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.
High grade gliomas account for about 75 to 80 per cent of primary malignant brain tumours — cancer that originates in the brain. In the UK, about 4,550 adults and 350 children are diagnosed with brain tumours each year. Gliomas are the most common brain tumour in children, and aggressive gliomas can be very difficult to treat successfully — 70 to 90 per cent of patients die within two years of diagnosis.
The work was funded by the Children's Brain Tumor Foundation, the National Institutes of Health, the National Brain Tumor Society, the Ryan McGee Foundation, Musicians Against Childhood Cancer, the Noyes Brain Tumor Foundation, ALSAC, Samantha Dickson Brain Tumour Trust, Air and Ground, The Connie and Albert Taylor Trust, the Joe Foote Foundation, Cancer Research UK and the NHS.
Notes to editors: The Institute of Cancer Research (ICR) is Europe's leading cancer research centre, and has been ranked the UK's top academic research centre, based on the results of the Higher Education Funding Council's Research Assessment Exercise. The ICR works closely with partner The Royal Marsden NHS Foundation Trust to ensure patients immediately benefit from new research. Together the two organisations form the largest comprehensive cancer centre in Europe.
The ICR has charitable status and relies on voluntary income, spending 95 pence in every pound of total income directly on research. As a college of the University of London, the ICR also provides postgraduate higher education of international distinction
Over its 100-year history, the ICR's achievements include identifying the potential link between smoking and lung cancer which was subsequently confirmed, discovering that DNA damage is the basic cause of cancer and isolating more cancer-related genes than any other organisation in the world. The ICR is home to the world's leading academic paediatric childhood cancer drug development unit. In the next 10 years its scientists aim to develop effective drugs to treat the four cancers responsible for the majority of childhood cancer deaths. More information: www.icr.ac.uk
The Children's Brain Tumour Research Centre (CBTRC) at The University of Nottingham brings together researchers from clinical and basic science arenas, both locally and internationally. The activity of the centre is directed at increasing our understanding of the biological nature of childhood and adolescent brain tumours and using this knowledge to optimize the health outcomes for the child and family.
Researchers in the CBTRC are currently testing hypotheses concerned with neurodevelopment, the application of novel imaging and genetic techniques aimed at comprehensive assessment of tumour biology, optimisation of drug selection and CNS targeting. Major funders of the CBTRC include Cancer Research UK the Samantha Dickson Brain Tumour Trust and the Joe Foote Foundation.
The University of Nottingham is ranked in the UK's Top 10 and the World's Top 100 universities by the Shanghai Jiao Tong (SJTU) and the Times Higher Education-QS World University Rankings.
More than 90 per cent of research at The University of Nottingham is of international quality, according to RAE 2008, with almost 60 per cent of all research defined as 'world-leading' or 'internationally excellent'. Research Fortnight analysis of RAE 2008 ranks the University 7th in the UK by research power. In 27 subject areas, the University features in the UK Top Ten, with 14 of those in the Top Five.
The University provides innovative and top quality teaching, undertakes world-changing research, and attracts talented staff and students from 150 nations. Described by The Times as Britain's "only truly global university", it has invested continuously in award-winning campuses in the United Kingdom, China and Malaysia. Twice since 2003 its research and teaching academics have won Nobel Prizes. The University has won the Queen's Award for Enterprise in both 2006 (International Trade) and 2007 (Innovation — School of Pharmacy), and was named 'Entrepreneurial University of the Year' at the Times Higher Education Awards 2008.
Nottingham was designated as a Science City in 2005 in recognition of its rich scientific heritage, industrial base and role as a leading research centre. Nottingham has since embarked on a wide range of business, property, knowledge transfer and educational initiatives (www.science-city.co.uk) in order to build on its growing reputation as an international centre of scientific excellence. The University of Nottingham is a partner in Nottingham: the Science City.
More information is available from Richard Grundy, Professor of Paediatric Neuro-Oncology, University of Nottingham, on +44 (0)115 823 0620, richard.grundy@nottingham.ac.uk; or Jane Bunce at the Institute of Cancer Research, jane.bunce@icr.ac.uk, +44 (0)207 153 5106, or +44 (0)7721 747900, or Tim Utton, Deputy Director of Communications, on +44 (0)115 846 8092, tim.utton@nottingham.ac.uk
Journal
Journal of Clinical Oncology