The Varied and Surprising Spectrum of Mutations in Epithelial Cells

Raymond Monnat, MD and David Eaton, Ph.D.
University of Washington
ES07033

Background: Epithelial cells, such as skin cells, cells that line the intestinal and respiratory tracts, etc., comprise about 60% of the cells in the human body and are the source of about 85% of human cancers. Despite these numbers and the importance of epithelial cells in normal biology and physiology and disease development, very few studies have been performed on the frequency or breadth of mutations in epithelial cell lines. To better understand the rate of mutation and the different mutations that occur in epithelial cells as a function of age, these investigators used epithelial cell cloning and DNA sequencing experiments to characterize mutations of the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene in kidney epithelial cells.

Advance: The researchers found a high frequency and unusual spectrum of kidney HPRT gene mutations suggesting that DNA damage or mutagenesis may be substantially different in kidney epithelium than in other epithelial cell types. Kidney epithelial cells contain abundant mitochondria and consume large amounts of oxygen to produce the energy necessary to function properly. Surprisingly these experiments show that kidney epithelial cells do not contain high numbers of oxidative damage induced HPRT mutations. This suggests that reactive nitrogen species or circulating mutagens that are concentrated or metabolized in kidney tissue may be more important sources of kidney epithelial cell mutations.

Implication: These findings suggest that the high-frequency, age-dependent increase and unusual mutations in kidney epithelial cells may play an important role in human kidney disease development. For example, mutation accumulation could cause decreases in kidney tubule function or functional cell numbers that accompany aging. The mutations could also increase the likelihood of kidney tubule diseases. These studies show that epithelial mutations may be more important in epithelial cell disease development that previously realized.

Citation: Colgin LM, Hackmann AF, Emond MJ, Monnat RJ Jr. The unexpected landscape of in vivo somatic mutation in a human epithelial cell lineage. Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1437-42.