Northern Institute for Cancer Research

Childhood Brain Tumours

Childhood Brain Tumours

About

Brain tumours are the most common cause of death from cancer in childhood. We carry out biological discovery to deliver the next generation of improved brain tumour therapies.

Research leaders

Dan Williamson
Simon Bailey
Steve Clifford

Our research

We run a multi-disciplinary, translational research programme. This brings together wide-range of expertise, from basic biological studies to international clinical trials

Our work focuses on two of the major high-risk brain tumour types of childhood.

Medulloblastoma is the most common malignant paediatric brain tumour. Atypical teratoid rhabdoid tumour (ATRT) is a commonly lethal tumour type. It arises most often in the first year of life.

Together, these diseases account for over 300 deaths in childhood every year in Europe.

Our principal approach to both tumours to understand their critical molecular features in detail. We using advanced next-generation genome-wide genetic and epigenetic technologies.

We use collections of primary and relapsed tumours linked to national and international clinical trials. We also use functional genomic models. We create these models to further understand their role in disease biology.

We use translational strategies to develop biomarkers. These can be used to personalise therapy through better diagnosis, classification and prediction of disease course.

We apply this understanding to develop novel therapies targeted against specific disease biology.

Medulloblastoma comprises four core molecular subgroups (by RNA-seq and t-SNE analysis)

Research Team

Senior Lecturers

Ed Schwalbe (Northumbria University)

Academic Clinical Lecturers

Rebecca Hill

Fellows

Debbie Hicks

Post-doctoral scientists and research bioinformaticians

Martina Finetti
Janet Lindsey
Sirintra Nakjang
Reza Rafiee
Fatma Scerif
Matthew Selby

Biomedical scientists and research technicians

Stephen Crosier
Amanda Smith

Post-graduate PhD students

Yura Grabowska
Alice Iliasova
Gemma Llargues-Sistac
Azira Ramili
Stacey Richardson
Shanel Swartz

Clinical Consultants

Dipyan Mitra (Radiologist, Newcastle upon Tyne Hospitals NHS Trust)
Abjhit Joshi (Neuropathologist, Newcastle upon Tyne Hospitals NHS Trust)

Childhood Cancer Research team

Research Partners

We work within national and international biological studies, clinical trials, and policy working groups to undertake our research and advance findings into clinical practice:

Children's Cancer and Leukaemia Group (CCLG)

National Cancer Research Institute (NCRI)

SIOP Europe

EPSSG Association

Genomics England

Research Partners
Funders

Recent Publications

Wong JP, Todd JR, Finetti MA, McCarthy F, Broncel M, Vyse S, Luczynski MT, Crosier S, Ryall KA, Holmes K, Payne LS, Daley F, Wai P, Jenks A, Tanos B, Tan A, Natrajan RC, Williamson D and Huang PH. Dual targeting of PDGFRα and FGFR1 displays synergistic efficacy in malignant rhabdoid tumours. Cell Rep. 2016. In press.

Sabel M, Fleischhack G, Tippelt S, Gustafsson G, Doz F, Kortmann R, Massimino M, Navajas A, von Hoff K, Rutkowski S, Warmuth-Metz M, Clifford SC, Pietsch T,Pizer B, Lannering B. Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study. J Neurooncol. 2016. 129(3): 515-24. PMCID: PMC5020107.

Ramaswamy V, Remke M, Bouffet E, Bailey S, Clifford SC, Doz F, Kool M, Dufour C, Vassal G, Milde T, Witt O, Hoff von K, Pietsch T, Northcott PA, Gajjar A, Robinson GW, Padovani L, André N, Massimino M, Pizer B, Packer R, Rutkowski S, Pfister SM, Taylor MD, Pomeroy SL. Risk stratification of childhood medulloblastoma in the molecular era: the current consensus. Acta Neuropathol. 2016. 131(6): 821–831. PMCID: PMC4867119

Morrissy AS, Garzia L, Shih DJH….Fleischhack G, Tippelt S, Ra Y-S, Bailey S, Lindsey JC, Clifford SC, Eberhart CG, Cooper MK….Malkin D, Marra MA, Taylor MD. Divergent clonal selection dominates medulloblastoma at recurrence. Nature. 2016. 529(7586): 351–357. PMID: 26760213

