Genetic predisposition to colorectal cancer

Cancer is a genetic disease. Most cancer-causing mutations are somatic, occurring in the affected tissue during the course of carcinogenesis; however, most cancers also have a hereditary component that is caused by predisposing mutations that affect the germline, are heritable and contribute to the initiation of carcinogenesis.Colorectal cancer is probably the type of cancer for which the most is known about the genes affected by cancer-causing mutations, their normal functions and their carcinogenic effects when mutated.High-penetrance mutations confer predisposition to colorectal cancer mainly in Lynch syndrome (which involves mutations in mismatch-repair genes) and in familial adenomatous polyposis (which involves mutations in the APC tumour suppressor). Together, these conditions account for 5% or less of all cases of colorectal cancer.Determining carriership for the mutations that underlie these conditions is important in the management and prevention of cancer in these patients and their families.Low-penetrance mutations account for a high proportion of all the attributable risk of colorectal cancer, in both familial and sporadic cases. These mutations are more difficult to identify, but — mainly due to the implementation of association studies — are increasingly being detected and characterized.The identification of both high- and low-penetrance mutations contributes significantly to our understanding of the molecular genetic processes occurring in cancer. This understanding facilitates the development of therapeutic drugs and preventive strategies.Gene–gene and gene–environment interactions have a significant influence on susceptibility to colorectal cancer. Our current understanding of these interactions is limited, and concerted research efforts in this area will be important for a full understanding of predisposition to this cancer.