Risk management for MUTYH (MYH) associated polyposis (MAP)

Familial predisposition to gastrointestinal polyps and early onset colorectal cancer (CRC) due to biallelic mutations in the MUTYH gene is an autosomal recessive condition.

This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour. The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up.

The risk management of an individual with a mutation in 2 or more genes that confer a predisposition to cancer should also be individualised.

• Individuals with demonstrated mutations in both copies of the MUTYH gene (biallelic MUTYH mutation carrier)

Exclusion Criteria

• Monoallelic MUTYH mutation carriers*
• Untested siblings (at 1 in 4 risk of MUTYH biallelic mutation)
• An individual with an APC gene mutation or other polyposis
• Other polyposis syndromes.

*For monoallelic MUTYH mutation carriers, the risk of developing CRC depends on their family history. Colonoscopy surveillance should be individualised.

**This data does not take into account the impact of surveillance.
***Source: Australian Institute of Health and Welfare (AIHW) 2018. Australian Cancer Incidence and Mortality (ACIM) books. 2015 data.

There is limited data on the efficacy of surveillance in prevention of CRC development in MUTYH biallelic carriers.

Colorectal polyps

The majority of, but not all patients with a biallelic MUTYH mutation and CRC have polyps at presentation. The polyps include adenomas and serrated polyps. The risk of CRC does not appear to correlate with the number of polyps.^r 29% of population-based biallelic MUTYH patients with CRC do not have co-existing adenomas.^r Thus colonoscopy surveillance is suggested for patients with biallelic MUTYH mutations independent of the presence of polyps.

Colorectal cancer

The mean age of diagnosis of CRC in patients with biallelic MUTYH gene mutations is 48–53 years.^rr In a recent study the risk of developing a primary or metachronous CRC within 5 years of follow-up was approximately 10%. The high risk of CRC development in patients under surveillance suggests an accelerated carcinogenesis mechanism. Thus regular colonoscopies and consideration for (sub)total colectomy are proposed.^r

Duodenal polyposis and cancer

There are no studies to show the efficacy of gastrointestinal endoscopy in reducing the risk for duodenal cancer in MAP. There is an increased risk for duodenal polyps and cancer and surveillance has been recommended on the basis of the similarities of the MAP phenotype and attenuated FAP.^r

Extraintestinal malignancies

Extraintestinal cancers have been described in patients with biallelic MUTYH gene mutation^r but whether they are causally linked is debated. No specific surveillance is recommended for these. Cutaneous manifestations include sebaceous gland tumours, lipomas and malignant skin cancers. The data is not sufficient to determine the prevalence. It is recommended for at least an initial dermatological evaluation to detect sebaceous lesions that may require specific treatment and to educate patients to the possibility of an increased risk for skin tumours.^r

Centre for Genetics Education NSW Health
Genetic Alliance Australia
Hereditary Cancer Registry 

Further references

For further references used to develop this protocol please see the history section.

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Bibliography

Nascimbeni, R., S. Pucciarelli, D. Di Lorenzo, et al. 2010. "Rectum-sparing surgery may be appropriate for biallelic MutYH-associated polyposis." Dis Colon Rectum 53(12):1670-1675.

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PURPOSE: The risk of cancer or severe polyposis of the rectal stump after total colectomy for MutYH-associated polyposis is scarcely defined. To evaluate this risk, we describe the findings of endoscopic surveillance of the rectal stump in a series of patients with biallelic MutYH mutations and polyposis. METHODS: This is a retrospective, observational, multicenter case series derived from 2 familial cancer registries. Biallelic, germ-line MutYH mutations were found in 14 patients with no adenomatous polyposis coli gene mutations. Eleven of them underwent total colectomy with ileorectal anastomosis and yearly proctoscopic surveillance thereafter. Phenotype and histology of rectal polyps were recorded at diagnosis and during follow-up. Development of adenomas and carcinomas during endoscopic surveillance of the rectal stump was observed. RESULTS: At diagnosis, 6 patients had attenuated polyposis (10-100 adenomas), 5 patients had classical polyposis, 8 patients had colon carcinoma, and no patient had rectal carcinoma. The mean number of rectal polyps at diagnosis was 2.64 +/- 2.11 (range, 0-6). No patients had rectal cancer. The most frequent MutYH mutations were Y165C/Y165C and G382D/G382D in 6 and 2 patients, respectively. During surveillance of the rectal stump after surgery (median duration, 5 y; range, 2-23 y), no patient developed rectal cancer. The mean number of adenomas per proctoscopy was 1.23 +/- 2.19 (range, 0-10 adenomas per proctoscopy). This study was limited by the small size and retrospective nature of the case series. CONCLUSION: Total colectomy with ileorectal anastomosis may be appropriate for patients with MutYH-associated polyposis, provided that they have no rectal cancer or severe rectal polyposis at presentation and that they undergo yearly endoscopic surveillance thereafter.

NCCN - Clinical Practice Guidelines in Oncology (NCCN Guidelines) - Genetics/Families High-Risk Assessment: Colorectal - Version3.2017

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Syngal, S., R. E. Brand, J. M. Church, et al. 2015. "ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes." Am J Gastroenterol 110(2):223-262; quiz 263

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This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

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