Genes act as instruction manuals for building the proteins that carry out countless functions. One of these is the Adenomatous Polyposis Coli (APC) gene, known for its role in regulating cell behavior. The protein produced by the APC gene helps to manage how cells grow and divide. When this gene functions correctly, it is a safeguard against abnormal cell activity, maintaining normal tissue structure and preventing disease.
The Function of the APC Gene
The APC gene is classified as a tumor suppressor, meaning its primary role is to prevent cells from growing and dividing too rapidly or in an uncontrolled manner. A useful analogy is to think of the APC protein as the braking system for a cell, ensuring that cell division proceeds at a safe and regulated pace. The APC protein performs this function by interacting with another protein called beta-catenin, which is involved in signaling pathways that encourage cells to grow.
The APC protein is part of a “destruction complex” that breaks down beta-catenin when it is no longer needed, preventing it from continuously signaling cells to multiply. This relationship is also important for cell adhesion and migration, helping ensure that cells stick together properly and stay within their designated tissue boundaries. Mutations in the APC gene often lead to a shortened, nonfunctional protein that cannot regulate beta-catenin, causing the braking system to fail and allowing for unchecked growth.
Familial Adenomatous Polyposis
The most well-known inherited disorder caused by a change in the APC gene is Familial Adenomatous Polyposis (FAP). FAP is an autosomal dominant condition, meaning an individual only needs to inherit one mutated copy of the gene to develop the disorder. While about 70-75% of people with FAP inherit it, the mutation can also occur spontaneously. People with FAP have one functioning copy of the gene and one non-working copy in every cell of their body.
This genetic predisposition leads to the development of hundreds to thousands of noncancerous growths, called adenomatous polyps, in the large intestine and rectum. These polyps often begin to appear during the teenage years. If left untreated, the sheer number of polyps makes the development of colorectal cancer a near certainty, with a risk approaching 100%.
A milder version of the condition, known as attenuated FAP (AFAP), also results from APC mutations. Individuals with AFAP develop fewer polyps, often between 20 and 100, and the onset of cancer occurs at a later age. Another variation is Gardner syndrome, which involves the colonic polyps of FAP along with other growths, such as bone tumors and skin cysts.
Connection to Sporadic Colorectal Cancer
While APC mutations are the cause of inherited syndromes like FAP, they also play a significant part in colorectal cancers that are not inherited. These are known as sporadic cancers, meaning they occur in individuals with no family history, and mutations in the APC gene are found in the majority of these tumors. The distinction lies in how the mutation arises.
In inherited conditions like FAP, a person is born with a “germline” mutation in one copy of the APC gene in all their cells. In sporadic cancer, the mutations are “somatic,” meaning they are acquired in a single colon cell during a person’s lifetime. For cancer to develop, both copies of the APC gene within that one cell must become inactivated, a process known as the “two-hit” hypothesis.
In sporadic cases, the first “hit” is a somatic mutation in one APC allele, and the second “hit” involves the loss of the other, healthy allele. The result is the loss of functional APC protein, which allows for uncontrolled cell growth and the formation of a polyp that can eventually progress to cancer.
Genetic Testing and Medical Management
Genetic testing for APC mutations is a consideration for individuals with specific risk factors. Candidates include those with a personal or strong family history of colorectal cancer, those diagnosed with numerous colon polyps, or individuals with signs of a syndrome like FAP. The test itself requires only a blood or saliva sample to analyze the DNA for pathogenic variants in the APC gene.
For individuals who test positive for an inherited APC mutation, a structured medical management plan is put into place. Surveillance is a primary component of this plan and includes several actions.
- Frequent colonoscopies to monitor for polyp development, typically starting between the ages of 10 and 15 for classic FAP.
- Upper endoscopies to screen for polyps in the stomach and small intestine, which can also occur in people with FAP.
- Prophylactic surgery, a colectomy (the surgical removal of the colon), is often recommended in a person’s late teens or early twenties to prevent cancer.
- Follow-up surveillance of any remaining rectal tissue or surgically created pouches is necessary depending on the type of surgery.
- Regular screenings for other potential health issues, such as thyroid exams and abdominal ultrasounds to check for liver tumors in young children.
This comprehensive management strategy is aimed at early detection and prevention.