SOMATIC MUTATIONS ARE FREQUENT AND INCREASE WITH AGE IN HUMAN KIDNEY EPITHELIAL-CELLS

We have used a primary cloning assay to determine the frequency of 6-t hioguanine (TG)-resistant tubular epithelial cells in kidney tissue fr om 72 human donors ranging in age from 2 to 94 years. The frequency of TG-resistant mutants ranged from similar to 5 x 10(-5) for donors in the first decade of life to similar to 2.5 x 10(-4) for donors in the eighth and later decades of life. Two different statistical analyses i ndicated that this increase in mutant frequency is exponential with ag e. We also observed a 2-fold higher TG-resistant mutant frequency in n ephrectomy kidneys containing a coincident renal carcinoma. DNA sequen ce analyses revealed HPRT gene mutations in each of 14 TG-resistant mu tants from seven unrelated donors. Thirteen of these 14 mutants result ed from independent mutational events. These results suggest that soma tic mutations are common in renal-and perhaps in other human-epithelia , and thus could play an important role in the genesis of age-associat ed disease.