Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer

Scott, Shaun P., Bendix, Regina, Chen, Philip, Clark, Raymond, Dork, Thilo and Lavin, Martin F. (2002) Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proceedings of The National Academy of Sciences of The United States of America, 99 2: 925-930. doi:10.1073/pnas.012329699


Author Scott, Shaun P.
Bendix, Regina
Chen, Philip
Clark, Raymond
Dork, Thilo
Lavin, Martin F.
Title Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer
Journal name Proceedings of The National Academy of Sciences of The United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2002-01-22
Sub-type Article (original research)
DOI 10.1073/pnas.012329699
Open Access Status Not Open Access
Volume 99
Issue 2
Start page 925
End page 930
Total pages 6
Place of publication Washington, D.C.
Publisher National Academy of Sciences of the U.S.
Language eng
Abstract The human genetic disorder ataxia-telangiectasia (A-T) is characterized by hypersensitivity to ionizing radiation and an elevated risk of malignancy. Epidemiological data support an increased risk for breast and other cancers in A-T heterozygotes. However, screening breast cancer cases for truncating mutations in the ATM (A-T mutated) gene has failed largely to reveal an increased incidence in these patients. It has been hypothesized that ATM missense mutations are implicated in breast cancer, and there is some evidence to support this. The presence of a large variety of rare missense variants in addition to common polymorphisms in ATM makes it difficult to establish such a relationship by association studies. To investigate the functional significance of these changes we have introduced missense substitutions, identified in either A-T or breast cancer patients, into ATM cDNA before establishing stable cell lines to determine their effect on ATM function. Pathogenic missense mutations and neutral missense variants were distinguished initially by their capacity to correct the radiosensitive phenotype in A-T cells, Furthermore missense mutations abolished the radiation-induced kinase activity of ATM in normal control cells, caused chromosome instability, and reduced cell viability in irradiated control cells, whereas neutral variants failed to do so. Mutant ATM was expressed at the same level as endogenous protein, and interference with normal ATM function seemed to be by multimerization. This approach represents a means of identifying genuine ATM mutations and addressing the significance of missense changes in the ATM gene in a variety of cancers including breast cancer.
Keyword Multidisciplinary Sciences
Ataxia-telangiectasia Heterozygotes
Dna-damage
Ionizing-radiation
Gene-product
Early-onset
Families
Phosphorylation
Risk
Identification
Expression
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
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Created: Wed, 17 Oct 2007, 20:29:03 EST