Carcinogen-specific induction of genetic instability

It has been proposed recently that the type of genetic instability in cance r cells reflects the selection pressures exerted by specific carcinogens. W e have tested this hypothesis by treating immortal, genetically stable huma n cells with representative carcinogens. We found that cells resistant to t he bulky-adduct-forming agent 2-amino-1 -methyl-6-phenylimidazo[4,5-b]pyrid ine (PhlP) exhibited a chromosomal instability (CIN), whereas cells resista nt to the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) exh ibited a microsatellite instability (MIN) associated with mismatch repair d efects. Conversely, we found that cells purposely made into CIN cells are r esistant to PhlP, whereas MIN cells are resistant to MNNG. These data demon strate that exposure to specific carcinogens can indeed select for tumor ce lls with distinct forms of genetic instability and vice versa.