Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.
Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women. In 2011, an estimated 141,210 new cases are expected to be diagnosed, and 49,380 deaths from CRC are expected to occur. Two kinds of observations indicate a genetic contribution to CRC risk: (1) increased incidence of CRC among persons with a family history of CRC; and (2) families in which multiple family members are affected with CRC, in a pattern indicating autosomal dominant inheritance of cancer susceptibility.[2,3,4,5,6] About 75% of patients with CRC have sporadic disease, with no apparent evidence of having inherited the disorder. The remaining 25% of patients have a family history of CRC that suggests a genetic contribution, common exposures among family members, or a combination of both. Genetic mutations have been identified as the cause of inherited cancer risk in some colon cancer–prone families; these mutations are estimated to account for only 5% to 6% of CRC cases overall. It is likely that other undiscovered major genes and background genetic factors contribute to the development of CRC, in conjunction with nongenetic risk factors.
Natural History of CRC
Colorectal tumors present with a broad spectrum of neoplasms, ranging from benign growths to invasive cancer, and are predominantly epithelial-derived tumors (i.e., adenomas or adenocarcinomas). Pathologists have classified the lesions into three groups: nonneoplastic polyps, neoplastic polyps (adenomatous polyps, adenomas), and cancers. The nonneoplastic polyps include hyperplastic, juvenile, hamartomatous, inflammatory, and lymphoid polyps, which have not generally been thought of as precursors of cancer. Research, however, suggests increased CRC risk in some families with multiple members affected with juvenile polyposis, Peutz-Jeghers syndrome, and hyperplastic polyposis.[7,8,9]
Epidemiologic studies have shown that a personal history of colon adenomas places one at an increased risk of developing colon cancer. Two complementary interpretations of this observation are (1) the adenoma may reflect an innate or acquired tendency of the colon to form tumors, and (2) adenomas are the primary precursor lesion of colon cancer. More than 95% of CRCs are carcinomas, and about 95% of these are adenocarcinomas. It is well recognized that adenomatous polyps are benign tumors that may undergo malignant transformation. They have been classified into three histologic types, with increasing malignant potential: tubular, tubulovillous, and villous. While there is no direct proof that most CRCs arise from adenomas, adenocarcinomas are generally considered to arise from adenomas,[11,12,13,14,15] based upon these important observations: (1) benign and malignant tissue occur within colorectal tumors; and (2) when patients with adenomas were followed for 20 years, the risk of cancer at the site of the adenoma was 25%, a rate much higher than that expected in the normal population. Also, three characteristics of adenomas that are highly correlated with the potential to transform into cancer include large size, villous pathology, and the degree of dysplasia within the adenoma. In addition, removal of adenomatous polyps is associated with reduced CRC incidence.[18,19] While most adenomas are polypoid, flat and depressed lesions may be more prevalent than previously recognized. Large, flat and depressed lesions may be more likely to be severely dysplastic, although this remains to be clearly proven.[20,21] Specialized techniques may be needed to identify, biopsy, and remove such lesions.