Study sheds new light on aggressive cancer in children

A new study involving researchers at The University of Nottingham has revealed how children with an aggressive cancer predisposition syndrome experience a never before seen flood of mutations in their disease in just six months.

The syndrome, called 'biallelic mismatch repair deficiency' (bMMRD) causes multiple brain tumours, lymphomas and gastrointestinal cancers by the age of 10. As a result these children rarely survive into adulthood.

While most cancers grow progressively, developing genetic mutations over many years, researchers at The Hospital for Sick Kids in Toronto, Canada, the Wellcome Trust Sanger Institute and the Children's Brain Tumour Research Centre in Nottingham, were shocked to find that children with this syndrome develop more mutations than any human cancers by far - as many as 20,000 mutations in as little as six months.

The new paper, published online in Nature Genetics, suggests a previously undiscovered mechanism for cancer progression which could lead to more targeted treatment for these patients and indeed for more common cancers.

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 replicating). This study 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 the investigators have dubbed the "great flood."

Professor Richard Grundy from the University's Children's Brain Tumour Research Centre said: "This study provides a major step forwards in understanding why certain children are more susceptible to developing multiple cancers and can screen for this eventuality. In turn, this study allows us to begin to understand the steps that lead to cancer developing. Ultimately, we hope this leads to treatments to avoid the presently inevitable consequences of this predisposition syndrome"

Dr Uri Tabori, co-principal investigator of the study from Genetics & Genome Biology at SickKids, Toronto said: "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. This has important implications for both diagnosis and targeted treatment of this devastating disease."

The Children's Brain Tumour Research Centre in Nottingham is part of an international consortium run by SickKids, Toronto, 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.