MUTYH-associated polyposis

• MAP predisposes to the development of colonic polyposis and cancer.
• The number of colonic polyps is in the order of a few adenomas to 100s, but rarely greater than 1000 (in contrast to familial adenomatous polyposis). Furthermore, colorectal cancer has been reported in MAP (defined by biallelic constitutional (germline) MUTYH pathogenic variants) in the absence of preceding polyposis.
• Polyps occurring in the context of MAP are usually adenomatous, but may be hyperplastic, sessile or mixed.
• Duodenal adenomas and cancers also occur with increased frequency in MAP.
• Association with other cancer types have not been confirmed.

The MUTYH gene

The MUTYH gene encodes for an enzyme (MYH glycosylase) involved in base excision repair. Impaired activity of this enzyme results in an excess of somatic G:C>T:A transversions at certain hotspots, most notably KRAS c.34G>T (p.Gly12Cys). This particular KRAS codon 12 variant is relatively infrequent in sporadic colorectal cancer, but has been demonstrated in 65% of MAP-associated colorectal cancers.

• MAP is an autosomal recessive condition, with affected individuals typically inheriting a variant allele from each parent.
• The frequency of MAP is estimated to be at least 1 in 40,000, but the condition is likely under-recognised given the variable phenotype and recessive mode of inheritance.
• Heterozygous carriers of a single MUTYH variant are typically asymptomatic, and therefore family history of an individual affected by MAP is often uninformative. As colorectal cancer and polyps are common in the general population, however, an apparently dominant mode of inheritance does not preclude a diagnosis of MAP.
• The frequency of MUTYH variants in the general population is ethnicity-specific, with 1%–2% of individuals of European ancestry carrying a pathogenic variant in this gene.
  • Two recurrent pathogenic variants (c.536A>G, p.Y179C and c.1187G>A, p.G396D) account for the vast majority of pathogenic variants in the white European population.
  • Other recurrent MUTYH variants have been reported in different populations.
• Each child of an individual with MAP has a 100% chance of inheriting a variant allele from their affected parent, but their risk of being affected by MAP depends on the carrier status of their other parent.
• Testing to determine the carrier status of the other parent of the child at risk is recommended in the first instance to inform their overall risk. This is particularly important if the proband is in a consanguineous relationship, or if their partner is from a population where the carrier frequency of MUTYH variants is particularly high (for example, European, Gujarati).
• Assuming the parents of an individual affected by MAP are both heterozygous carriers of a single MUTYH variant, each full sibling of an individual affected by MAP has:
  • a 50% (1-in-2) chance of inheriting a single MUTYH variant and being a healthy carrier;
  • a 25% (1-in-4) chance of inheriting both variant alleles and being affected by MAP; and
  • a 25% (1-in-4) chance of inheriting only normal MUTYH alleles.

Diagnosis

Constitutional (germline) MUTYH testing may be offered to a patient with adenomatous polyposis alongside APC and other genes associated with overlapping phenotypes as part of a multigene panel for polyposis predisposition (R211 – Inherited polyposis and early onset colorectal cancer- germline test) in the following scenarios:

• colorectal cancer before age 40 years;
• colorectal cancer and five or more adenomatous polyps;
• five or more adenomatous polyps before age 40 years, 10 or more adenomatous polyps before age 60 years or 20 or more adenomatous polyps at any age; or
• five or more adenomatous polyps (before age 60 years) and a first-degree relative with five or more adenomatous polyps (before age 60 years).

Constitutional (germline) MUTYH testing will also be included as part of multigene panel testing for polyposis predisposition (R211 – Inherited polyposis and early onset colorectal cancer- germline test) in individuals fulfilling criteria for serrated polyposis, or in individuals in whom hamartomatous polyposis is suspected, but an underlying diagnosis of MAP is much less likely to explain such phenotypes.

Referral to clinical genetics for consideration of constitutional (germline) MUTYH testing may be appropriate for patients with:

• Duodenal adenomas; or
• patients with bowel cancer and/or polyps and a family history of bowel cancer; and/or
• polyps suggesting recessive inheritance; or
• in patients with bowel polyps and cancer demonstrating the KRAS c.34G>T somatic variant.

Management

• Surveillance is best co-ordinated through an expert centre.
• Regular colonoscopy-based surveillance is recommended annually from age 18–20.
• Colorectal resection may be indicated for patients with MAP who are undergoing colonoscopic surveillance, relative indications for surgery are polyps >10mm in diameter, high grade dysplasia within polyps and a significant increase in polyp burden between screening examinations..
• Chemoprevention is not indicated in patients with MAP.
• Regular oesophagogastroduodenoscopy (OGD) from age 35 is recommended to manage gastric/duodenal polyposis, with frequency based on polyp burden and Spigelman classification.
• Surveillance for other cancer types in the context of MAP is not recommended.
• Referral of affected patients to clinical genetics should be arranged to discuss onward management, family planning implications, and cascade screening of partners and relatives at risk.

Family planning implications

The Human Fertilisation and Embryology Authority have approved the use of pre-implantation genomic testing for couples where both of the intended parents are carriers of a likely pathogenic/pathogenic variant in a gene associated with a recessive phenotype. It is best practice that discussions regarding this and other family planning options be undertaken by a specialist genetic counsellor or clinical geneticist.

Other options may include prenatal testing (invasive, or non-invasive if the intended father is a carrier of a different variant than the one carried by the intended mother) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children in adulthood.

For clinicians

• HEE Genomics Education Programme: MUTYH-associated polyposis factsheet
• NHS England: National Genomic Test Directory and eligibility criteria
• UK Cancer Genetics Group: Rare Disease Collaborative Networks

References:

• Monahan KJ, Bradshaw N, Dolwani S and others. ‘Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG)’. Britih Medical Journal Gut 2020: volume 69, issue 3, pages 411–444. DOI: 10.1136/gutjnl-2019-319915
• Terlouw D, Suerink M, Singh SS and others. ‘Declining detection rates for APC and biallelic MUTYH variants in polyposis patients, implications for DNA testing policy’. European Journal of Human Genetics 2020: volume 28, issue 2, pages 222–230. DOI: 10.1038/s41431-019-0509-z

For patients

• St Mark’s Hospital: MUTYH-associated polyposis information (PDF, 12 pages)