Radiation-induced micronucleus induction in lymphocytes identifies a high frequency of radiosensitive cases among breast cancer patients: a test for predisposition?

D Scott,W Burrill,El Levine,Sa Roberts,Jbp Barber

doi:10.1038/bjc.1998.98

Abstract

Enhanced sensitivity to the chromosome-damaging effects of ionizing radiation is a feature of many cancer-predisposing conditions. We previously showed that 42% of an unselected series of breast cancer patients and 9% of healthy control subjects showed elevated chromosomal radiosensitivity of lymphocytes irradiated in the G2 phase of the cell cycle. We suggested that, in addition to the highly penetrant genes BRCA1 and BRCA2, which confer a very high risk of breast cancer and are carried by about 5% of all breast cancer patients, there are also low-penetrance predisposing genes carried by a much higher proportion of breast cancer patients, a view supported by recent epidemiological studies. Ideally, testing for the presence of these putative genes should involve the use of simpler methods than the G2 assay, which requires metaphase analysis of chromosome damage. Here we report on the use of a simple, rapid micronucleus assay in G0 lymphocytes exposed to high dose rate (HDR) or low dose rate gamma-irradiation, with delayed mitogenic stimulation. Good assay reproducibility was obtained, particularly with the HDR protocol, which identified 31% (12 out of 39) of breast cancer patients compared with 5% (2 out of 42) of healthy controls as having elevated radiation sensitivity. In the long term, such cytogenetic assays may have the potential for selecting women for intensive screening for breast cancer.

Highlights

Using an assay for detecting X-ray induced chromosome damage in lymphocytes in the G2 phase of the cell cycle we found that approximately 40% (21 out of 50) of an unselected series of breast cancer cases showed elevated chromosomal radiosensitivity compared with normal, healthy controls (Scott et al, 1994)
As our G2 chromosomal radiosensitivity testing gave a figure for sensitivity that was some tenfold greater, we proposed the existence of other low penetrance genes that predispose to breast cancer, in addition to the A-T gene (Scott et al, 1994)
There was only a weak correlation between HRD and low dose rate (LDR) responses in patients [r = 0.18, P = 0.29] and normals (r = 0.33, P = 0.04). This may be due to the experimental variability of the LDR assay but may indicate that the high dose rate (HDR)

Summary

Methods

The controls were selected from normal volunteers including some spouses of the breast cancer patients. The five control subjects comprised two men and three women and ranged in age from 23 to 46 years. These individuals are hereafter referred to as 'controls'. A further 42 normal volunteers were each tested on a single occasion and are subsequently referred to as 'normals'. Nineteen of the normals were tested in a planned series in which one of the five controls, one or two normals and one or two cancer patients were tested in parallel in each experiment (series A). Normals comprised 28 women and 14 men between 23 and 72 years of age

Results

Discussion

Conclusion