Author:
Bardelli Alberto,Cahill Daniel P.,Lederer Gabi,Speicher Michael R.,Kinzler Kenneth W.,Vogelstein Bert,Lengauer Christoph
Abstract
It has been proposed recently that the type of genetic instability
in cancer cells reflects the selection pressures exerted by specific
carcinogens. We have tested this hypothesis by treating immortal,
genetically stable human cells with representative carcinogens. We
found that cells resistant to the bulky-adduct-forming agent
2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
(PhIP) exhibited a chromosomal instability (CIN), whereas cells
resistant to the methylating agent
N-methyl-N′-nitro-N-nitrosoguanidine
(MNNG) exhibited a microsatellite instability (MIN) associated with
mismatch repair defects. Conversely, we found that cells purposely made
into CIN cells are resistant to PhIP, whereas MIN cells are resistant
to MNNG. These data demonstrate that exposure to specific carcinogens
can indeed select for tumor cells with distinct forms of genetic
instability and vice versa.
Publisher
Proceedings of the National Academy of Sciences
Cited by
142 articles.
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