Simple and complex genetics of colorectal cancer susceptibility

AbstractThere are several hereditary conditions associated with an increased risk of colorectal cancer (CRC). These include well‐characterized autosomal dominant syndromes, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). A novel autosomal recessive form of FAP, caused by mutations in the base excision repair gene MYH, has recently been recognized. This discovery has provided further evidence for the importance of DNA repair mechanisms in CRC development, already documented by the involvement of the mismatch repair in HNPCC. Additional CRC‐predisposing conditions, such as hyperplastic polyposis and hereditary mixed polyposis syndrome, are being outlined. Heterogeneity of genetic mechanisms has important consequences for counseling and surveillance in hereditary CRC. Nevertheless, classical mendelian conditions represent only a minor share of the total CRC population burden. Alleles of the same genes that are involved in hereditary syndromes might also act as low penetrance variants, as shown for APC 1307K in the Ashkenazi. However, the level of complexity of multifactorial CRC is such that current tools appear inadequate to pinpoin