National Neuroblastoma Genetics Reference Centre Amplification of the MYCN gene and the presence of chromosome rearrangements are strongly linked to aggressive tumour behaviour. Children possessing these indicators and deemed high-risk will require intensive treatment, whilst those without and classified lower risk will likely respond to less toxic therapies, sparing them the risk of long term side effects. The National Neuroblastoma Genetics Reference Centre aims to rapidly screen children to identify these indicators (or lack thereof) and thus determine the appropriate treatment. Principal investigators: Prof Deborah A. Tweddle, University of Newcastle and Dr Nick Bown, Northern Genetics Service. Project grant: £75,082 Date of award: August 2014 Background Neuroblastoma is the most common childhood malignant solid tumour outside the central nervous system. Around 100 cases are diagnosed in the UK each year. Treatment in the UK and elsewhere in the world depends on which risk group the patient falls into – low, medium (intermediate) or high. A patient is assigned a particular risk group dependent on their age, spread of disease, and the genetic abnormalities present in the tumour. Treatment for patients with high-risk disease, around 50% of all patients with neuroblastoma, is much more intensive than for those with intermediate and low-risk disease because more treatment is needed to achieve a cure. The presence of amplified MYCN or amplified or mutated ALK genes and chromosomal gains or deletions are all indicators that neuroblastoma may be high-risk. What difference will this project make? The National Neuroblastoma Genetics Reference Centre aims to provide a comprehensive service genetic characterisation of all neuroblastoma tumours at diagnosis and a subset at relapse, including MYCN status, segmental chromosomal abnormalities, and ALK mutation and amplification status. This information is then inputted into SIOPEN trial databases to inform the development of new genetic techniques and treatments. Here is a clip of Prof Deborah Tweddle talking about the work of the Neuroblastoma Genetics Reference Centre at our 2016 Neuroblastoma Parent Education Conference. What makes this project stand out? Due to the rarity of the disease, individual genetics laboratories encounter very few neuroblastoma tumours per year. The National Neuroblastoma Genetics Reference Centre establishes a centralised laboratory, assuring rapid and accurate information for risk assignment so that paediatric oncologists can select the most appropriate treatment for each child. This provides high quality, comprehensive database of genetic results to aid researchers and the formation of a neuroblastoma network. Dr Mark Gaze, Consultant in Clinical Oncology at the University College London Hospitals and Great Ormond Street Hospital for Children NHS Foundation Trusts, and, Chairman of the National Cancer Research Institute Neuroblastoma Group is very supportive of the Centre’s work: "Neuroblastoma is not a single disease with a uniform pattern of behaviour, but comprises a range of tumours with very different behaviours, depending on the precise molecular genetic makeup. It is important to identify this as accurately as possible for each individual patient, not simply to predict prognosis, but to enable the best choice of treatment." "While much work has been performed across the world on the molecular and genetic characterisation of neuroblastoma, research continues into the best methodology for identifying specific chromosomal abnormalities and gene mutations, and also to determine their significance as predictive and prognostic biomarkers. The picture at the time of initial diagnosis is not necessarily complete, as there is growing evidence that relapsed tumours may display different biological features." "As innovative analytical techniques are under continual development, and being used alongside more established technology, it makes sense to have a single Neuroblastoma National Reference Centre to undertake these tests. With about 100 cases per year, it is more cost-effective to centralise expertise and equipment with quality assurance, rather than try to replicate it at each of the 20 principal treatment centres across the country. In addition, a centralised research-based laboratory with a higher throughput is more likely to discover new findings which will be of value to the patients of the future. For all these reasons, I am very grateful to Solving Kids’ Cancer for its continued financial support for the Neuroblastoma National Reference Centre – this investment will contribute to the selection of the most effective and least toxic treatment schedules for patients, saving lives and leading to an improved quality of life for survivors." Dr Kate Wheeler, Consultant Paediatric Oncologist, Oxford Children’s Hospital, OUH NHS Foundation Trust and Chair of the NCRI CCL CSG Neuroblastoma Group 2010-2016 commending the Centre’s work said: "The Newcastle Neuroblastoma Genetics Reference Centre provides a unique and very necessary service for all patients in the UK with both newly diagnosed and relapsed neuroblastoma." "This quality assured laboratory undertakes prompt and real time analysis of neuroblastoma tissue to determine important molecular information used to stratify the patient’s treatment. Analysis is undertaken of MYCN by FISH, Segmental Chromosomal Alterations by SNP array and ALK sequencing. The results are promptly reported back to the referring local paediatric oncologist who is then able together with the clinical staging of the patient, to determine the most appropriate treatment programme." "The Newcastle laboratory provides an essential clinical service that is fully supported by the UK National Groups, the NCRI CCL CSG Neuroblastoma Group and the CCLG Neuroblastoma Special Interest Group. In addition it contributes to the European (SIOPEN) Neuroblastoma Biology Group within the network of European National Reference Laboratories in providing a vital service for producing robust tumour molecular diagnostics for all patients in clinical trials. The UK is fortunate to have this excellent, well-established and internationally respected neuroblastoma molecular diagnostics service. Despite many attempts, ongoing secure NHS funding has never been established for this essential service and the financial contribution from the Solving Kids Cancer Charity over the past few years has been critical in allowing the essential work of this laboratory to continue and flourish to the benefit of many children with neuroblastoma." About the research team Dr Nick Bown is Consultant Clinical Scientist, Head of Cytogenetics Laboratory and Associate Lecturer, University of Newcastle. He studied at undergraduate level at the University of York, and received his MSc and PhD from the University of Newcastle. His specialism is cytogenetics. Prof Deborah Tweddle is Professor of Paediatric Oncology at the Newcastle Cancer Centre in the Northern Institute for Cancer Research, and Honorary Consultant in Paediatric & Adolescent Oncology at the Great North Children’s Hospital. She studied at undergraduate level at the University of Manchester and received her PhD in Molecular Oncology from Newcastle University. She is Chair of UK Children’s Cancer & Leukaemia Group’s Neuroblastoma Special Interest Group, and a member of the National Cancer Research Institute (NCRI)’s New Agents Group, of the NCRI Children’s Cancer & Leukaemia, Clinical Studies Group Neuroblastoma subgroup, and of SIOPEN and the SIOPEN Biology Group. Her specialism is in neuroblastoma. Acknowledgements Our special thanks to Vanessa, her family and fundraisers for providing the funding to ensure continuity of this vital service for all families affected by neuroblastoma. “It was with great pleasure when back in 2014, Solving Kids’ Cancer approached my wife and I about funding this innovative and exciting project. We didn’t hesitate to agree to this funding as we knew a project like this would bring together a huge amount of valuable information, and retain it all under the one roof! This information will allow researchers the chance to find out more about this horrible disease and how best to approach new and not-yet-tried forms of treatment. You, Vanessa’s team of fundraisers, made it possible and have now moved research forward over the last three years, giving kids with a future diagnosis of Neuroblastoma, a much better chance of beating the disease and leading a normal and happy life; for this, my family are immensely proud and grateful!” – Vanessa’s parents, Chris and Connie Riddle.