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The International BMMRD Consortium

Patients & Families

Welcome to our Biallelic Mismatch Repair Deficiency Consortium  

We are a group of oncologists, gastroenterologists, surgeons, pathologists, molecular geneticists, genetic counsellors and researchers who work together to try to understand the hereditary cancer syndrome BMMRD and cancers associated with it.

Hereditary means that something is passed down from parent to child through genes.  

  • Our role is to identify families that have this possible hereditary cancer syndrome.
  • By doing so, we can find those who have a higher risk to develop certain types of
    cancers and recommend appropriate ways to reduce their risks.

Frequently Asked Questions

Is cancer hereditary?
What is Biallelic Mismatch Repair Deficiency (BMMRD)?
What types of cancer are seen in BMRRD?
What are other features of BMMRD?
More About the Digestive Tract
What causes BMMRD?
What is the relationship between BMMRD and Lynch syndrome?
How is BMMRD inherited?
How does genetic testing work?
What if the tumour sample does not have characteristics of BMMRD?
What if the tumour showed features of BMMRD, but no genetic mutation was seen in the blood test?
What if I have BMMRD or a Lynch Sydnrome gene mutation?
Can my children be tested for the mutation?
What if my relative (or I) did not inherit the Lynch Syndrome gene mutation known to be running in my family?
Screening for BMMRD
Screening for Lynch sydnrome
Other Lynch sydnrome screening
Support resources

Is cancer hereditary?

Everyone has a chance of developing cancer in their lifetime.

As we get older, the cells that line our organs are damaged by environmental factors, such as diet, lifestyle and as a normal part of the aging process. Over time, this damage adds up and can lead to cancer. This is thought to explain the majority of cases of cancer, which we call sporadic (happens by chance). A smaller number of cancers are explained by a hereditary factor (something running in a family) that increases one’s risk to develop cancer.

This page will review a hereditary cancer condition called Biallelic Mismatch Repair Deficiency or BMMRD

We will review:

  • Cancers that are associated with BMMRD.
  • Background genetics.
  • The testing process.
  • Screening information.

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What is Biallelic Mismatch Repair Deficiency (BMMRD)? 

BMMRD (Biallelic Mismatch Repair Deficiency) in Europe also known as CMMRD (Constitutional Mismatch Repair Deficiency) is very rare genetic condition which increases a person’s risk of develop cancer at very young ages, starting in childhood.   

Biallelic means both copies of the gene are affected.

Mismatch Repair refers to the types of genes impacted.

Deficiency means “not working.”

BMMRD is sometimes called CMMRD (Constitutional Mismatch Repair Deficiency).

Constitutional means that the person is born with deficiency in mismatch repair genes.

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What types of cancer are seen in BMRRD?

The main types of cancers seen in children with BMMRD are brain and central nervous system cancers, blood (lymphoma and leukemia) and digestive tract cancers (colon, small bowel).  

Individuals affected with BMMRD may also develop small growths in the digestive tract, called polyps, and if not removed, these can develop into cancer.  

There have been reports of other types of cancers in BMMRD, but these are the most common.

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What are other features of BMMRD?

People with BMMRD may also have one or more birthmarks that are light-dark brown patches on the skin, called café-au-lait macules.
Cafe-au-lait mascules
Figure 1. café-au-lait macules

It is important to note that these patches can be seen in children who do not have BMMRD, however, if someone has many of these birthmarks, it can be a hint of BMMRD.    

There is a different genetic condition that is also associated with multiple café-au-lait spots and it is called Neurofibromatosis Type I or NF1.   It can sometimes be confused with BMMRD because of this similar feature.

Individuals with NF1 and BMMRD may also get freckling near the armpit or in their eyes and other small bumps on their skin or tongue.  

NF1 and BMMRD are very different so it is important for a doctor to determine which condition is causing these skin findings. Genetic testing can be helpful in sorting this out. 

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More About the Digestive Tract 

The digestive system is made up of many organs that are needed to digest food.  After you swallow food, it travels past the esophagus (throat) into the stomach.  Fluids from the stomach liver and pancreas help break up the food as it enters the small bowel called the duodenum

Most of the nutrition is removed in the small bowel and the digested food moves into the large bowel, also known as the colon.  It travels through the colon which looks like an upside “U” until it reaches the sigmoid and rectum and is excreted through the anus.  The job of the large bowel is to removes any remaining liquid and water from the waste to turn it into a solid.

