A recent hypothesis suggests that the type of genetic instability in cancers is the result of Darwinian selection pressures exerted by specific carcinogens. In the May 8 Proceedings of the National Academy of Sciences, Bardelli et al. describe experiments to test whether chromosomal instability (CIN) is induced by bulky-adduct-forming agents, whereas microsatellite instability is selected by methylating agents (Proc Natl Acad Sci USA 2001, 98:5770-5775). They used a variant colorectal cell line, HCT116-H3, with no genomic instability. When Bardelli et al. treated the cells with 2-amino-1-methyl-6-phenylimidazol[4,5-b]pyridine (PhIP), a bulky-adduct-forming carcinogen found in well-cooked beef, they isolated resistant clones that displayed a CIN phenotype. In contrast, exposure to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) lead to the isolation of characteristic MIN cell lines. Conversely, controlled induction of the CIN phenotype (by expression of a dominant-negative hBUB1 allele) was associated with PhIP resistance. These results prove that the...