Genome maintenance and mutagenesis in embryonic stem cells.
Widespread loss of heterozygosity (LOH) in cancer cells is often thought to result from chromosomal instability caused by mutations affecting DNA repair/genome maintenance; however, the origin of LOH in most tumors is unknown. In a recent study, we examined the ability of carcinogenic agents to induce LOH in diploid mouse embryo-derived stem (ES) cells. Brief exposures to nontoxic levels of several carcinogens stimulated genome-wide LOH, with maximum per-gene frequencies approaching one percent. These results suggest that LOH contributes significantly to the carcinogenicity of a variety of mutagens, and that genome-wide LOH may result from prior exposure to genotoxic agents rather than from a state of chromosomal instability during the carcinogenic process. Mechanisms in stem cells that influence carcinogen-induced LOH are likely to play central roles in the etiology of nonhereditary cancers that often arise after extensive carcinogen exposures.
Lin
Qing
Q
Department of Microbiology and Immunology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232-2363, USA.
Donahue
Sarah L
SL
Ruley
H Earl
HE
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D016678:Genome / Q000235:genetics*; D019656:Loss of Heterozygosity / Q000235:genetics; D051379:Mice; D016296:Mutagenesis; D009369:Neoplasms / Q000235:genetics / Q000473:pathology
D002273:Carcinogens