How carcinogens (or telomere dysfunction) induce genetic instability: associated-selection model

Carcinogens induce carcinogen-specific genetic instability (defects in DNA repair). According to the 'direct-selection' model, defects in DNA repair p er se provide an immediate growth advantage. According to the 'associated-s election' model, carcinogens merely select for cells with adaptive mutation s. Like any mutations, adaptive mutations occur predominantly in geneticall y unstable cells. The 'associated-selection' model predicts that carcinogen -driven selection minimizes cytotoxic but maximizes mutagenic effects of ca rcinogens. A purely mutagenic (neither cytotoxic, nor cytostatic) environme nt will favor effective DNA repair, whereas any growth-limiting conditions (telomerase deficiency, anticancer drugs) will select for genetically unsta ble cells. Genetic instability is a postmark of selective pressure rather t han a hallmark of cancer per se. Once selected, genetic instability facilit ates the development of resistance to any other growth-limiting conditions. As an example, a putative link between prior exposure to carcinogens and t he ability to develop a telomerase-independent growth is discussed. (C) 200 1 Published by Elsevier Science B.V. on behalf of the Federation of Europea n Biochemical Societies.