell Cycle Proteins, Chromosome Mapping, DNA Mutational Analysis, DNA-Binding Proteins, Female, Gene Frequency/genetics, Genes, Dominant/*genetics, Genetic Predisposition to Disease/genetics, *Genetic Testing, Genotype, Humans, Lod Score, Male, Microsatellite Repeats/genetics, Mutation/*genetics, Pedigree, Protein-Serine-Threonine Kinases/*genetics/metabolism, Tumor Cells, Cultured, Tumor Suppressor Proteins
DOI: 10.1093/jnci/94.3.205
ISSN: 0027-8874
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: © Oxford University Press
Deposited On: 27 Jan 2016 06:26
Last Modified: 26 Jun 2017 21:01

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