Study Sheds New Light on Syndrome Associated With Aggressive Pediatric Cancer
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 very short periods of time. The findings were published by Shlien et al in Nature Genetics.
The syndrome, called biallelic mismatch repair deficiency, causes multiple brain tumors, lymphomas, and gastrointestinal cancers by the age of 10. While most cancers grow progressively, developing genetic mutations over many years, researchers at SickKids, the Wellcome Trust Sanger Institute, and the Children's Brain Tumour Research Centre discovered that children with biallelic mismatch repair deficiency develop more mutations than any other cancers by far—as many as 20,000 mutations in as little as 6 months.
The findings suggest a previously undiscovered mechanism for cancer progression, which could lead to more targeted treatment for these patients, as well as for those with more common cancers.
‘Great Flood’ of Cancer
Children with biallelic mismatch repair deficiency have mutations in the genes responsible for mismatch repair, and therefore cannot fix mistakes in DNA while cells are replicating. The study identified a secondary mutation that occurs only in tumor cells in the enzyme polymerase, 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.”
Richard Grundy, MD, PhD, Professor of Pediatric Neuro-Oncology and Cancer Biology at 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 syndrome.”
Study Findings
Uri Tabori, MD, coprincipal investigator of the study and Scientist at Genetics & Genome Biology at SickKids, 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. However, 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 biallelic mismatch repair deficiency. The secondary mutation in the enzyme polymerase causes a unique signature of mutations that is present in 100% of the cases. This has important implications for both diagnosis and targeted treatment of this devastating disease.”
Using genetic and clinical information and tumor samples gathered from each patient, the research team was able to take a deeper look at biallelic mismatch repair deficiency 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 tumor can sustain, and the type of mutation that occurs, which we found is unique to biallelic mismatch repair deficiency cancers,” said Adam Shlien, PhD, lead author of the study, Associate Director of Translational Genetics, and Scientist in Genetics & Genome Biology at SickKids.
Dr. Shlien continued, “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 biallelic mismatch repair deficiency syndrome, researchers are now able to detect children who are carriers just by sequencing the tumor.
“If a child has a very high number of mutations, then we know immediately that they have this cancer predisposition syndrome,” said Dr. Shlien.
Additional Treatment Possibilities
The team may have also found a clue that may help to develop a novel treatment that promotes tumor cell death. The observation that tumor cells reach a threshold of 20,000 mutations and cannot overcome it suggests that the tumor cannot withstand any more, and more mutations may cause cell death. Future research may explore how certain pharmacologic agents may push these cancer cells over the mutational edge and cause tumor cells to die.
Researchers hope findings from this study will also lead to more effective treatments for more common cancers such as recurrent malignant gliomas, colon, and gynecologic cancers, since these cancers share the same mutations in the mismatch repair genes as biallelic mismatch repair deficiency patients.
Dr. Shlien, Dr. Tabori, and Peter J. Campbell, PhD, of the Wellcome Trust Sanger Insitute, are the corresponding authors of the Nature Genetics article.
The study was supported by BRAINchild Canada, the Canadian Institutes of Health Research (CIHR), Wellcome Trust Sanger Institute, and SickKids Foundation.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
