MUTYH-Associated Adenomatous Polyposis Factsheet

MUTYH-associated adenomatous polyposis (MAP) is a cancer predisposition syndrome caused by having two MUTYH pathogenic variants (mutations). Carriers of one MUTYH pathogenic variant have a milder clinical presentation.

Clinical Features

Individuals with MAP typically develop 10 - 100 colon polyps: adenomatous or a combination of adenomatous and other polyps. Without surveillance, patients with MAP have a nearly 100 percent risk of developing colon cancer. In addition to colon polyps, individuals with MAP may also develop gastric and duodenal adenomas and other types of polyps, such as sessile serrated and hyperplastic polyps. MAP is not associated with any unique physician exam findings, although reported rarely are features such as thyroid nodules, benign adrenal lesions, jawbone cysts and CHRPE (congenital hypertrophy of retinal pigment epithelium).

Cancer Risks Associated with MAP

Adapted from GeneReviews 2021 and NCCN v.1.2023

Tumor Characteristics

A molecular hallmark of cancers caused by MAP is the presence of a specific somatic KRAS variant (c.34G>T in codon 12) which is found in 60-90% of MAP-associated colorectal cancers.

Prevalence of MAP

About 0.7% of all colorectal cancer is due to MAP. An estimated 1 in 20,000 - 40,000 individuals of northern European ancestry have MAP (carry two MUTYH pathogenic variants). It is estimated that 1%-2% of this population carries one MUTYH pathogenic variant. MAP may be less frequent in other specific ethnic populations.

Diagnosis

A diagnosis is established in individuals with clinical characteristics who have two pathogenic variants identified in the MUTYH gene.

Genetic testing is recommended for individuals with ≥ 20 polyps, and may be considered in individuals with 10-20 polyps with other personal and/or family features.

Genetics & Inheritance

MAP is an autosomal recessive condition caused by pathogenic variants in both copies of an individual’s MUTYH genes. All children of individuals with MAP are at least carriers and will have MAP if they also inherit an MUTYH pathogenic variant from their other parent. Men and women are equally likely to inherit, and pass on, a pathogenic variant. 

Clinical Testing

Clinical testing includes gene sequencing and deletion/duplication analysis, most often as part of a multigene panel. Sequencing detects 99% of individuals with MAP.

Management

Screening recommendations vary depending on whether an individual is affected or unaffected with cancer, has two pathogenic variants (MAP) or one pathogenic variant (carrier), has a family history of colorectal cancer, and polyp burden. Refer to NCCN guidelines for specific recommendations.

For individuals with MAP, increased colorectal and gastrointestinal surveillance (colonoscopy and upper endoscopy) are recommended. Colectomy with ileorectal anastomosis (IRA) or proctocolectomy may be considered depending on polyp burden.

Management of MUTYH Carriers

Current guidelines recommend increased colonoscopy screening for unaffected MUTYH carriers (one pathogenic variant) with a first-degree relative with colorectal cancer. In a large population-based study, carriers had a moderately increased risk of colorectal cancer compared to the general population (2.5 times greater, particularly with a family history of CRC). Other studies have not shown this increased risk consistently; therefore, more research is needed to inform clinical management. 

Other Genes that Contribute to Polyposis

There are other hereditary cancer syndromes that increase the risk for polyps and colorectal cancer, including Familial Adenomatous Polyposis (FAP), Attenuated Familial Adenomatous Polyposis (AFAP), Juvenile Polyposis syndrome, Peutz-Jeghers syndrome, and Cowden syndrome. The presentation of these syndromes in a family may overlap with that of MAP, but can sometimes be distinguished based on characteristic features, such as physical exam findings and polyp pathology. In addition, a number of common genetic susceptibility variants are thought to increase polyp and colorectal cancer risk, indicating there are likely other genes that contribute to polyp development which have not yet been identified. See GeneReviews for more information about the genetic differential diagnosis for MAP.

Select Guidelines & Resources

Resources

American Society of Clinical Oncology (2022): MUTYH-Associated Polyposis.

GeneReviews (2021): MUTYH-Associated Polyposis.

National Cancer Institute (2023): Genetics of Colorectal Cancer PDQ – Major Genetic Syndromes.

Guidelines

American College of Gastroenterology (2015): Clinical Guideline on Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes.

American College of Medical Genetics & National Society of Genetic Counselors (2014): Referral Indications for Cancer Predisposition Assessment. (See Addendum, 2019).

National Comprehensive Cancer Network (v.1.2023): Genetic/Familial High Risk Assessment: Colorectal (Free registration required for access).

Updated August 2023