| Summary: | 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
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