CMMRD – risk management

Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessive cancer predisposition syndrome caused by biallelic pathogenic variants in one of the four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2).

The care of an individual who has developed a related tumour or cancer 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 pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

• Unaffected known biallelic MMR-gene pathogenic variant carrier.

Exclusion criteria

• A biallelic MMR-gene pathogenic variant carrier already diagnosed with a relevant cancer/tumour.
• A monoallelic MMR-gene pathogenic variant carrier - refer to MMR genes (Lynch syndrome) – risk management.
• Individuals with a variant of uncertain significance.

Cancer/tumour type	Risk for this group to age 75 yearsr* [median age at diagnosis]	General population risk to age 75 years**
Colorectal adenoma	>90% [9 years]	Unable to obtain
Colorectal carcinoma	70% [16 years]	3.7%**
Brain cancer	70% [9 years]	0.52%**
Small bowel adenoma	50% [12 years]	Unable to obtain
Small bowel cancer	10% [28 years]	0.18%**
Lymphoma	20-40% [5 years]	1.7%**
Leukaemia	10-40% [8 years]	1.1%**
Endometrial carcinoma	<10%	1.7%**
Urinary tract malignancies	<10%	Unable to obtain

*As only small numbers of biallelic pathogenic variant carriers have been reported, these risk figures are subject to multiple biases, including ascertainment and reporting bias.
**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)

There is currently no international consensus on screening. Comprehensive surveillance protocols have been proposed by several expert groups but none have been systematically studied.^rrrr Refer to Evidence for risk management guidelines section below.

Surveillance should be considered on an individualised basis and if instituted ideally surveillance should be coordinated through a multidisciplinary service with expertise in CMMRD. Enrolment in clinical trials evaluating screening protocols should be discussed.

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk.

The impact of lifestyle on cancer risk should be discussed e.g. exercise regularly, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

Cancer/tumour type	Recommendations
		Age:	Strategy and frequency:
Brain	Surveillance	By age 2-3 months^	Recommend MRI^^ 6 monthly
Colorectal	Surgical	Consider preventative colectomy, especially if multiple colorectal adenoma
	Surveillance	From age 6 years	Recommend annual colonoscopy
	Risk-reducing medication	There is no data about the potential benefit of aspirin for colorectal cancer prevention in the paediatric age group or in individuals with CMMRD
Gastric	Surveillance	From age 8 years	Consider annual upper GI endoscopy
Duodenal	Surveillance	From age 8 years	Consider annual upper GI endoscopy
Small bowel	Surveillance	From age 8 years	Consider annual video capsule endoscopy
Haematological	Surveillance	No evidence of benefit for screening of asymptomatic individuals
Endometrial	Surveillance	There is no evidence for transvaginal ultrasound (TVU) and/or aspiration biopsy
Ovarian	Surveillance	No evidence of benefit Do not offer serum CA125 and/or transvaginal ultrasound. See Cancer Australia for further information
Urinary tract	Surveillance	From age 10 years	Consider annual urine cytology and dipstick
All	Surveillance	From age 6 years	Recommend annual whole-body MRI
		Biannual clinical review and physical examination including neurological exam
	Education	Awareness of potential signs and symptoms of CMMRD-associated tumours Video resource for patients, families and clinicians available here

Abbreviation: MRI - magnetic resonance imaging
^{^}Brain tumours can be seen in the first year of life and screening is recommended from the time of diagnosis.  In the case of prenatal diagnosis consider in utero MRI or early postnatal head ultrasound scan.  Formal MRI should be done by the age of 2-3 months, ideally while scan can be performed without general anaesthetic.
^{^^}Gadolinium contrast, used in some MRI protocols, accumulates in the dentate nucleus and globus pallidus. The likelihood of this occurring increases with repeated dosing. Although there is no clear evidence of harm associated with this finding, longer term prospective studies are needed.

There are limited data on the effectiveness of cancer screening in biallelic MMR-gene pathogenic variant carriers. Published recommendations represent expert opinion and are mostly extrapolated from cancer screening studies in other groups at increased risk of specific cancers.^rr

The International Replication Repair Deficiency Consortium (IRRDC) (formerly the BMMRD Consortium) recently reported tumour and survival data for a cohort of patients (N=110), some of whom had surveillance and the majority of whom were followed prospectively (81%).^rr The 4-year overall survival was 79% in patients undergoing the full surveillance schedule, versus 15% for patients not undergoing surveillance. On the basis of this evidence surveillance for GI, solid and CNS tumours is now recommended for unaffected individuals with CMMRD.

Colorectal adenoma

Colorectal adenomas are common (estimated lifetime penetrance >90%) with more than 50% of reported CMMRD cases having adenoma detected before age 10 years.^r Multiple colorectal adenomas have been diagnosed in a child aged 6 years.^r There is in vitro evidence that CMMRD-related adenoma show faster progression from benign to malignant than equivalent lesions in heterozygotes (i.e. Lynch syndrome). Consider increasing colonoscopy to 6 monthly if adenoma are detected.

