A Novel Method to Screen for Dominant Negative ATM Mutations in Familial Breast Cancer
Abstract
The ATM gene is mutated in the autosomal recessive disorder, ataxia telangiectasia (A-T), which is characterised by cancer predisposition, cerebellar ataxia and immunodeficiency. One of the most controversial topic in breast cancer genetics is whether mutations in the A TM gene predispose women to breast cancer. Studies of A-T families appear to have an elevated frequency of breast cancer in females, particularly in obligate heterozygotes whose risk may be increased as much as 7-fold. By contrast, most studies of sporadic breast cancer have not found an increased frequency of germline A TM mutations compared with controls, and linkage analysis of markers close to ATM in multiple-case families has provided no evidence that the ATM gene predisposes women to breast cancer. Nevertheless, two recurrent A TM mutations, T7271G and IVS1-6T->G, were recently reported to be associated with breast cancer (Stankovic et al., 1998; Broeks et al., 2000). We analysed these two pathogenic mutation in ATM in female-breast cancer only, non-BRCA1/2 families in the Australian based Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) and observed that 3% of the families carried one of the two mutations in ATM analysed (Chenevix-trench et al, 2002). We have shown that both mutations act as dominant negatives in that ATM kinase activity was markedly reduced in the heterozygous carriers of these mutations. These observations suggest that a proportion of hereditary breast cancer may be due to ATM mutations, and that the increased breast cancer risk may be restricted to a subset of A TM mutations.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2004
- Accession Number
- ADA425752
Entities
People
- Kum K. Khanna
Organizations
- QIMR Berghofer Medical Research Institute