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The International BMMRD Consortium

Management of patients and families with BMMRD

Diagnosis
Patient Management
Management of BMMRD Cancers
Novel therapies
Clinical Data Collection and Biorepository


Diagnosis

The first important step is to establish the correct diagnosis of BMMRD.

This diagnosis must be made by a genetic counsellor/medical geneticist and involve counselling of family members.

The initial diagnostic screening for BMMRD includes immunohistochemical (IHC) analysis for MLH1, MSH2, MSH6 and PMS2 protein expression in tumours. Additionally, loss of expression of the same protein and negative staining pattern for the corresponding protein by IHC is seen in normal cells contained within tumours.

Consortium results on a large cohort of tumours (n=33) confirm tumour immunohistochemistry as 100 per cent sensitive and specific in diagnosing MMR deficiency of the corresponding gene; at the same time MSI was neither sensitive nor specific as a screening tool. Therefore, in contrast to Lynch syndrome, MSI should not be used as an initial screening test for BMMRD.

Confirmation of a diagnosis of BMMRD must be done through identification of a germ-line mutation in one of the MMR genes.

Since many of the mutations in the MMR genes are not well characterized and PMS2 sequencing is challenging, functional and additional assays were recently developed. This enables a diagnosis to be established based on clinical and molecular data in a more rapid fashion and allows for counselling, adequate surveillance and therapy to patients and family members.
 

MMR diagnosis chart
Figure 1. Algorithm for evaluation of patients with suspected biallelic mismatch repair deficiency (BMMRD). *Once familial adenomatous polyposis and MYH-associated adenomatous polyposis is ruled out.

Any patient with gastrointestinal cancer, glioma, T-cell lymphoma and either of café-au-lait spots, consanguinity, or family history of colon cancer should be screened for any of the 4 mismatch repair genes.

Similarly, high index of suspicion should be raised for “NF1” patients with history of consanguinity and any of the above cancers.

The Consortium provides recommendations for the treating team and counselling for patients in regards to the diagnosis of BMMRD and in specific cases can perform diagnostic tests as needed.

Please contact us for additional consultation if diagnosis is unclear.

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Patient Management

Once diagnosis of BMMRD is made (either genetically or clinically/molecularly) the installment of the surveillance protocol should start as soon as possible. It is important to adhere to the current surveillance guidelines for both BMMRD and heterozygous family members (Lynch syndrome).

Guidelines for surveillance are changing consistently and are updated by the Consortium regularly.

Individuals with Lynch syndrome benefit from a strict surveillance protocol (www.NCCN.org) and from preventive colectomy. Therefore, such a diagnosis may benefit parents and other family members.

Since the risk of gliomas and lymphoma is extremely high for biallelic MMR patients, a surveillance protocol may be beneficial for children with BMMRD.

To download surveillance protocol please click here.

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Management of BMMRD Cancers

Once a diagnosis of BMMRD cancer is made several specific issues need to be considered:

1) Before starting therapy, assessment for the presence of other cancers is imperative since some BMMRD patients may have concurrent cancers and this may affect the treatment plan.  

A PET-CT scan can detect most malignant BMMRD tumors and could be used as a single tool in case of time restraints.

2) Most BMMRD cancers respond to therapy similar to sporadic cancers form the same tissues. In contrast to other cancer predisposition syndromes such as Fanconi anemia and Gorlin syndrome, excess toxicity from chemotherapy and radiation treatments are uncommon.

3) Specific chemotherapeutic agents such as purine analogues and alkylating agents such as temozolomide require adequate mismatch repair to exert their tumor cell toxicity. Consideration of including these agents in the treatment protocols can be important.

4) Monitoring during therapy should include the regular surveillance protocol, as additional cancers could occur in a metachrounous fashion and could be treated if detected early.

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Novel therapies

Several groups including the International BMMRD Consortium are working on introduction of novel therapies for patients with BMMRD cancers. More information can be found on the research page.

Immune checkpoint inhibition has recently shown to have encouraging responses in BMMRD brain and gastrointestinal tumors.

We recommend that you consider joining the upcoming clinical trials of immune checkpoint inhibitors and/or contacting our team before starting any such therapy, because severe and even life threatening toxicities, which are specific to BMMRD, can occur.

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Clinical Data Collection and Biorepository

The International BMMRD Consortium collects data on surveillance, treatment and outcome of patients on a variety of tumors as well as biological material from our patients and family members for clinical and research testing.

This data is shared with physicians or other caregivers as needed.

We recommend that you contact us for updates as well as to utilize our consultants for any questions regarding these patients and families.

If you have further questions about or require assistance in the diagnosis of BMMRD or management of your patient, please contact us.