Family History

People with one or more first-degree relatives (parent, sibling, or child) with colorectal cancer but without one of the genetic syndromes have approximately twice the risk of developing colorectal cancer as individuals at average risk. In those with a single first-degree relative, the risk significantly increases in the fourth decade and continues to rise with age (Fuchs, Giovannucci, Colditz, et al., 1994). Risk appears to be further increased if more than one first-degree relative has colorectal cancer and if the relatives' cancers occurred before age 55. Winawer and colleagues showed that an increased risk also exists in close relatives (parents and siblings) of people having an adenomatous polyp diagnosed prior to age 60 (Winawer, Zauber, Gerdes, et al., 1996).

Genetic Syndromes

Familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) are two specific forms of hereditary colorectal cancer syndromes in which the majority of affected persons will develop colorectal cancer.

FAP accounts for about 1 percent of new cases of colorectal cancer in the United States. Affected individuals develop adenomatous polyps in the second and third decade of life, have hundreds to thousands of polyps throughout the colon by their 30s, and nearly a 100 percent chance of developing colorectal cancer by their fourth decade.

Turcot's Syndrome (familial colorectal and brain cancer) and Gardner's syndrome (familial colorectal cancer, osteomas, and benign soft tissue tumors) are variants of FAP and involve a genetic defect of the adenomatous polyposis coli gene on the long arm of chromosome 5. They are inherited as an autosomal dominant syndrome.

HNPCC accounts for approximately 5 percent of new cases of colorectal cancer per year and has two main forms: one without a family history of other cancers and one with an increased familial occurrence of other types of cancers, typically of the ovaries and uterus. Mutations primarily in four genes on chromosomes 2, 3, and 7 (hMLH1, hMSH2, hPMS1, and hPMS2) are associated with 70 to 80 percent of cases. HNPCC occurs at an early age - in the fourth to fifth decade - and the cancers are located predominantly proximal to the splenic flexure. Adenomatous polyps precede the development of cancer but do not occur in unusually large numbers as seen in FAP. People with HNPCC develop adenomatous polyps at a younger age than people without HNPCC, and the polyps exhibit more advanced pathology (Jarvinen, 1985; Jass, 1994).

The clinical distinction between patients with HNPCC and those with a family history of colorectal cancer in the absence of a diagnosed genetic syndrome is sometimes unclear. Because HNPCC is not characterized by multiple polyps or other clinically apparent abnormalities, the syndrome is defined by clinical history in the absence of genetic testing. A common method of classification is the Amsterdam Criteria: the existence of three or more relatives with histologically documented colorectal cancer, one of whom is a first-degree relative of the other two; one or more cases of colorectal cancer in the family diagnosed before age 50; and colorectal cancer involving at least two generations (Vasen, Mecklin, and Kahn, 1991).

Inflammatory Bowel Disease (IBD)

Patients with IBD are at substantially increased risk for colorectal cancer compared with the general population, although IBD contributes only a small proportion (less than 1 percent) of all new cases of colorectal cancer. The risk associated with ulcerative colitis and Crohn's colitis is comparable in extent, duration, and age of onset to that of IBD (Gillen, Walmsley, Prior, et al., 1994).

Cancers that develop in patients with IBD are usually flat and infiltrating. They usually do not arise from adenomatous polyps but from areas of precancerous dysplasia. Patients with moderate to severe dysplasia have a high probability of having cancer somewhere in the colon (Lennard-Jones, Melville, and Morson, 1990). The degree of risk for colorectal cancer depends on the extent and duration of the IBD and the age of onset (Lennard-Jones and Connell 1995; Lennard-Jones, Melville, and Morson, 1990; Katzka, Brody, Morris, and Katz, 1983). Patients are most at risk if they have pancolitis (colitis throughout the entire bowel) or ulceration extending proximally to the splenic flexure and less at risk when disease is limited to the rectum and sigmoid colon (Lennard-Jones, Melville, and Morson, 1990; Greenstein, Sachar, and Smith, 1979). The cumulative incidence of colorectal cancer in patients with pancolitis is 30 percent in 35 years (Greenstein, Sachar, and Smith, 1979; Ekbom, Helmick, Zack, et al., 1990).

Prior Colorectal Cancer

Individuals with a history of prior colorectal cancer are at increased risk of developing another (metachronous) cancer. In a study by Morson (1984), 4,119 patients were followed for up to 40 years. Risk of colorectal cancer was 1.9 percent in the first 10 years but rose over the course of the study to about four times the lifetime risk of average-risk people.