MUTYH polyposis, also known as MUTYH-associated polyposis (MAP), is a rare inherited condition that significantly increases an individual’s lifetime risk of developing certain cancers, particularly colorectal cancer. This disorder arises from specific genetic changes passed down through families, affecting how the body repairs its DNA. Understanding this genetic predisposition is important for identifying individuals at risk and implementing strategies to manage their health proactively.
Understanding the MUTYH Gene
The MUTYH gene maintains DNA integrity. It is involved in base excision repair (BER), a process that corrects DNA damage. The MUTYH protein acts as a DNA glycosylase, an enzyme that scans newly synthesized DNA strands and removes adenine bases incorrectly paired with 8-oxoguanine (8-oxoG). If uncorrected, this mispairing can lead to a G:C to T:A transversion mutation during DNA replication.
Mutations in both copies of the MUTYH gene impair this repair function, allowing DNA errors to accumulate. This accumulation increases the likelihood of mutations in other genes that regulate cell growth, such as APC and KRAS, contributing to cancer development. The inheritance pattern for MUTYH polyposis is autosomal recessive, meaning an individual must inherit a mutated copy of the MUTYH gene from each parent to develop the condition.
Parents who carry one mutated copy of the MUTYH gene are typically unaffected, but they can pass the mutation to their children. There is a 25% chance for each child to inherit two mutated copies and develop MAP, a 50% chance to be a carrier, and a 25% chance to inherit no mutated copies. Approximately 1% to 2% of the general population are carriers of a single MUTYH gene mutation.
Health Risks and Clinical Presentation
The primary health concern associated with MUTYH polyposis is the development of abnormal growths, or polyps, in the colon and rectum. These polyps are adenomatous, meaning they have the potential to become cancerous over time. Individuals with MUTYH polyposis can develop a varying number of these polyps, ranging from a few to hundreds.
The risk of developing colorectal cancer is elevated for individuals with MUTYH polyposis, with a lifetime risk potentially reaching 80-90% without appropriate surveillance. Colorectal cancer can sometimes develop even in individuals with few or no visible polyps. The onset of colorectal cancer in individuals with MAP often occurs between the ages of 40 and 60, but it can appear earlier.
Beyond colorectal cancer, individuals with MUTYH polyposis also face an increased risk of other cancers. Duodenal adenomas are common, and there is an increased risk of duodenal cancer, with a lifetime risk of approximately 4%. Other associated cancers include those of the ovary (with a lifetime risk of 6-14% for women), bladder, thyroid, and skin. Evidence also suggests an increased risk for breast and endometrial cancers.
Diagnosis of MUTYH Polyposis
Diagnosing MUTYH polyposis relies primarily on genetic testing, the definitive method for identifying mutations in the MUTYH gene. This testing looks for pathogenic variants in both copies of the gene to confirm a diagnosis. Genetic testing is often recommended for individuals who present with specific clinical indicators.
These indicators include a personal history of multiple colorectal polyps, 10 or more adenomas, or early-onset colorectal cancer. Testing may also be considered for those with 10-20 polyps, especially if there is a family history of colorectal cancer or polyposis. It is particularly relevant when other common polyposis syndromes, such as Familial Adenomatous Polyposis (FAP), have been ruled out.
Genetic testing can be performed using gene sequencing and deletion/duplication analysis, often as part of a multigene panel that screens for various hereditary cancer syndromes. This comprehensive approach helps to differentiate MUTYH polyposis from other conditions that might present with similar polyp formations. Identifying these specific mutations allows for a precise diagnosis and guides subsequent management strategies.
Managing MUTYH Polyposis
Managing MUTYH polyposis involves regular surveillance to detect and remove polyps early, thereby reducing the risk of colorectal cancer. Colonoscopies are the primary tool for this surveillance, recommended every one to two years starting between the ages of 25 and 30. During these procedures, any suspicious polyps are removed.
If the number and density of polyps become too high to manage effectively with polypectomy alone, surgical options such as a subtotal colectomy or proctocolectomy may be considered. In addition to colon surveillance, upper endoscopy with side viewing duodenoscopy is recommended starting between ages 30 and 35, with follow-up frequency depending on initial findings of duodenal polyps. Duodenal polyps showing dysplasia or villous changes should be excised.
Individuals with MUTYH polyposis also undergo surveillance for other cancers. Annual physical examinations, thyroid ultrasounds, and skin examinations by a dermatologist are often considered. Family screening is also an important aspect of management, as it allows for the identification of other family members who may have inherited the MUTYH mutations and would benefit from similar surveillance and preventive measures.