Polyps can grow in the stomach, small bowel, and large bowel (colon and rectum).

 

 

Figure 2. The Digestive System 

 

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What causes BMMRD? 

BMMRD is hereditary, meaning that it can be passed down from parents to child through genes.  Genes carry instructions to help our body work properly.  There are two copies of every gene, one you inherit from mom and the other from dad.

There are five genes currently known to be associated with BMMRD.  These genes are known as mismatch repair genes or MMR genes because their job is to repair any genetic mismatches that can happen when our cells grow and divide.  If they don’t work properly, a cell may grow out of control which results in cancer.  

The 5 mismatch repair (MMR) genes are:

  • PMS2
  • MSH6
  • MLH1
  • MSH2
  • EPCAM

Individuals with BMMRD have a mutation in both copies of their MMR gene, one inherited from mom and one inherited from dad. PMS2 is the gene affected in about half of the BMMRD families identified.

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What is the relationship between BMMRD and Lynch syndrome?

We know that a person with BMMRD has mutations in both copies of their mismatch repair (MMR) genes, one they inherited from mom and the other from dad. This means both mom and dad have a mutation in one copy of their mismatch repair (MMR) gene.

Having a mutation in one copy of the MMR gene causes a genetic condition called Lynch syndrome or LS.

Individuals with Lynch syndrome are at higher risk to develop colorectal and endometrial (womb) cancer in adulthood. Other types of digestive, urinary tract and ovarian cancers have been seen in Lynch syndrome patients, but they are much more rare.

Despite the fact that both parents have Lynch syndrome (which was probably running through generations of the family), most BMMRD families do not have a strong history of cancer.

Since both child and parents have different genetic conditions, cancer screening and surveillance recommendations are tailored differently to reduce the chance of developing cancer.

How is BMMRD inherited? 

If both parents have Lynch syndrome, there is a 25% chance to pass on BMMRD with each pregnancy.  This is called autosomal recessive inheritance.  There is also a 50 per cent chance for each pregnancy to inherit Lynch syndrome (like mom and dad) and a 25 per cent chance to inherit no MMR mutation.       

All children of someone with BMMRD would have Lynch syndrome. It would be very rare for a child of someone with BMMRD to have BMMRD themselves.  It could only happen if someone with BMMRD partners with someone who has Lynch syndrome, which is a rare condition. It would be unusual to meet someone with Lynch syndrome by chance, but odds increase if you partner with a blood-relative, such as a cousin.

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How does genetic testing work? 

A person referred to a genetics clinic will be asked to give family history and all medical information.

If a family is suspected of having BMMRD, genetic testing may be offered.

Steps in genetic testing for BMMRD:

  • First step: Look at tumor samples.  Most tumors associated with BMMRD show special characteristics. If these characteristics are seen then we move on to the second step: genetic testing using a blood sample.
  • Second step: Genetic testing using a blood sample looks for a mutation in one of the five genes that are known to be associated with BMMRD.  If mutations are found in both copies of the gene, then BMMRD is confirmed. At that point, relatives can be tested to see if they have BMMRD, Lynch syndrome or no MMR mutation.

Sometimes the testing process does not find a mutation in a family.  In these cases we may not be able to confirm or rule out a hereditary cancer syndrome. Still, we may be highly suspicious based on the types of cancers reported, the preliminary tumour test result and features like café-au-lait macules.

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What if the tumour sample does not have characteristics of BMMRD? 

If the tumour does not have features of BMMRD, it means that BMMRD may not be the cause of the cancer.   Our suspicion may still be high for BMMRD based on the type of cancer seen and if café-au-lait macules are observed.

The tumour test is just a screening tool, so it cannot completely rule out BMMRD.  It also does not rule out other hereditary causes, so additional testing may be ordered (for example, Neurofibromatosis Type 1 testing).

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What if the tumour showed features of BMMRD, but no genetic mutation was seen in the blood test? 