Clifford SC, Lannering B, Schwalbe EC, Hicks D, O'Toole K, Nicholson SL, Goschzik T, Mühlen Zur A, Figarella-Branger D, Doz F, Rutkowski S, Gustafsson G, Pietsch T, SIOP-Europe PNET Group. Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial. Oncotarget. 2015. 6(36): 38827–38839. PMCID: PMC4770740

Hill RM, Kuijper S, Lindsey JC, Petrie K, Schwalbe EC, Barker K, Boult JKR, Williamson D, Ahmad Z, Hallsworth A, Ryan SL, Poon E, Robinson SP, Ruddle R, Raynaud FI, Howell L, Kwok C, Joshi A, Nicholson SL, Crosier S, Ellison DW, Wharton SB, Robson K, Michalski A, Hargrave D, Jacques TS, Pizer B, Bailey S, Swartling FJ, Weiss WA, Chesler L, Clifford SC. Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease. Cancer Cell. 2015. 27(1): 72–84. PMCID: PMC4297293

Lindsey JC, Kawauchi D, Schwalbe EC, Solecki DJ, Selby MP, McKinnon PJ, Olson JM, Hayden JT, Grundy RG, Ellison DW, Williamson D, Bailey S, Roussel MF, Clifford SC. Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance. Oncogene. 2015.  34(36): 4746–4757. PMCID: PMC4386991

Parkes J, Hendricks M, Ssenyonga P, Mugamba J, Molyneux E, Schouten-van Meeteren A, Qaddoumi I, Fieggen G, Luna-Fineman S, Howard S, Mitra D, Bouffet E, Davidson A, Bailey S, SIOP PODC. SIOP PODC adapted treatment recommendations for standard-risk medulloblastoma in low and middle income settings. Pediatric blood & cancer. 2015. 553–564. PMID: 25418957

Bull KS, Kennedy CR, Bailey S, Ellison DW, Clifford SC. Improved health-related quality of life outcomes associated with SHH subgroup medulloblastoma in SIOP-UKCCSG PNET3 trial survivors. Acta Neuropathol. 2014. 128(1): 151–153. PMCID: PMC4313076

Shih DJH, Northcott PA, Remke M, Korshunov A, Ramaswamy V, Kool M….Van Meir EG, Clifford SC, Bourdeaut F, Delattre O, Doz FF, Hawkins CE, Malkin D, Grajkowska WA, Perek-Polnik M, Bouffet E, Rutka JT, Pfister SM, Taylor MD. Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol. 2014. 32(9): 886–896. PMCID: PMC3948094

Lindsey JC, Schwalbe EC, Potluri S, Bailey S, Williamson D, Clifford SC. TERT promoter mutation and aberrant hypermethylation are associated with elevated expression in medulloblastoma and characterise the majority of non-infant SHH subgroup tumours. Acta Neuropathol. 2014. 127(2): 307–309. PMCID: PMC4313075

Gottardo NG, Hansford JR, McGlade JP, Alvaro F, Ashley DM, Bailey S, Baker DL, Bourdeaut F, Cho Y-J, Clay M, Clifford SC, Cohn RJ, Cole CH….Shelat AA, Stewart CF, Sullivan M, Taylor MD, Wainwright B, Walwyn T, Weiss WA, Williamson D, Gajjar A. Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group. Acta Neuropathol. 2014.   189–201. PMCID: PMC3895219

Zhukova N, Ramaswamy V, Remke M, Martin DC, Castelo-Branco P….Hawkins CE, Malkin D, Clifford SC, Pfister SM, Taylor MD, Tabori U. WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma. Acta Neuropathol Commun. 2014. 2(1): 174. PMCID: PMC4297452

Ptasinska A, Assi SA, Martinez-Soria N, Imperato MR, Piper J, Cauchy P, Pickin A, James SR, Hoogenkamp M, Williamson D, Wu M, Tenen DG, Ott S, Westhead DR, Cockerill PN, Heidenreich O, Bonifer C. Identification of a dynamic core transcriptional network in t(8;21) AML that regulates differentiation block and self-renewal. Cell Rep. 2014. 8(6): 1974–1988. PMCID: PMC4487811

