Clinical features of 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 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 and gastric polyps, with associated increased cancer risks, have also been reported to occur with increased frequency in MAP.
- Non-gastrointestinal tumours, including endometrial, breast, pancreatic, skin and thyroid, have also been reported in MAP, but formal association with other cancer types has not been confirmed.
- Non-neoplastic features more typical of FAP have also been reported in MAP, including congenital hypertrophy of the retinal pigment epithelium (CHRPE), adrenal adenomas and dental anomalies.
Genetics of MUTYH-associated polyposis
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.
Inheritance and genetic counselling
- 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 and management
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 <40 years;
- colorectal cancer and ≥5 adenomatous polyps;
- ≥5 adenomatous polyps <40 years, ≥10 adenomatous polyps <60 years or ≥20 adenomatous polyps at any age; or
- ≥5 adenomatous polyps <60 years) and a first-degree relative with ≥5 adenomatous polyps (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 constitutional variant in APC 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:
- gastric polyposis; 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.
- Surveillance is best co-ordinated through an expert centre.
- Regular colonoscopy-based surveillance is recommended annually from age 18–20.
- Prophylactic panproctocolectomy with ileal pouch-anal anastomosis, or prophylactic total colectomy with ileorectal anastomosis may be indicated in patients with severe colonic phenotype if the polyp burden is no longer manageable conservatively.
- The role of chemoprevention in patients with MAP is uncertain.
- Regular oesophagogastroduodenoscopy 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 uncertain.
- 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 genetic 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.
- HEE Genomics Education Programme: MUTYH-associated polyposis factsheet
- NHS England: National Genomic Test Directory and eligibility criteria
- 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)’. 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’. Eur J Hum Genet 2020: volume 28, issue 2, pages 222-230. doi: 10.1038/s41431-019-0509-z
- St Mark’s Hospital: MUTYH-associated polyposis information