IDENTIFICATION OF A POTENTIALLY RADIOSENSITIVE SUBGROUP AMONG PATIENTS WITH BREAST-CANCER

Background: The description of genes and genetic syndromes, such as ataxia-telangiectasia, that predispose some women to breast cancer will provide greater insight into the genetic basis of cancer susceptibility. Purpose: Our goal was to establish cell lines from patients with breast and bladder cancers, to screen for enhanced levels of radiation-induced arrest in the G(2) phase of the cell cycle such as is observed in ataxia-telangiectasia heterozygotes, and to correlate G(2) arrest with other prognostic indicators of these cancers and in vivo radiosensitivity. Methods: Epstein-Barr virus-transformed lymphoblastoid cells were established from 108 female patients with breast cancer and 24 age-matched female control subjects, and from 45 patients with bladder cancer and 18 age-matched control subjects. Cells were exposed to 3 Gy of gamma radiation, and the percentages of cells in G(1) and G(2) phases were determined at 18 and 24 hours after irradiation by fluorescence-activated cell sorter analysis. Postirradiation delay in G(2) phase was determined by calculating the percentage of cells in G(2) and by using the ratio G(2)/G(1). Results: When we determined the percentage of cells in G(2) phase at 18 hours after irradiation in 108 lymphoblastoid cells from breast cancer patients, we observed an increase of between 3% and 38% in the number of cells in G(2) phase in comparison with cells that were not irradiated. Comparison with previous G(2)-phase arrest data for ataxia-telangiectasia heterozygotes using a cutoff point at 29% delay demonstrated that 20% and 8% of the breast cancer cell lines of the ease patients and control subjects, respectively, fell into that category (P<.001). At the same time after irradiation, it was not possible to distinguish between bladder cancer cell lines (7%) and those of the corresponding control group (6%). Assessment of radiation effects by G(2)/G(1) ratio showed that 18% of the breast cancer patients and 8% of the control subjects were in the high range. When G(2) arrest was correlated with other prognostic factors, we found that case patients with a greater G(2) block were more likely to have had a family history of breast cancer (P<.006) and more aggressive tumors when assessed by number of involved lymph nodes (P<.002) and tumor size (P<.05). Furthermore, an adverse response to radiotherapy was observed in a group of patients with high G(2) arrest. Implications: While the postirradiation increase in G(2)-phase arrest in cells from breast cancer patients observed in this study may indicate genetic heterozygosity for ataxia-telangiectasia, it might also reflect other genetic abnormalities important to breast cancer. -