Depending on the family history and the tumour result, BMMRD may still be a possibility in the family.  

A genetic counsellor would look at the results together with the family history and discuss screening recommendations for the family.

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What if I have BMMRD or a Lynch sydnrome gene mutation?

If a mutation is identified in both copies of the MMR genes, it confirms BMMRD.  If a mutation is detected in just one copy ofMMR gene, it confirms Lynch syndrome.  Your genetic counsellor will discuss screening recommendations for you and your family as well as the availability of genetic testing for your at-risk family members.

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Can my children be tested for the mutation?

Genetic testing will be offered and can even be done during family planning. Speak to your genetic counsellor for more information.

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What if my relative (or I) did not inherit the MMR gene mutation known to be running in my
family?
 

This would mean they do not have BMMRD or Lynch Syndrome.  Their risk to develop cancer would be the same as someone in the general population. Population screening recommendations would be given.

It also means their children would not be at risk to inherit BMMRD or Lynch syndrome.

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Screening for BMMRD 

Blood work

  • Complete blood count (routine blood test).

Brain Screening

  • Ultrasound at birth and then MRI every 6 months.

Colorectal screening

  • Colonoscopy (a procedure used to see inside the colon and rectum) every year starting at age 6.
  • If there are too many polyps in the colon, surgery may be recommended.

Small Bowel screening

  • Side-viewing upper endoscopy (a procedure used to see inside the stomach and beginning of small bowel) every year starting at age 8.
  • Camera pill (a pill that you swallow and it takes pictures of the small bowel) every year starting at age 8.

Gynecological Screening

  • The effectiveness of screening for the gynecologic cancers is limited and its value has yet to be established.  Consider pelvis and trans-vaginal ultrasound every year starting at age 25.

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Screening for Lynch syndrome

Colorectal Cancer Screening*

  • Colonoscopy (a procedure used to see inside the colon and rectum) every 1-2 years starting at age 20-25.
  • Some families may be advised to start screening at an earlier age.


Gynecological Cancer Screening**

  • Trans-vaginal and pelvic ultrasound every year.
  • CA125 blood test every year.
  • Discuss oral contraceptive use with physician.
  • Pay attention to signs and symptoms of endometrial cancer such as irregular or heavy vaginal bleeding and go see your doctor immediately if either of these symptoms occurs.
  • Prophylactic (preventative) removal of uterus, fallopian tubes and ovaries may be considered when child-bearing is completed.

*Evidence shows that regular colonoscopy reduces the risk of developing colorectal cancer in Lynch syndrome patients.

**The effectiveness of screening for the gynecologic cancers is limited and its value has yet to be established.

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Other Lynch syndrome screening 

At this time, routine screening for other Lynch syndrome-related cancers has not been shown to be effective. Based on family history of other types of cancer, other screening procedures may be recommended on an individual basis. 

Some families with Lynch syndrome may develop specific skin findings (lesions) called keratoacanthomas or sebaceous adenomas/carcinomas).  Any unusual skin findings should be reported to a doctor.

Individuals with Lynch syndrome are encouraged to discuss all changes in general health with their doctor.

Please note: Screening recommendations must be given by a genetics specialist and/or doctor after a complete assessment of a family.

Please talk to your doctor if you have questions or concerns about screening recommendations for you.

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Support resources 

An international BMMRD group was created for families with BMMRD around the world, to help learn more about BMMRD, so we can improve diagnosis and treatment of cancer and better support the families.

Please contact Dr. Nataliya Zhukova, Program Coordinator for the BMMRD group at nataliya.zhukova@sickkids.ca for more information.

The Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital, in the Zane Cohen Centre, Toronto, Canada, was established in 1980 to offer education and support to families with LS and other types of hereditary cancer .

Our Consortium collaborates research with other international groups that also specialize in hereditary cancers. Through research we aim to learn more about possible causes, treatments, effective screening and the genetics of colorectal and other cancers associated with BMMRD and Lynch syndrome.

This website page is meant to provide an overview of BMMRD syndrome and not to replace a thorough genetics assessment.  

If you have any questions about the information provided, please contact us or another genetics clinic or speak to your physician.

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