How do low-penetrance genes modulate the effect of carcinogens?
Low-penetrance genes such as those involved in DNA repair and carcinogen metabolism interfere with the relationships between external exposure to carcinogenic agents and target cells. This may happen in several different ways. According to one model, the low-penetrance gene enhances the carcinogenic activity of an agent by multiplying it by a constant. This is what has been observed with CYP1A1 MsPI in one pooled analysis (Vineis et al., 2003): Figure 3 shows that with increasing duration of exposure to smoking, the risk of lung cancer increases more rapidly among those with the polymorphic genotype than in those with the common variant of the gene, in an approximately constant way. This behavior is what can be expected when the effect of the polymorphism is to quantitatively increase the amount of available carcinogen metabolite, proportionally to the substrate (procarcinogen). A second model is based on the concept of saturation, that is, at higher doses both the active form and the
