Lessons from Hereditary Colorectal Cancer

A large body of evidence supports the idea that accumulated genetic changes underlie the development of neoplasia. This multistep process is well illustrated by colorectal cancers, which typically develop over decades and appear to require at least seven genetic events for completion. Even so, inheritance of a single altered gene can result in a marked predisposition to colorectal cancer in two distinct syndromes, Familial Adenomatous Polyposis (FAP) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Recent evidence suggests that the genetic defect in FAP affects the rate of tumor initiation by targeting the gatekeeper function of the APC gene. In contrast, the defect in HNPCC largely affects tumor progression by targeting the genome guardian function of DNA mismatch repair. Studies of these syndromes have provided unique insights into both inherited and sporadic forms of human tumors.