Somatic Mutations Are Frequent and Increase with Age in Human Kidney Epithelial Cells

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Abstract
We have used a primary cloning assay to determine the frequency of 6-thioguanine (TG)-resistant tubular epithelial cells in kidney tissue from 72 human donors ranging in age from 2 to 94 years. The frequency of TG-resistant mutants ranged from ∼5 × 10 −5 for donors in the first decade of life to ∼2.5 × 10 −4 for donors in the eighth and later decades of life. Two different statistical analyses indicated that this increase in mutant frequency is exponential with age. We also observed a 2-fold higher TG-resistant mutant frequency in neph-rectomy kidneys containing a coincident renal carcinoma. DNA sequence analyses revealed HPRT gene mutations in each of 14 TG-resistant mutants from seven unrelated donors. Thirteen of these 14 mutants resulted from independent mutational events. These results suggest that somatic mutations are common in renal—and perhaps in other human—epithelia, and thus could play an important role in the genesis of age-associated disease.