Genetics of colorectal cancer

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. As such, it assumes a significant role in both health policy decision-making and scientific research. CRC has been a model for investigating the molecular genetics of cancer development and progression; this is in part due to the easily detectable, sequential transition of cells from normal colonic epithelium to adenoma and then to adenocarcinoma. In addition, familial syndromes that predispose to CRC, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), have significantly contributed to our understanding of the genetic mechanisms underlying CRC formation. It is now well recognized that hereditary CRC syndromes are due to germline mutations of genes that function as tumor suppressors or, less frequently, oncogenes. Accumulation of subsequent mutations in other genes with related functions results in the stepwise progression to carcinoma. It is important to note that somatic changes in similar genes are involved in the formation of sporadic CRC. The identification of these important CRC-related genes may help facilitate the early diagnosis, prevention, and treatment of CRC. This article reviews the various familial CRC syndromes along with their genetic etiology, as well as discusses the principle of genetic testing for these conditions.

Figure 1

The causes of colorectal cancer. Sporadic CRC refers to those cases that occur in individuals over age 50 years without any identifiable predisposing factors. Familial cases are those with a family history of CRC but exclusive of FAP, HNPCC, and the hamartomatous polyposis syndromes. The approximate percentage of distribution for each condition is as follows: sporadic, 75%; familial, 15%; HNPCC, 5%; FAP, 1%; IBD, 1%; MAP, 1%; hamartomas, < 1%. Key: IBD = inflammatory bowel disease; MAP = MYH-associated polyposis

Figure 2

The genetic paradigm of colorectal cancer. The formation of CRC requires the sequential mutation of several genes. This includes the inactivation of TSGs (in green) and activation of oncogenes (in red). There are 2 independent pathways that can cause CRC, depending upon which TSG is first inactivated. Inactivation of the APC gene is found in about 85% of sporadic CRC, and inactivation of the mismatch repair genes, including MSH2, MLH1, and PMS2, is found in the remaining 15%. Key: COX-2 = cyclo-oxygenase-2.