Genetics of Colorectal Cancer

Irfan M. Hisamuddin, MD; Vincent W. Yang, MD, PhD

In This Article

Abstract and Introduction

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.

CRC is one of the most common malignancies in the Western world. Although the mortality rate associated with CRC has been gradually declining in recent years, likely as a result of increasing screening and diet/lifestyle modifications, it is still estimated that this malignancy will lead to over 56,000 deaths in the United States in 2004, making it the second leading cause of cancer mortality.[1] Thus, CRC remains a major health concern and demands continuing efforts in developing strategies of screening and prevention.

Among the various causes of CRC, approximately 75% can be attributed to sporadic disease, in which there is no apparent predisposing etiology. The remaining cases of CRC are accounted for by familial incidences and inflammatory bowel disease (Figure 1). Although some familial cases consist of well-described hereditary CRC syndromes, including FAP, HNPCC, and the hereditary hamartomatous polyposis syndromes, the majority of familial disease has no clearly identifiable genetic etiology.

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

In this report, we review the genetics of CRC, with a special emphasis on familial cases with defined genetic etiology. However, it is clear that additional research is needed to ultimately identify the genes involved in all of the hereditary forms of CRC. This latter determination will help improve the early detection of individuals at higher risk for developing this malignancy.


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