Schwalbe EC, Hayden JT, Rogers HA, Miller S, Lindsey JC, Hill RM, Nicholson SL, Kilday JP, Adamowicz-Brice M, Storer L, Jacques TS, Robson K, Lowe J, Williamson D, Grundy RG, Bailey S, Clifford SC. Histologically defined central nervous system primitive neuro-ectodermal tumours (CNS-PNETs) display heterogeneous DNA methylation profiles and show relationships to other paediatric brain tumour types. Acta Neuropathol. 2013. 126(6): 943-6. PMCID: PMC4313077.

Zhukova N, Ramaswamy V, Remke M, Pfaff E, Shih DJ, Martin DC, Castelo-Branco P….Schüller U, Hill RM, Lindsey JC, Schwalbe EC, Bailey S, Ellison DW, Hawkins C, Malkin D, Clifford SC, Korshunov A, Pfister S, Taylor MD, Tabori U. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol. 2013. 31(23): 2927-35. PMCID: PMC4878050.

Lastowska M, Al-Afghani H, Al-Balool HH, Sheth H, Mercer E, Coxhead JM, Redfern CPF, Peters H, Burt AD, Santibanez-Koref M, Bacon CM, Chesler L, Rust AG, Adams DJ, Williamson D, Clifford SC, Jackson MS. Identification of a neuronal transcription factor network involved in medulloblastoma development. Acta Neuropathol Commun. 2013. 1(1): 35. PMCID: PMC3893591

Schwalbe EC, Williamson D, Lindsey JC, Hamilton D, Ryan SL, Megahed H, Garami M, Hauser P, Dembowska-Baginska B, Perek D, Northcott PA, Taylor MD, Taylor RE, Ellison DW, Bailey S, Clifford SC. DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathol. 2013. 125(3): 359–371. PMCID: PMC4313078

Rehe K, Wilson K, Bomken S, Williamson D, Irving J, Boer Den ML, Stanulla M, Schrappe M, Hall AG, Heidenreich O, Vormoor J. Acute B lymphoblastic leukaemia-propagating cells are present at high frequency in diverse lymphoblast populations. EMBO Mol Med. 2013. 5(1):38–51. PMCID: PMC3569652

Lannering B, Rutkowski S, Doz F, Pizer B, Gustafsson G, Navajas A, Massimino M, Reddingius R, Benesch M, Carrie C, Taylor R, Gandola L, Björk-Eriksson T, Giralt J, Oldenburger F, Pietsch T, Figarella-Branger D, Robson K, Forni M, Clifford SC, Warmuth-Metz M, Hoff von K, Faldum A, Mosseri V, Kortmann R. Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: results from the randomized multicenter HIT-SIOP PNET 4 trial. J Clin Oncol. 2012. 30(26): 3187–3193. PMID: 22851561

Missiaglia E, Williamson D, Chisholm J, Wirapati P, Pierron G, Petel F, Concordet J-P, Thway K, Oberlin O, Pritchard-Jones K, Delattre O, Delorenzi M, Shipley J. PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J Clin Oncol. 2012. 30(14):1670–1677. PMID: 22454413

Jones DTW, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho Y-J, Pugh TJ….Bueren von AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo M-L, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012. 488(7409): 100–105. PMCID: PMC3662966

Ptasinska A, Assi SA, Mannari D, James SR, Williamson D, Dunne J, Hoogenkamp M, Wu M, Care M, McNeill H, Cauchy P, Cullen M, Tooze RM, Tenen DG, Young BD, Cockerill PN, Westhead DR, Heidenreich O, Bonifer C. Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding. Leukemia. 2012. 26(8):1829–1841. PMCID: PMC3419980

Northcott PA, Shih DJH, Peacock J, Garzia L, Morrissy AS, Zichner T, Stütz AM….Bouffet E, Scherer SW, Rutka JT, Malkin D, Clifford SC, Jones SJM, Korbel JO, Pfister SM, Marra MA, Taylor MD. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012. 488(7409): 49–56. PMCID: PMC3683624