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Inherited gene variations reveal precision therapy potential for rare cancer syndrome
7 minute read

Inherited gene variations reveal precision therapy potential for rare cancer syndrome


Global research led by SickKids finds new strategies to help diagnose and treat a rare and aggressive cancer predisposition syndrome.

An international team of researchers led by The Hospital for Sick Children (SickKids) have, for the first time, developed strategies to diagnose and treat an aggressive syndrome that leads to cancer in almost all cases. 

Headshot of Anirban Das
Dr. Anirban Das

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare genetic condition. Children who inherit the syndrome are considered “predisposed” to cancer, meaning they have a high likelihood of developing many different types of cancer – most commonly in the brain, digestive system and blood. In the past, these patients rarely survived to adulthood.  

Research into CMMRD published in The Lancet Oncology studied more than 330 malignant tumours from 201 patients with the syndrome from the International Replication Repair Deficiency Consortium (IRRDC). The research team, including PhD student Ayse Ercan, observed that patients with CMMRD develop a new tumour every two years, suggesting the condition is the most aggressive human cancer predisposition syndrome. 

The researchers also discovered that the type and severity of CMMRD is dependent on the specific inherited gene variation. Currently, there are four major genes associated with CMMRD: MLH1, MSH2, MSH6 and PMS2. 

“All patients with CMMRD are not the same, and how we approach their care is dependent on many factors. Developing targeted therapies based on gene-specific cases could help patients with CMMRD have better health outcomes,” said Dr. Anirban Das, co-lead author of the paper, Staff Physician in the Division of Haematology/Oncology and Project Investigator in the Genetics & Genome Biology program at SickKids. 

Findings inform a more targeted screening protocol for patients with CMMRD  

Dr. Uri Tabori

All day, cells in the human body are dividing and multiplying – it's a process essential to life. Occasionally, a change during cell division can cause a slight variation in genetic material. A process called the DNA mismatch repair system clears these errors to maintain regular function in cells. In patients with CMMRD, the DNA mismatch repair system is unable to clear errors. As a result, genetic variations can accumulate and can lead to cancer. 

In order to identify cancers as early as possible, many individuals with CMMRD undergo regular screening to stay on top of cancers that might be developing. The research team found that 90 per cent of patients with CMMRD will develop at least one cancer by the age of 18 and if they survive to the age of 40, all will develop multiple cancers.

Preventative monitoring can be very successful, but new findings suggest that this screening protocol has the highest impact among patients with variations in the MLH1 or MSH2 genes. In addition, patients with variations in MSH6 and PMS2 received the greatest benefit from treatment with immunotherapy.  

Until now, it was not known that the type and severity of CMMRD was predictable based on the specific gene affected,” says Dr. Uri Tabori, co-lead author of the paper, Section Head of the Neuro-Oncology and a Senior Scientist in the Genetics and Genome Biology program. 

“We show how the different links between affected genes and variant types determine the type of cancer, onset and outcome for each patient. Knowing these variations will help inform the future individualization of patient care through Precision Child Health,” Tabori says. 

Global collaboration informs care in real time 

The IRRDC, a collaborative network of physicians, scientists, policy makers, patients and families from more than 50 countries, was established in 2007 by Tabori and other SickKids physicians including Dr. Eric Bouffet, Director, Paediatric  Neuro-Oncology Program and Dr. Carol Durno. 

Now run by Das and Tabori, the IRRDC hosts weekly rounds to discuss global patient cases and manage more than 150 patients participating in active immunotherapy under the expertise of a SickKids-led team. 

“Global collaboration is an essential part of learning more about CMMRD and developing future care. The consortium allows us to help patients in real time from diagnosis to treatment,” says Das.  

By sharing data and patient stories, the international team has worked together to see patients with CMMRD live past university age for the first time. Future research on the syndrome may further improve the diagnosis, management and prognosis for those with CMMRD. 

This research was supported by the Canadian Institutes for Health Research (CIHR), Stand Up to Cancer, Children’s Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan’s Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold’em for Life and SickKids Garron Family Cancer Center.

  • Dr. Peter Dirks, Chief, Division of Neurosurgery 
  • Dr. Birgit Etlr-Wagner, Radiologist-in-Chief, Department of Diagnostic Imaging 
  • Dr. Cynthia Hawkins, Neuropathologist, Department of Paediatric Laboratory Medicine 
  • Dr. David Malkin, Senior Staff Oncologist, Division of Haematology/Oncology  
  • Dr. Anita Villani, Staff Oncologist, Division of Haematology/Oncology 
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