Chromosomal radiosensitivity and low penetrance predisposition to cancer

This mini-review summarises studies in this Institute on the sensitivity of cells of patients with common cancers to the chromosome-damaging effects of ionising radiation, in the context of related studies. Using the 90th percentile of healthy controls (n >200) as the cut-off point between a normal and a sensitive response, 40% of patients with breast cancer (n = 166) were sensitive when cells were irradiated in the G2 phase of the cell cycle. Smaller studies showed that patients with colorectal, head and neck (at < 45 years) and childhood cancers also exhibited degrees of enhanced sensitivity, whereas cervical and lung cancer cases did not. Cells from breast and head and neck cases irradiated in G(0) also showed increased sensitivity. We propose that such elevated sensitivity is a marker of low penetrance predisposition to cancer. The strongest support for this hypothesis was our demonstration of the Mendelian heritability of chromosomal radiosensitivity in 95 family members of breast cancer cases. Challenges for the future include more heritability studies, identification of the underlying genetic determinants, assessment of the associated cancer risk (spontaneous and radiogenic) and population screening for cancer prevention strategies.