ABSTRACT
Work relevant to ascertaining the truth or falsity of the mutator hypothesis began in the 1950s several decades before the mutator hypothesis itself, and continues to this day. These efforts have encountered two diffi culties: 1. The exact model or pathway of carcinogenesis is unknown, and as we will discuss below, the available experimental data can be fi t with different models. This is termed model topology uncertainty (Beckman 2010) (Table 1). Depending on the way the question is asked, differing model topologies can lead to different conclusions. 2. Exact values of key parameters are quite uncertain, again leading to the possibility of different conclusions depending on how the question is asked. For example, the wild type mutation rate per base pair per cell generation has been variously measured from 10-11 to 10-9, a 100 fold range (Albertini et al. 1990; Cervantes et al. 2002), and estimates of the number of cell generations before cancer begins can range 30-fold from approximately 170 to 5000 (Baca et al. 1985; Baker et al. 1995; Tomlinson et al. 2002). The product of these two parameters is important in many models of carcinogenesis, and based on the above can vary up to 3,000 fold. Effi ciency of carcinogenesis and FQM are designed to reduce the sensitivity of conclusions to this parameter value uncertainty (Table 1) and to model topology uncertainty (Beckman 2010). Previous attempts to resolve the mutator hypothesis debate fall into two categories: modeling of cancer epidemiology data and evaluation of the mutational burden of tumors.
