Study identifies highest mutation load in any human cancer

Kids with aggressive cancer predisposition syndrome experience flood of cancer mutations in just six months

TORONTO – The most aggressive childhood cancer predisposition syndrome called biallelic mismatch repair deficiency (bMMRD) causes multiple brain tumours, lymphomas and gastrointestinal cancers by age 10 and virtually all children with bMMRD will develop multiple different types of cancer in the first two decades of life. As a result, these children rarely reach adulthood.

While most cancers grow progressively, accumulating genetic mutations over many years, researchers at The Hospital for Sick Children (SickKids) and the Wellcome Trust Sanger Institute were shocked to find that children with this syndrome develop more mutations than any human cancers by far – as many as 20,000 cancer mutations in as little as six months! This rapid burst of cancer mutations in such a short period of time has never before been described and suggests a novel mechanism for cancer progression that could lead to more targeted treatment for these patients.

Children with biallelic mismatch repair deficiency, or bMMRD, have mutations in the genes responsible for mismatch repair and therefore cannot fix mistakes in DNA while the cell is dividing (or when it is replicating). This study, published in the Feb. 2 online edition of Nature Genetics, identifies a secondary mutation which occurs only in tumour cells in an enzyme called polymerase, which is a second safeguard that helps to effectively repair mutations while the DNA replicates. The combination of these two mutations leaves patients with no ability to repair mistakes that may occur while DNA is replicating, and causes a rapid wave of cancer that one of the investigators has dubbed the “great flood.”

“In other cancer predisposition syndromes like BRCA1 and Li Fraumeni syndrome, we know that there is a genetic mutation that predisposes the individual to cancer, but we do not know the secondary mutation, or genetic driver that actually causes the cancer to occur. Our findings indicate the genetic driver that causes this ‘great flood’ of cancer mutations in patients with bMMRD.  The secondary mutation in the enzyme polymerase causes a unique signature of mutations that is present in 100 per cent of the cases,” says Dr. Uri Tabori, co-principal investigator of the study and, Staff Oncologist and Scientist in Genetics & Genome Biology at SickKids. “This has important implications for both diagnosis and targeted treatment of this devastating disease.”

Five years ago, SickKids established an international consortium that offers free genetic testing, genetic counseling and surveillance of cancers in children and family members with bMMRD. Using genetic and clinical information and tumour samples gathered from each patient,  the research team was able to take a deeper look at this cancer predisposition syndrome and for the first time they are able to tell the story of how this cancer develops.

“We were able to describe how many mutations develop, how fast they occur, how many mutations the tumour can sustain, and the type of mutation that occurs, which we found is unique to bMMRD cancers,” says Dr. Adam Shlien, lead author of the study and Associate Director of Translational Genetics and Scientist in Genetics & Genome Biology at SickKids. “Additionally, by studying a rare cancer syndrome we were able to have an unobstructed view on how cancer develops and learn not only about how we can help these patients, but also about cancer progression in general.”

Because the high number of mutations is so specific to bMMRD syndrome, researchers are now able to detect children carriers just by sequencing the tumour. “If the child has a very high number of mutations then we know immediately that they have this cancer predisposition syndrome,” says Shlien who is also Assistant Professor in Laboratory Medicine & Pathology at the University of Toronto.

The team may have also found a clue that may help to develop a novel treatment that promotes tumour cell death. The observation that tumour cells reach a threshold of 20,000 mutations and cannot overcome it suggests that the tumour cannot withstand any more and more mutations may cause cell death. Future research may explore how certain pharmacological agents may push these cancer cells over the mutational edge and cause the tumour cells to die, suggests Shlien.  

Tabori adds that this study really demonstrates that, “we are on the cusp of an evolution in how we do medicine. I like to call it ‘reverse genetics’ where we study the genetics of the tumour to get to know the patient, rather than studying the patient to figure out the tumour.”

Findings from this study can teach us on how to treat more common cancers such as colon, gynecological cancers and recurrent malignant gliomas (cancer in the brain or spine) since they share the same mutations in the mismatch repair genes as our bMMRD patients, says Tabori and Shlien.

The study was supported by BRAINchild Canada, the Canadian Institutes of Health Research (CIHR), Wellcome Trust Sanger Institute and SickKids Foundation.