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 from 72 human donors ranging in age from 2 to 94 years. The frequency of TG-resistant mutants ranged from approximately 5 x 10(-5) for donors in the first decade of life to approximately 2.5 x 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 nephrectomy 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.
Martin
G M
GM
Department of Pathology, University of Washington, Seattle 98195, USA.
Ogburn
C E
CE
Colgin
L M
LM
Gown
A M
AM
Edland
S D
SD
Monnat
R J
RJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D001483:Base Sequence; D002277:Carcinoma / Q000503:physiopathology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D004848:Epithelium; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency / Q000235:genetics*; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D007672:Kidney Cortex / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D007680:Kidney Neoplasms / Q000503:physiopathology; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009392:Nephrectomy; D013866:Thioguanine / Q000494:pharmacology*
D017931:DNA Primers; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine