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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Abstract

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 IVS10-6T-->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.

RESULTS:

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

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.

Impact and interest:

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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
eng
CA69638/CA/NCI NIH HHS/
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: 27 Jan 2016 06:26

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