The frequency of illegitimate TCR beta/gamma gene recombination in human lymphocytes: influence of age, environmental exposure and cytostatic treatment, and correlation with frequencies of t(14;18) and hprt mutation

Chromosome translocations in lymphoid malignancies often involve V(D)J reco mbinase mediated events giving rise to aberrant T-cell receptor (TCR) and i mmunoglobulin genes, which have been suggested to be useful as markers of g enomic instability, genotoxic exposure and cancer risk. Illegitimate rearra ngements involving the TCR beta/gamma loci on chromosome 7 create TCR beta/ gamma hybrid genes which occur at low frequency in peripheral blood lymphoc ytes (PBLs) of normal healthy individuals. To evaluate the utility of this marker, we studied the possible effects of age and genotoxic exposures on t he TCR beta/gamma gene variant frequency (VF), and compared the frequencies of hypoxanthine guanine phosphoribosyl transferase (hprt) mutation, hprt e xon 2/3 deletion, t(14;18) and TCR beta/gamma gene rearrangements in cells from the same donors. The TCR beta/gamma VF ranged five-fold among 16 middl e aged blood donors with a mean of 0.74 +/- 0.29/10(5) PBLs, which is consi stent with our previous estimate in healthy subjects, The TCR beta/gamma VF was found to increase from birth until early adult life, and then to decre ase with increasing age. Four testis cancer patients, who 6 years earlier h ad been treated with etoposide and other cytostatic drugs, showed TCR beta/ gamma VF similar to that in healthy controls. No increase of the TCR beta/g amma VF was found among non-smoking PAM-exposed aluminum smelter workers co mpared to non-smoking controls. Smoking smelter workers showed decreased TC R beta/gamma VF compared to non-smoking workers and controls, but in a foll ow-up study 2 years later the difference was no longer statistically signif icant, although the smoking smelter workers still showed a lower TCR beta/g amma VF than the controls. No correlation was obtained between the TCR beta /gamma VF and the t(14;18) or hprt mutant frequency (MF) in a group of heal thy individuals. However, there was a statistically significant correlation between the TCR beta/gamma VF and the hprt exon 2/3 deletion frequency in PBL DNA from the same donors. These results show that the TCR beta/gamma VF in healthy individuals changes with age and correlates with the frequency of hprt exon 2/3 deletion, another marker of aberrant V(D)J recombination i n T-cells. However, no effect of smoking or present or previous exposure to genotoxic agents on TCR beta/gamma VF was observed in this study. Thus, fu rther studies are needed to prove the utility of TCR beta/gamma gene rearra ngement as a marker of genotoxic exposure. (C) 1999 Elsevier Science B.V. A ll rights reserved.