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MUTYH-associated polyposis – risk management

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Familial predisposition to gastrointestinal polyps and early onset colorectal cancer (CRC) due to biallelic pathogenic variants in the MUTYH gene is an autosomal recessive condition called MUTYH-associated polyposis (MAP).

The care of an individual who has developed a related tumour or cancer should be individualised based on their clinical situation, their family history and the monitoring they need as part of their treatment and post-treatment follow-up.

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

  • Individuals with demonstrated pathogenic variants in both copies of the MUTYH gene (biallelic MUTYH pathogenic variant carrier)

Exclusion criteria

  • Monoallelic MUTYH pathogenic variant carriers*
  • Untested siblings (at 1 in 4 risk of MUTYH biallelic pathogenic variant)
  • Individuals with an APC gene pathogenic variant or other polyposis syndromes
  • Individuals with a variant of uncertain significance

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

Cancer/tumour type MUTYH by age
40 years		 MUTYH by age
50 years		 MUTYH by age
60 years		 MUTYH by age
70 years		 General population risk by age 70 years
Colorectal cancer 12%r** 20-40%rr** 43-63%rr** 86%r** 2.5%***
Extraintestinal malignancies     20%r 38%r Unable to obtain
Upper gastrointestinal cancer/polyps      

Duodenal cancer: 4%r

Duodenal polyps: 17-34%r

Gastric polyps: 11%

 Unable to obtain

**This data does not take into account the impact of surveillance.
***Source: Australian Institute of Health and Welfare (AIHW) 2021 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/cancer-risk-data-visualisation>. (2017 data)

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

Cancer/tumour type Recommendations
Colorectal cancer Surgical
  • Consider prophylactic subtotal colectomy depending on age of presentation, number, degree of dysplasia and polyp burden
Surveillance Age Strategy and frequency

From age 20 years
  • If no polyps are detected repeat every 2 years. If polyps are detected, annual colonoscopy until surgery is indicated
  • Surveillance of residual rectum or ileal pouch is required following subtotal colectomy. Frequency determined by polyp burden
Risk-reducing medication
  • None of proven benefit
Upper gastrointestinal cancer/polyps Surveillance Age Strategy and frequency

From age 35 years 
  • Upper gastrointestinal endoscopy:
    • If normal repeat every 5 years
    • If polyps are detected, frequency of endoscopy dependent on Spigelman criteria
Extraintestinal malignancies Surveillance
  • No surveillance recommended

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 biallelic MUTYH gene pathogenic variants 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 pathogenic variants independent of the presence of polyps.

Colorectal cancer

The mean age of diagnosis of CRC in patients with biallelic MUTYH gene pathogenic variants is age 48-53 years.rr In one study the risk of developing a primary or metachronous CRC within 5 years of follow-up was approximately 10%.r The high risk of CRC development in patients under surveillance suggests an accelerated carcinogenesis mechanism. Thus, regular colonoscopies are proposed.r Subtotal colectomy with rectum sparing may be appropriate in the absence of rectal cancer or rectal polyposis with regular ongoing surveillance of the rectal stump.r

A genotype-phenotype correlation has been reported for Y165C homozygotes being at increased risk for CRC.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, though the age of presentation is older and frequency of polyposis is less in the MAP phenotype.rr A recent study has suggested that surveillance chromoendoscopy enhances the detection rate of duodenal adenomas and there is a significant increase in the Spiegelman stage based on the numbers of polyps.r

A genotype-phenotype correlation has been reported for Y165C homozygotes being at increased risk for duodenal polyps and cancer.r

Extraintestinal malignancies

Extraintestinal cancers have been described in patients with biallelic MUTYH gene pathogenic variants,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.

Other cancers

Increased risk of other cancer types has been suggested (including cancer of the ovary, bladder, breast and endometrium) but more research is required as data is conflicting. Screening and advice should be based on the family history of these cancers.r

Siblings (brothers/sisters) are at 25% risk of having inherited both pathogenic variants (and having the condition), and are at up to 50% risk of having inherited one pathogenic variant (and being a carrier for the condition). Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss genetic testing.

Informing family members about hereditary cancer

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Bibliography

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

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.

Version 9

Date Summary of changes
15/09/2023

New eviQ cancer genetics risk management template changes applied - PDF of changes.

Version number changed to V.9.

Version 8

Date Summary of changes
13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template:

  • Target population:
    • Added to exclusion criteria "Individuals with a variant of uncertain significance".
  • Cancer/tumour risk management guidelines:
    • Template sentence updated.
    • Lifestyle factors sentence moved above table.

Version number increased to V.8.

