Dissection of complex genetic and epigenetic interactions underlying nf1 cancer susceptibility using mouse models

Abstract

NF1 is notable for the variable expressivity of the disease. Although NF1 is fully penetrant, patients with the disease show a broad range of phenotypes. This presents a problem for patients and their doctors, because it is difficult to predict which disease complications an individual will develop. This has led to an interest in identifying the sources of phenotypic variation associated with the disease. Inherited factors, environmental factors, and diet can all influence phenotypic variation and differential susceptibility in many diseases, including NF1. Comparison of both inter- and intra-familial phenotypic variance in patients has implicated heritable factors independent of the inherited NF1 allele, as well as environmental factors. Studies in a mouse model of NF1 malignancies have demonstrated that modifier genes unlinked to NF1, as well as the sex of the individual and the inheritance of the disease from the mother or father, affects the risk for developing different types of tumors. Taken together, these data suggest that subtle differences in the genetic and epigenetic background of NF1 patients can have far reaching implications on the risk of developing NF1-associated tumors. In this chapter, we will focus on what is known about heritable factors affecting NF1 variable expressivity in both humans and mouse models. These factors, once characterized, can be used by patients and clinicians to predict the future course of the disease.