The role of heterozygosity for ataxia telangiectasia in breast cancer

• Main Author: Bebb, Gwyn
• Format: Others
• Language: English
• Published: 2009
• Online Access: http://hdl.handle.net/2429/11366

Epidemiological data suggest that women carriers for ataxia telangiectasia (AT), a cancer predisposition and radiation sensitivity syndrome have an increased risk of breast cancer. If so, the ATM would represent a novel breast cancer gene. Confirming this association has many implications, but attempts to verify it have proved difficult because AT carriers have no clinical phenotype. This thesis describes a series of studies designed to investigate a possible role for the ataxia telangiectasia gene in the development and management of breast cancer. The first half of the thesis describes attempts to perfect two phenotypic assays to identify AT carriers based on in vitro cellular responses to ionizing radiation. Enhancement of chromosomal radiation-sensitivity by caffeine failed to improve discrimination of AT heterozygotes, suggesting that caffeine simulates the cellular AT defect. Studies of radiationinduced apoptosis revealed an impaired ability to implement the death pathway in AT cells. AT heterozygous lymphoblasts, but not primary lymphocytes, were discriminated by this assay. The paradoxical apoptotic response of AT cells deserves further investigation. Logically, the second half of the thesis applies knowledge of a candidate gene for ataxia telangiectasia (ATM) in two separate approaches. The first was to screen a series of sporadic breast cancer patients for mutations in the ATM gene using the protein truncation test (PTT). No mutations were found. Although this does not confirm the association between AT and breast cancer, neither does it exclude it. A large scale sequencing exercise of the whole ATM gene may be the required next step. The second looked for evidence of loss of heterozygosity (LOH) at the ATM locus in breast cancer by comparing tumour-derived with constitutional DNA. ATM LOH occurred at a high frequency suggesting it may be a mechanism underlying breast carcinogenesis. The radio-therapeutic implication of ATM LOH is being assessed by five-year survival and recurrence data. Investigating the role of ATM in breast cancer has implications in all aspects of breast cancer management. Not only does it shed light on breast cancer aetiology but also on predisposition and screening. Most exciting however, is the possibility that future anti-cancer therapy may be dictated by the genetic make-up of tumour and patient === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate