Cancer Susceptibility Genes and Common Gene Variants That Increase Cancer Risk Ragnhild A. Lothe and Anne-Lise B0rresen-Dale Department of Genetics, Institute for Cancer Research, University Clinic of the Norwegian Radium Hospital, Oslo, Norway Most cancers result from an interaction between genetic and environmental factors and these factors can determine an individual’s cancer risk. Approximately 1% of all cancers arise in individuals with a clear hereditary cancer syndrome following Mendelian inheritance where environmental factors are thought to play a minor role (Fig. 1). Further, it is estimated that

10-15% of all cancers are due to inherited components, resulting in the so-called familial clustering of cancer. However, in most other cancers, a substantial genetic predisposition may also be present without obvious familial clustering. These genetic components include dominant mutations with a reduced penetrance, as well as more common genetic polymorphisms that influence an individual’s response to environmental exposure. Most cancers however occur in the genetically low-risk population group, referred to as sporadic cases. The influence of genetic factors decreases and the impact of environmental factors increases with aging (Fig. l). Knowledge of the spectrum of both genetic and environmental risk factors for developing cancer and how they interact, will be instrumental in future risk assessment and in prevention programs.

Figure 1 Environmental and genetic factors influence cancer risk. Up to 5% of all cancers are hereditary cases, 10-15% are estimated to account for familial clustering of cancer, and the rest are sporadic cases. The influence of environmental factors is low in hereditary cancer diseases and high in individuals at population risk level. The risk of cancer increases with age. The hereditary cases are generally younger than the sporadic cases with the same tumor type. The frequency of the “risk allele” is low for those genes predisposing to hereditary cancer, implying the low incidence of these diseases, whereas the cancer risk is very high, often obligatory, in the individuals carrying the mutated gene. *For allele variants associated with cancer risk, see Table 2.