The Adenomatous polyposis coli (APC) gene is a type of gene known as a tumor suppressor. In its healthy form, it provides instructions for making a protein that regulates cell growth and division. When specific mutations occur in this gene, its ability to control cell proliferation is impaired. This loss of function is strongly linked to an increased risk for developing certain types of cancer, particularly colorectal cancer. These genetic changes can be inherited, predisposing an individual to cancer from birth, or they can be acquired during a person’s lifetime.
The Normal Function of the APC Gene
The APC gene’s primary role is to regulate cell growth, particularly within the intestinal lining. It produces the APC protein, which prevents cells from multiplying uncontrollably. A primary function is regulating the protein beta-catenin. The APC protein binds to beta-catenin, signaling for its breakdown when no longer needed.
This function ensures that cell division proceeds at a controlled pace. The APC protein also helps cells adhere to form tissues and ensures new cells receive the correct number of chromosomes after division. These actions maintain tissue stability and prevent the initial changes that could lead to tumor formation.
How APC Gene Mutations Lead to Cancer
When the APC gene is mutated, it produces a short, nonfunctional protein. This defective protein cannot manage beta-catenin levels, causing it to accumulate inside the cell. This buildup promotes rapid and unchecked cell growth.
This uncontrolled growth is the first step toward cancer. In the colon and rectum, this overgrowth leads to noncancerous growths called polyps, or adenomas. Over time, additional genetic mutations can occur within the polyp cells, driving their transformation into malignant tumors.
An inherited (germline) mutation is present in every cell from birth and passed through families, dramatically increasing lifetime cancer risk. A somatic mutation is acquired in a single cell later in life and is not inherited. The risk associated with an inherited mutation is substantially higher.
Familial Adenomatous Polyposis (FAP)
The primary inherited condition from APC mutations is Familial Adenomatous Polyposis (FAP). FAP is an autosomal dominant disorder, meaning inheriting just one copy of the mutated gene from a parent is enough to cause the condition. The defining characteristic of classic FAP is the development of hundreds to thousands of adenomatous polyps throughout the colon and rectum.
These polyps begin to appear during adolescence. Without treatment, the development of colorectal cancer is nearly certain. The average age of cancer diagnosis in individuals with FAP who do not undergo preventative surgery is around 39 years. A milder form, attenuated FAP (AFAP), involves fewer polyps and a later onset of cancer, but the risk remains significantly elevated.
FAP’s effects are not limited to the colon, and individuals are at risk for other growths and cancers:
- Osteomas (harmless bony growths on the jaw and skull).
- Congenital hypertrophy of the retinal pigment epithelium (CHRPE), which are non-vision-impairing pigmented lesions in the eye.
- Desmoid tumors, which are non-cancerous but aggressive connective tissue growths that can compress organs.
- Cancers of the thyroid, small intestine (duodenum), pancreas, and stomach.
Genetic Testing and Screening
Genetic testing and counseling are recommended for at-risk individuals. Testing is considered for anyone with a personal or family history of FAP, numerous colorectal polyps, or early-age colorectal cancer. It is also recommended for those with extracolonic signs like desmoid tumors. A blood sample is used to analyze the APC gene for mutations.
Genetic counseling helps families understand the test results, including cancer risks and the chances of passing the mutation to children. If a mutation is found, predictive testing can be offered to relatives who have not yet developed symptoms. This allows for early identification of who is at risk.
Individuals with a confirmed APC mutation require intensive screening protocols. Surveillance for classic FAP begins in early adolescence (ages 10-15) with annual colonoscopies. Regular upper endoscopies are also recommended, starting around age 25, to screen for polyps in the stomach and duodenum. Additional screening, like thyroid ultrasounds, may be advised based on family history.
Managing APC-Associated Conditions
The management of conditions caused by APC mutations is centered on preventing cancer and treating related health issues. For individuals with classic FAP, cancer prevention involves prophylactic surgery to remove the colon (a colectomy). This surgery is recommended in the late teens or early twenties, once polyps develop but before they become malignant. Removing the colon almost eliminates the risk of colorectal cancer.
A total proctocolectomy involves removing the colon and rectum, often followed by creating an ileal pouch-anal anastomosis (IPAA) to allow for relatively normal bowel function. Another option is a subtotal colectomy with an ileorectal anastomosis (IRA), where the colon is removed but the rectum remains. This procedure is less complex but requires lifelong surveillance of the remaining rectum due to cancer risk.
Chemoprevention uses medications like nonsteroidal anti-inflammatory drugs (NSAIDs) to help reduce the number and size of polyps. These medications are not a substitute for surgery but may be used to manage polyp growth after surgery. Treatments for other FAP-related conditions, like desmoid tumors, are complex and may involve surveillance, medication, or surgery.