The Adenomatous Polyposis Coli (APC) gene provides instructions for making the APC protein, a component with a role in multiple cellular functions. When a gene undergoes a mutation, its instructional code is altered, which can lead to a faulty or nonfunctional protein. These changes can disrupt normal cellular processes and undermine the cell’s natural control mechanisms.
Mutations within the APC gene are significant because they predispose individuals to specific health conditions. The impairment of the APC protein can initiate a cascade of events with considerable health implications.
The Normal Function of the APC Gene
The APC gene is a tumor suppressor gene, which creates proteins to regulate cell activities like division and life span. One of its primary functions is to help control how frequently a cell divides, how it adheres to other cells, and its ability to move. These actions prevent cells from growing and dividing in an uncontrolled manner, a hallmark of tumor development.
A primary part of the APC protein’s role is carried out through its interaction with a protein called beta-catenin. The APC protein is a component of a “destruction complex,” which also includes proteins like axin and GSK3β. This complex identifies and marks beta-catenin for degradation when it is not needed. By managing beta-catenin levels, the APC protein prevents the constant activation of genes that stimulate cell growth.
Beyond its role in cell growth, the APC protein contributes to the stability of the cell’s cytoskeleton and is involved in cell adhesion. The protein also has a function in ensuring the correct number of chromosomes is passed on to each new cell during division, helping maintain genomic stability.
Impact of APC Gene Mutations
Mutations in the APC gene disrupt its ability to produce a functional protein. The most common types are truncating mutations, which introduce a premature stop signal in the gene’s instructions. This results in an abnormally short and nonfunctional APC protein that lacks the regions needed to bind with beta-catenin.
The failure of the mutated APC protein to form a functional destruction complex is a primary problem. Without a working complex, beta-catenin accumulates in the cytoplasm and travels into the cell’s nucleus. There, it activates specific genes that drive cell proliferation, such as MYC and cyclin D1, leading to a constant, unregulated signal to grow.
This unchecked cell proliferation is an early step in the formation of adenomatous polyps, which are abnormal growths that can develop into cancer. The loss of normal APC function is a foundational event that allows subsequent genetic errors to accumulate. While linked to inherited cancer syndromes, somatic (non-inherited) mutations disrupting the APC pathway are also found in most sporadic colorectal cancers.
Conditions Associated with APC Mutations
Inherited APC mutations are strongly linked with a condition called Familial Adenomatous Polyposis (FAP). FAP is characterized by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, beginning during adolescence. If the colon is not surgically removed, the risk of developing colorectal cancer for individuals with classic FAP is nearly 100%, often by age 40.
A milder variant, known as attenuated FAP (AFAP), is also caused by APC mutations. Individuals with AFAP develop fewer polyps, between 10 and 100, and the onset of both polyps and cancer occurs at a later age. The specific location of the mutation within the APC gene can influence whether an individual develops classic FAP or AFAP.
Beyond the colon, APC mutations are associated with a range of other growths. These extracolonic manifestations can include:
- Desmoid tumors (noncancerous but locally invasive fibrous tumors)
- Osteomas (benign bone growths on the jaw and skull)
- Dental abnormalities, such as extra teeth
- Congenital hypertrophy of the retinal pigment epithelium (CHRPE), which are benign spots on the retina
Individuals with FAP also have an elevated risk for several cancers, including:
- Thyroid
- Small bowel
- Stomach
- Pancreas
- Hepatoblastoma (a childhood liver cancer)
Inheritance Patterns and Genetic Testing
Inherited APC mutations are passed down in an autosomal dominant pattern. This means a mutation in just one of the two copies of the APC gene is enough to significantly increase an individual’s risk for FAP. A person with an APC mutation has a 50% chance of passing the altered gene to each of their children.
In some cases, an individual is the first in their family to have FAP. This occurs through a de novo mutation, where the genetic change arises spontaneously in the egg or sperm cell of a parent or in the embryo. It is estimated that 20-30% of people with FAP have a de novo mutation.
Genetic testing for APC mutations is recommended for individuals with clinical signs of FAP, such as having more than 10 to 20 colorectal polyps, or for those with a known family history. The test involves analyzing a blood or saliva sample to look for pathogenic variants in the APC gene. Genetic counseling before and after testing helps individuals understand the implications of the results for their health and for their family members.
Management and Surveillance Strategies
For individuals with a pathogenic APC mutation, management focuses on intensive surveillance and preventive measures to detect polyps and cancer early. This includes frequent colonoscopies, beginning in late childhood or early adolescence, between ages 10 and 15 for classic FAP. Upper endoscopies are also performed regularly to monitor for polyps in the stomach and duodenum.
The primary strategy to prevent colorectal cancer in FAP is a prophylactic colectomy, the surgical removal of the colon. This surgery is recommended when a large number of polyps develop or when advanced polyps are found, often in a person’s late teens or early twenties. Different surgical options exist, with the choice depending on the severity of polyposis in the rectum.
Surveillance also extends to the extracolonic manifestations. This may involve annual thyroid exams and ultrasounds to screen for thyroid cancer and abdominal imaging to monitor for desmoid tumors. Research into chemoprevention, using medications like nonsteroidal anti-inflammatory drugs (NSAIDs), has been explored to reduce the number and size of polyps. However, these medications do not eliminate the need for surveillance or eventual surgery.