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  » Cancer: risk chart  »  Family History as a Risk Factor for Colorectal Cancer

Among the earliest studies of family history of colorectal cancer were those of Utah families that reported a higher number of deaths from colorectal cancer (3.9%) among the first-degree relatives of patients who had died from colorectal cancer, compared to sex- and age-matched controls (1.2%). This difference has since been replicated in numerous studies that have consistently found that first-degree relatives of affected cases are themselves at a two- to threefold increased risk of colorectal cancer. Despite the various study designs (case-control, cohort), sampling frames, sample sizes, methods of data verification, analytic methods, and countries where the studies originated, the magnitude of risk is consistent.

Data from a cancer family clinic patient population estimated the lifetime risk of colorectal cancer for different family history categories.

When the family history includes 2 or more relatives with colorectal cancer, the possibility of a genetic syndrome is increased substantially. The first step in this evaluation is a detailed review of the family history, to determine the number of relatives affected, their relationship to each other, the age at which the colorectal cancer was diagnosed, the presence of multiple primary colorectal cancer, and the presence of any other cancers consistent with an inherited colorectal cancer syndrome.

Autosomal Dominant Inheritance of Colorectal Cancer Predisposition

Several genes associated with colorectal cancer risk have been identified; these are described in detail in the Colon Cancer Genes section of this summary. All gene mutations known to cause a predisposition to colorectal cancer are inherited in an autosomal dominant fashion. Thus, the family characteristics that suggest autosomal dominant inheritance of cancer predisposition are important indicators of high risk and of the possible presence of a cancer-predisposing mutation. These include the following:

1. Vertical transmission of cancer predisposition. Vertical transmission refers to the presence of a genetic predisposition in sequential generations.

2. Inheritance risk of 50% for both males and females. When a parent carries an autosomal dominant genetic predisposition, each child has a 50% chance of inheriting the predisposition. The risk is the same for both male and female children.

3. Other clinical characteristics also suggest inherited risk:

  • Cancers in people with an autosomal dominant predisposition typically occur at an earlier age than sporadic (nongenetic) cases.
  • An autosomal dominant predisposition to colorectal cancer may include a predisposition to other cancers, such as endometrial cancer, as detailed in the Major Genetic Syndromes section of this summary.
  • In addition, 2 or more primary cancers may occur in a single individual. These could be multiple primary cancers of the same type (e.g., 2 separate primary colorectal cancers) or primary cancer of different types (e.g., colorectal and endometrial cancer in the same individual).

Hereditary colorectal cancer has 2 well-described forms: familial adenomatous polyposis (FAP, including an attenuated form of polyposis, AFAP), due to germline mutations in the APC gene,and hereditary nonpolyposis colorectal cancer (HNPCC), which is caused by germline mutations in mismatch repair genes. Many other families exhibit aggregation of colorectal cancer and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial colorectal cancer (FCC).

Difficulties in Identifying a Family History of Colorectal Cancer Risk

The accuracy and completeness of family history data must be taken into account in using family history to assess individual risk in clinical practice, and in identifying families appropriate for cancer research. A reported family history may be erroneous, or a person may be unaware of relatives with cancer. In addition, small family sizes and premature deaths may limit how informative a family history may be. Also, some persons may carry a genetic predisposition to colorectal cancer but do not develop cancer, giving the impression of "skipped" generations in a family tree.

When family histories of colon cancer were checked in a research study, a sensitivity of 73% (95% confidence interval (CI) 54%-86%) was obtained. In this study of Utah patients, the investigators compared self-reported family history of colon cancer to a computerized Utah Population Database, which was created by linking genealogical records with the state cancer registry. The kappa score, a measure of overall agreement between the reported family history and the database, was 0.56 (95% CI 0.45-0.66), indicating moderately good agreement. Thus, what patients tell clinicians about their family histories is a reasonably good indicator of actual history.

Other Risk Factors for Colorectal Cancer

Other factors that influence colorectal cancer risk include age, diet, and level of physical activity. Dietary factors that appear to increase colorectal cancer risk include high red meat and fat intake; protective dietary factors include fiber, vegetables, and dietary folate, though recent work suggests that low dietary fiber does not appear to be a risk factor for colorectal cancer in women. Putative risk factors include parity, smoking, and alcohol intake. Nonsteroidal anti-inflammatory drugs (e.g., aspirin) and hormone replacement therapy appear to have a protective effect against both colorectal cancer and colon polyps. (Refer to the PDQ summary on Prevention of Colorectal Cancer for more information.)

Genetic factors appear to influence the age of onset of colorectal cancer. People who have a first-degree relative with colorectal cancer are estimated to have an average onset of colorectal cancer about 10 years earlier than people with sporadic colorectal cancer. The increased cancer risk conferred by a family history of colorectal cancer appears to manifest itself primarily in people under age 60. Markedly early onset of cancer is seen in hereditary conditions conferring an increased risk of colorectal cancer with a mean age of diagnosis of colorectal cancer in the early 30s for FAP and 40s for HNPCC.

For the most part, the effects of other nongenetic risk factors have not been evaluated in people who are genetically susceptible to colorectal cancer. Studies of carcinogen metabolic polymorphisms, such as glutathione-s transferase and N-acetyl transferase, suggest that there may be some influence on risk of colorectal cancer, through interactions with micronutrients or other environmental factors; however, these data are too preliminary to apply in a clinical setting.