Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Introduction
Table 1. Estimated Relative and Absolute Risk of Developing Colorectal Cancer (CRC) continued...
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.
- 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.
- The presence of multiple polyps may suggest a hereditary colon cancer predisposition syndrome. As susceptibility to oligopolyposis (as few as 10–15 polyps) has become apparent, clinicians, and GI endoscopists in particular, increasingly consider the possibility of inherited conditions, such as AFAP, MYH-associated polyposis, and POLD1/POLE, even when the family history appears entirely negative. Because oligopolyposis also involves diverse pathology (including hamartomas, sessile serrated polyps, and sessile serrated adenomas), careful attention to polyp count and polyp histologies helps to determine whether genetic testing and/or further clinical evaluation is appropriate.