The first clear demonstration of a link between cancer predisposition and enhanced sensitivity to the chromosome-damaging effects of ionising radiation was in the recessively inherited disorder, ataxia telangiectasia (AT). Subsequently, 20 other rare cancer-prone conditions have been shown to exhibit some degree of elevated chromosomal radiosensitivity. The most common of these are carriers of the AT gene (heterozygotes), estimated to comprise about 0.5% of the general population and to have an enhanced risk of breast cancer, such that about 5% of all breast cancer cases could be AT heterozygotes, although more recent studies suggest that this figure is an overestimate. Using a G_2-phase assay on lymphocytes, we attempted to detect AT gene carriers amongst an unselected series of 135 breast cancer patients and found that 42% showed an enhanced sensitivity. Such sensitivity was also seen in 6% (6/105) of healthy controls (Figure 1). Clearly, these proportions are much higher than even the highest estimates of AT heterozygotes. We postulated the existence of other genes, like the ATM gene, that confer an enhanced risk of breast cancer at a low level of penetrance. This is in contrast to the high degree of penetrance associated with the breast cancer-predisposing genes BRCA1 and BRCA2 that are mutated in less than 5% of patients.
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