Dominant negative ATM mutations in breast cancer families


Autoria(s): 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.
Data(s)

2002

Resumo

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.

Identificador

http://eprints.qut.edu.au/92175/

Publicador

Oxford University Press

Relação

DOI:10.1093/jnci/94.3.205

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.

Direitos

© Oxford University Press

Fonte

Faculty of Health; Institute of Health and Biomedical Innovation

Palavras-Chave #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
Tipo

Journal Article