Version 7

Date Summary of changes
11/03/2020

Protocol reviewed at October 2019 cancer genetics reference committee meeting. Discussion continued via email. Approved for publication with the following changes made:

Lifetime risk of cancer:

  • Upper gastrointestinal cancer/polyps - MUTYH by age 70 years: "Cancer 4%" and "Polyps 17%" replaced with "Duodenal cancer: 4%; Duodenal polyps 17-34%; Gastric polyps 11%"

Cancer risk management guidelines:

  • Colorectal cancer:
    • R1C4: "prophylactic colectomy" changed to "prophylactic subtotal colectomy"
    • R2C4: "following colectomy" changed to "following subtotal colectomy"
  • Upper gastrointestinal cancer/polyps:
    •  Age to begin changed from "25 years" to "35 years"
    • Strategy and frequency changed from "From 25 years" to "From 35 years"

Evidence for risk management guidelines:

  • Colorectal cancer: "Thus regular colonoscopies and consideration for (sub)total colectomy are proposed." changed to "Thus regular colonoscopies are proposed. Subtotal colectomy with rectum sparing may be appropriate in the absence of rectal cancer or rectal polyposis with regular ongoing surveillance of the rectal stump."
  • Duodenal polyposis and cancer: ", though the age of presentation older and frequency of polyposis is less in the MAP phenotype.3,4 A recent study has suggested that surveillance chromoendoscopy enhances the detection rate of duodenal adenomas and there is a significant increase in the Spiegelman stage based on the numbers of polyps." added.
  • Extraintestinal malignancies: "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." deleted.

"Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up.

Version number increased to V.7. Review in 2 years.
18/12/2020 The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template:
  • Related pages: added link to "Cancer predisposition genes: population carrier frequency" 
  • Lifetime risk of cancer table:
    • Heading changed to "Lifetime risk of cancer/tumour"
    • Risk for general population updated to include AIHW 2016 data
  • Cancer risk management guidelines:
    • Heading changed to "Cancer/tumour risk management guidelines"
    • Sentence added above table "The choice of risk management strategy should take into account current age, other health issues and residual cancer risk." 
    • Surveillance: "Age to begin" changed to "Age"
    • Other table formatting changes
  • Support and information: template wording updated.
15/06/2022

Protocol reviewed at March 2022 cancer genetics reference committee meeting. Discussions continued via email and MS Teams. Approved for publication with the following changes made:

  • Summary: minor wording changes.
  • Cancer risk management guidelines: minor wording changes.
  • Evidence for risk management guidelines: 
    • Colorectal cancer: added 'A genotype-phenotype correlation has been reported for Y165C homozygotes being at increased risk for CRC.'
    • Duodenal polyposis and cancer: added 'A genotype-phenotype correlation has been reported for Y165C homozygotes being at increased risk for duodenal polyps and cancer.'
    • Other cancers: subsection added.

Review in 2 years.

Version 6

Date Summary of changes
22/12/2011

Approved at December 1 2011 reference committee meeting and published on eviQ.
01/05/2014

Discussed at March 5, 2014 reference committee meeting and the following changes made: 

  • Exclusion criteria - updated.
  • Lifetime risk of cancer table - updated.
  • Cancer risk management guidelines table - colorectal - surveillance updated,
    upper gastrointestinal cancer/polyps - surveillance updated,
    extraintestinal malignancies - surveillance - information added.
  • Evidence for risk management guidelines - updated.
  • Reference list reviewed and updated.

For review 2nd yearly.
23/07/2014

Following discussion of ID 178 Risk management for FAP at the March 5, 2014 reference committee meeting the following additional information has been added:

  • Cancer risk management guidelines table - colorectal - surveillance - added 
    •  Annual surveillance of residual rectum or ileal pouch is required following colectomy.
31/07/2015 Link to AGSA changed to Genetic Alliance Australia.
07/01/2016 Sentence added to Risk Management template: "The impact of lifestyle on cancer risk should be discussed".
14/04/2016 Sentence added to Risk Management template: "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". 
31/05/2017 Transferred to new eviQ website. Version number changed to V.3.
11/12/17 

Protocol reviewed and presented at May, 2017 reference committee meeting. Discussion continued via email and the following changes made: 

  • lifetime risk of cancer table - statistics updated
  • version number change to V.4.
29/03/2019

Protocol underwent minor review and was presented at Nov 2018 reference committee meeting. Discussion continued via email and approved with the following changes made:

  • Summary: Sentence added from updated template.
  • Lifetime risk of cancer table: general population risk age aligned with oldest reported MUTYH risk age in table.
  • Cancer risk management guidelines table: Upper GI cancer/polyps - surveillance: frequency of upper GI endoscopy changed from every 4 years to 5 years.
  • Version number changed to V.5. For review at next scheduled date.
28/08/2019 Protocol title changed from 'Risk management for MUTYH (MYH) associated polyposis (MAP)' to 'MUTYH associated polyposis – risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.6.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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13 Oct 2024