Bloom's syndrome (BS) is an autosomal recessive disorder conferring high propensity for cancer and displaying a high degree of genetic instability; the frequency of sister chromatid exchange is characteristically 10 times above background. The symmetrical four‐armed chromatid interchanges are much more readily detected in peripheral blood lymphocytes of BS patients, suggesting that the frequency of somatic recombination is also increased. In the present study, the rate of spontaneous loss of HLA‐A allele expression was estimated following fluctuation analysis in cultured T lymphocytes using a flow‐cytometric assay. It was found to be 10 times or more higher than normal in lymphocytes from a BS patient. Molecular and chromosome analyses showed that all 13 independent variants from the patient were most likely derived from somatic recombinations. Further tests for loss of heterozygosity at a closely linked proximal locus, HLA‐DQA1, showed that as many as half of the recombinants retained heterozygosity irrespective of the donor. The results suggest that the HLA region is hyperrecombinogenic in somatic cells and that the elevated recombination rate in BS cells results from the general increase at ordinary sites and not from random creation of unusual sites for recombination.
Dose-survival curves were obtained for matched samples of peripheral T-lymphocytes and skin fibroblasts from a total of 22 patients who underwent various surgical procedures using loss of colony-forming ability as the end point. The results showed that the mean D10 (dose required to kill 90% of cells) +/- SD was 3.58 +/- 0.21 Gy for T-lymphocytes irradiated in G0 and 3.19 +/- 0.37 Gy for skin fibroblasts irradiated in log phase. The coefficients of variation were found to be 6 and 11%, respectively. Contrary to the expectation, regression analysis of D10 values for the two types of cells revealed no significant correlations. The absence of correlation most probably derives from the fact that the apparent interindividual variability of dose-survival curves is caused primarily by random experimental fluctuations at least in the case of lymphocytes. Possible reasons for the greater variability observed in the fibroblast assay are discussed.
A recently developed dose-survival assay using human G0 T lymphocytes from peripheral blood was employed to assess possible interindividual variation of cellular radiosensitivity by comparing variability between a single test for different individuals and repeated tests for a single donor. The surviving fraction at each X-ray dose level fluctuated similarly between the two groups, and the X-ray dose required to kill 90% of the cells (D10) was 3.59 +/- 0.18 Gy (mean +/- SD) for 31 different individuals and 3.66 +/- 0.21 Gy for 28 repeated tests of one individual. Analysis of variance to compare the two sets of data showed that variation in the D10 value was not significantly greater in the former group. Analysis of D50 and D90 showed similar results. These results support the hypothesis that interindividual variation in cellular radiosensitivity is quite small, if it exists at all, as far as can be determined by the loss of colony-forming ability of irradiated G0 lymphocytes.
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