Colorectal cancer

One of the most commonly reported cancers is colorectal carcinoma (CRC), with approximately 50% of reported CRC diagnosed under age 16 years.^rr Colonoscopy is of proven benefit in a number of inherited colorectal polyposis syndromes and it is reasonable to assume at least some benefit in CMMRD. In the presymptomatically screened cohort all GI tumours were detected prior to symptom onset.^r There is no published data on the long term benefits of preventative colectomy in CMMRD.

Small bowel cancer

A recent report from the IRRDC detailed the outcome of video capsule endoscopy (VCE) for small bowel surveillance in 17 patients with CMMRD (total of 38 procedures).^r Three patients had small bowel neoplasia detected by VCE (2 with adenoma with high grade dysplasia at 16 and 13 years, 1 with jejunal adenocarcinoma at 15 years). However 4 patients with negative VCE were subsequently diagnosed with duodenal neoplasia (false negatives).

Haematological malignancy

The IRRDC reported haematological malignancies in 19% of 105 patients undergoing surveillance with the protocol published in 2017. There is no evidence that routine full blood count in asymptomatic individuals leads to earlier detection of haematological malignancy, reduced mortality or improved survival and this is not recommended.^rr

Urinary tract malignancy

The IRRDC  reported urinary tract malignancies in 3-4% of 105 patients undergoing surveillance with the protocol published in 2017. They recommend annual urinalysis from age 10 years. There is no evidence that this leads to reduced mortality or improved survival.^rr

Brain tumours

Brain tumours have similar penetrance to CRC, but with a younger median age at diagnosis (9 years). There are multiple reports of brain tumours in children under age 5 years.^rrrr

General

• Clinicians should be aware of the increased risk for malignancies that are usually diagnosed in adulthood.
• Clinicians should be aware of the increased risk of a second malignancy after a first diagnosis.
• Education to patients and families should be tailored to the specific situation.

Both parents and all offspring are at 100% risk of inheriting one of the two identified MMR-gene pathogenic variants, and are at risk of developing Lynch syndrome.

Siblings (brothers/sisters) are at 25% risk of having inherited both pathogenic variants and having CMMRD, and are at up to 50% risk of having inherited one pathogenic variant and are at risk of developing Lynch syndrome.

Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss genetic testing. 

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Bibliography

Bakry, D., M. Aronson, C. Durno, et al. 2014. "Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium." Eur J Cancer 50(5):987-996.

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BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. METHODS: We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. RESULTS: Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had cafe-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. DISCUSSION: CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.

Version 5

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: Summary: Template sentence updated. Target population: Added to exclusion criteria "Individual 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.5.

Version 4

Date	Summary of changes
28/10/2021	Protocol reviewed at July 2021 paediatric reference committee meeting. Discussion continued via email and MS Teams. Approved for publication with the following changes made:  Summary: 'or biallelic deletion in EPCAM affecting MSH2 function.' deleted from first sentence Lifetime risk of cancer/tumour: risk for general population updated to include AIHW 2017 data Cancer/tumour risk management guidelines Brain - Surveillance: 'From age 2 years', 'Consider MRI 6–12 monthly' changed to 'By age 2-3 months', 'Recommended MRI 6 monthly'. Footnote added to the table Colorectal - Surveillance: 'From age 5 years' changed to 'From age 6 years' Gastric - Surveillance: 'Consider annual upper GI endoscopy' changed to 'Recommended annual upper GI endoscopy' Haematological - Surveillance: 'No evidence of benefit' changed to 'No evidence of benefit for screening of asymptomatic individuals' Urinary tract - Surveillance: 'No evidence of benefit' changed to 'From age 10 years', 'Consider annual urine cytology and dipstick' All - Surveillance: added 'From age 6 years', 'Recommend annual whole-body MRI' All- Education: section added Evidence for risk management guidelines Second paragraph added 'BMMRD Consortium' changed to 'IRRDC' throughout Haematological malignancy: paragraph reworded Urinary tract malignancy: paragraph added General: bullet points added Website resources: Added link to 'International Replication Repair Deficiency consortium – Education night talks' Removed links to 'C4CMMRD' and 'IBMMRC'. Version number increased to V.4. Review in 2 years.

Version 3

Date	Summary of changes
20/12/2019	"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.3.
28/01/2021	The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template: Summary: template sentence added Lifetime risk of cancer/tumour table: risk for general population updated to include AIHW 2016 data 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."  Other table formatting changes Support and information: template wording updated.

Version 2

Date	Summary of changes
28/08/2019	Protocol title changed from 'Risk management for constitutional mismatch repair deficiency' to 'CMMRD - risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.2.

Version 1

Date	Summary of changes
22/07/2019	Protocol developed and presented at the February 2019 paediatric cancer genetics reference committee meeting. Discussion continued over email. Approved as version V.1. Review in 1 year.