Heterozygous ATM mutations do not contribute to early onset of breast cancer

• Published in: Nature genetics Vol. 15; no. 3; pp. 307 - 310
• Main Authors: FitzGerald, Michael G, Bean, James M, Hegde, Sanjay R, Unsal, Hilal, MacDonald, Deborah J, Harkin, D. Paul, Finkelstein, Dianne M, Isselbacher, Kurt J, Haber, Daniel A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.03.1997
• Subjects: Adult; Age of Onset; Asian; Ataxia Telangiectasia Mutated Proteins; Base Sequence; Biological and medical sciences; Black or African American; Black People - genetics; Breast Neoplasms - epidemiology; Breast Neoplasms - genetics; Breast Neoplasms - physiopathology; Cell Cycle Proteins; DNA Primers; DNA-Binding Proteins; Exons; Female; Frameshift Mutation; Genetic Carrier Screening; Gynecology. Andrology. Obstetrics; Humans; Introns; Jews; Leucine Zippers; Mammary gland diseases; Medical sciences; Middle Aged; Point Mutation; Polymerase Chain Reaction; Protein Serine-Threonine Kinases; Proteins - genetics; Sequence Deletion; Tumor Suppressor Proteins; Tumors; United States; United States; Human; Epidemiology; Mammary gland diseases; Association; Gene; Risk factor; Predisposition; Ataxia telangiectasia; Genetics; Early; Tumor; Mammary gland; Mutation
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng0397-307

Ataxia telangiectasia (AT) is a recessive syndrome, including cerebellar degeneration, immunologic defects and cancer predisposition, attributed to mutations in the recently isolated ATM (ataxia telangiectasia, mutated) gene. AT is diagnosed in 1/40,000 to 1/100,000 live births, with carriers calculated to comprise approximately 1% of the population. Studies of AT families have suggested that female relatives presumed to be carriers have a 5 to 8-fold increased risk for developing breast cancer, raising the possibility that germline ATM mutations may account for approximately 5% of all breast cancer cases. The increased risk for breast cancer reported for AT family members has been most evident among younger women, leading to an age-specific relative risk model predicting that 8% of breast cancer in women under age 40 arises in AT carriers, compared with 2% of cases between 40-59 years. To test this hypothesis, we undertook a germ-line mutational analysis of the ATM gene in a population of women with early onset of breast cancer, using a protein truncation (PTT) assay to detect chain-terminating mutations, which account for 90% of mutations identified in children with AT. We detected a heterozygous ATM mutation in 2/202 (1%) controls, consistent with the frequency of AT carriers predicted from epidemiologic studies. ATM mutations were present in only 2/401 (0.5%) women with early onset of breast cancer (P = 0.6). We conclude that heterozygous ATM mutations do not confer genetic predisposition to early onset of breast cancer.