Genetic dissection of murine susceptibilities to liver and lung tumors based on the two-stage concept of carcinogenesis

Inbred mouse strains exhibit strain-specific susceptibilities to spontaneous and induced tumors, indicating that the individual risks for neoplastic development are largely under genetic control. Recent advances in linkage analysis have made it routine to chromosomally map the mouse genes responsible for the strain variations in tumor susceptibility using segregating crosses. It is also possible to characterize their biological functions using the positional information. These types of studies are still severely hampered for human cases due to the remarkable genetic heterogeneity and impossibility of experimental crosses. In this article, previous work on genetic susceptibility to mouse liver and lung tumors is reviewed in view of the classical two-stage concept of carcinogenesis. According to this central concept, the tumor susceptibility genes should affect either the first stage, 'initiation', or the second stage,'promotion', or both. At least some genes seem to be specifically involved in initiation or promotion, in line with the fact that initiation and promotion are due, to a certain extent, to independent mechanisms. This notion should be also applicable to human carcinogenesis and may provide important clues for prevention of initiation and promotion in populations with a genetic predisposition for cancer development.