Genetics of children's brain tumour unlocked

Researchers have identified an important cancer gene that could lead to more effective drugs being developed to fight paediatric high grade glioma, a disease which currently has a poor prognosis.

The discovery, published in the Journal of Clinical Oncology, was one of a number of significant genetic differences found between the adult and youth form of the disease. Gliomas are the most common brain tumour in children.

Clinicians and scientists at The Institute of Cancer Research (ICR) and The University of Nottingham on behalf of the UK Children’s Cancer and Leukaemia Group, and St Jude Children’s Research Hospital in the US, conducted by far the most comprehensive analysis to date of paediatric high-grade glioma, making a detailed scan of the genome of 78 newly-diagnosed patients.

They compared these paediatric tumour samples with the genome of adult gliomas, looking through 500,000 individual pieces of DNA for variations in the number of copies of each. In paediatric gliomas, a gene called PDGFRA on chromosome 4q12 was commonly amplified and there were often extra copies of chromosome 1q. These changes are rarely seen in the adult form of the disease.

Clinical differences between gliomas in adults and youth had already been observed, for example growth in disparate areas of the brain, but this is the first study to establish that the underlying genetics differ.

“We found significant differences between the genomes of adult and young people’s gliomas,” says Dr Chris Jones, Leader of the Paediatric Molecular Pathology Team at the ICR. “This is an important finding because it means studies on adult gliomas cannot simply be applied to younger patients, and it has particular implications for drug trials.”

The researchers also tracked gene activity in 53 of the tumour samples, and compared the results with adult gliomas. Paediatric glioma tumours that did not have the PDGFRA alteration were nevertheless found to have associated genes switched on, suggesting that this biological pathway is a key to the development of this childhood cancer. The PDGFRA gene carries instructions for making a protein found on the cell surface, which is part of a pathway that helps control cell growth, proliferation and survival — processes that are commonly disrupted in cancer.

“This cancer gene is unusually active in paediatric high-grade gliomas and is likely to be an important drug target,” said Professor Richard Grundy from the Children's Brain Tumour Research Centre at The University of Nottingham.

In addition, 10 children in the study had glioma that arose after they were treated with radiotherapy to the brain for a previous cancer. Analysis of these children’s tumours revealed they had the gene alterations at even higher frequency than the other cancers studied, which had been triggered by other factors. The presence of these alterations irrespective of the trigger for the cancer also indicates that they are crucial to glioma development.