Germline Genetics in Colorectal Cancer Susceptibility and Prognosis

Population-based studies indicate that approximately 35% of an individual’s risk of developing colorectal cancer (CRC) is due to inherited genetic factors (Lichtenstein et al. 2000). Indeed, approximately 50,000 individuals diagnosed with CRC in the United States each year will have at least one other family member with CRC (Kaz & Brenthall, 2006). Classically, genetic susceptibility to CRC is described as three types: Low, moderate and high risk. In reality, the risk of developing colorectal cancer due to genetic factors exists on a continuum from very low to very high risk (Figure 1). In addition to colon cancer susceptibility, genetic variants are likely to play a role in response to therapy and prognosis of colon cancer. This Chapter will provide an overview of the current knowledge in genetic susceptibility to hereditary and non-hereditary CRC, the complexities and issues around the identification of germline genetic risk factors, and the current and future use of genetic information in the clinic. High penetrance risk includes inheritance of mutations in genes which segregate in a Mendelian fashion in families and confer a high lifetime risk of disease. Hereditary cancer syndromes are those in which a mutation confers a high lifetime risk of developing CRC. Several syndromes have been described. The two most familiar CRC syndromes are Familial Adenomatous Polyposis (FAP) and Lynch Syndrome (LS) (Table 1). Moderately-penetrant mutations are mutations or polymorphic variants which can manifest as colon cancer clustering in families but without a clear cancer syndrome or inheritance pattern. Lowpenetrance variants are those which are present in a reasonably high frequency in the general population, but have small influences on risk and are not themselves sufficient for the development of colon cancer.