Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Introduction
Table 1. Estimated Relative and Absolute Risk of Developing Colorectal Cancer (CRC)
|Family History||Relative Risk of CRC||Absolute Risk (%) of CRC by Age 79 ya|
|CI = confidence interval.|
|a Data from the Surveillance, Epidemiology, and End Results database.|
|b The absolute risks of CRC for individuals with affected relatives was calculated using the relative risks for CRCand the absolute risk of CRC by age 79 yearsa.|
|No family history||1||4a|
|One first-degree relative with CRC||2.3 (95% CI, 2.0–2.5)||9b|
|More than one first-degree relative with CRC||4.3 (95% CI, 3.0–6.1)||16 b|
|One affected first-degree relative diagnosed with CRC before age 45 y||3.9 (95% CI, 2.4–6.2)||15b|
|One first-degree relative with colorectal adenoma||2.0 (95% CI, 1.6–2.6)||8b|
When the family history includes two or more relatives with CRC, 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 CRC was diagnosed, the presence of multiple primary CRCs, and the presence of any other cancers (e.g., endometrial) consistent with an inherited CRC syndrome. (Refer to the Major Genetic Syndromes section of this summary for more information.) Young subjects who report a positive family history of CRC are more likely to represent a high-risk pedigree than older individuals who report a positive family history. Computer models are now available to estimate the probability of developing CRC. These models can be helpful in providing genetic counseling to individuals at average risk and high risk of developing cancer. At least three validated models are also available for predicting the probability of carrying a mutation in a MMR gene.[49,50,51]
Figure 1 shows the types of colon cancer cases that arise in various family risk settings.
Figure 1. The fractions of colon cancer cases that arise in various family risk settings. Reprinted from Gastroenterology, Vol. 119, No. 3, Randall W. Burt, Colon Cancer Screening, Pages 837-853, Copyright (2000), with permission from Elsevier.
Inheritance of CRC Predisposition
Several genes associated with CRC risk have been identified; these are described in detail in the Colon Cancer Genes section of this summary. Almost all gene mutations known to cause a predisposition to CRC are inherited in an autosomal dominant fashion. To date, at least one example of autosomal recessive inheritance, MYH-associated polyposis (MAP), has been identified. (Refer to the MYH-Associated Polyposis (MAP) section of this summary for more information.) 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:
- Vertical transmission of cancer predisposition in autosomal dominant conditions. (Vertical transmission refers to the presence of a genetic predisposition in sequential generations.)
- 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.
- Although most cancers occurring in an isolated patient are likely de novo mutations (e.g., adenomatous polyposis coli [APC]), cancers developing within a single generation can suggest autosomal recessive inheritance (as seen in MAP). (Refer to the De novo mutation rate section in the Colon Cancer Genes section of this summary for more information.)
- Other clinical characteristics also suggest inherited risk:
- Cancers in people with a hereditary predisposition typically occur at an earlier age than in sporadic (nongenetic) cases.
- A predisposition to CRC may include a predisposition to other cancers, such as endometrial cancer, as detailed in the Major Genetic Syndromes section of this summary.
- In addition, two or more primary cancers may occur in a single individual. These could be multiple primary cancers of the same type (e.g., two separate primary CRCs) or primary cancer of different types (e.g., colorectal and endometrial cancer in the same individual).
- The presence of non-neoplastic extracolonic features may suggest a hereditary colon cancer predisposition syndrome (e.g., congenital hypertrophy of the retinal pigment epithelium and desmoids in familial adenomatous polyposis [FAP]).
- An uncommon tumor (e.g., adrenocortical, sebaceous carcinoma, ampullary, and small bowel) may serve as a clue to the presence of a hereditary cancer syndrome, such as Li-Fraumeni or FAP.