ABSTRACT
Cancer is a genetic disease (Vogelstein and Kinzler 2004). Decades of research in molecular genetics have identified a number of important genes responsible for the genesis of various types of cancer (Futreal et al. 2004) and drugs targeting these mutated cancer genes have brought dramatic therapeutic advances and substantially improved and prolonged the lives of cancer patients (Huang and Harari 1999). However, cancer is extremely complex and heterogeneous. It has been suggested that 5% to 10% of the human genes probably contribute to oncogenesis (Strausberg, Simpson, and Wooster 2003), while current experimentally validated cancer genes only cover 1% of human genome (Futreal et al. 2004), suggesting that there are still hundreds or even thousands of cancer genes that remain to be identified. For example, in breast cancer, known susceptibility genes, including BRCA1 (Miki et al. 1994) and BRCA2 (Wooster et al. 1995), can only explain less than 5% of the total breast cancer incidence and less than 25% of the familial risk (Oldenburg et al. 2007). The same challenge is also faced by other types of cancer and other complex diseases, such as diabetes (Frayling 2007) and many brain diseases (Burmeister, McInnis, and Zollner 2008; Folstein and Rosen-Sheidley 2001). There is a long way to go from changes in genetic sequence to visible clinical phenotypes. The complex molecular interaction networks, together with environmental factors, further lower the penetrance of a single causal gene and complicate the relationship between genes and diseases. This high complexity and low penetrance might explain why so many disease genes remain unidentified.
