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-thioguanine (TG)-resistant tubular epithelial cells in kidney tissue from72 human donors ranging in age from 2 to 94 years. The frequency ofTG-resistant mutants ranged from approximately 5 x 10(-5) for donors in thefirst decade of life to approximately 2.5 x 10(-4) for donors in the eighthand later decades of life. Two different statistical analyses indicatedthat this increase in mutant frequency is exponential with age. We alsoobserved a 2-fold higher TG-resistant mutant frequency in nephrectomykidneys containing a coincident renal carcinoma. DNA sequence analysesrevealed HPRT gene mutations in each of 14 TG-resistant mutants from sevenunrelated donors. Thirteen of these 14 mutants resulted from independentmutational events. These results suggest that somatic mutations are commonin renal--and perhaps in other human--epithelia, and thus could play animportant role in the genesis of age-associated disease.