PURPOSE: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. PATIENTS AND METHODS: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. RESULTS: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. CONCLUSION: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

David J H Shih Marc Remke Vijay Ramaswamy Betty Luu Yuan Yao Xin Wang Adrian M Dubuc Livia Garzia John Peacock Stephen C Mack Xiaochong Wu Adi Rolider A Sorana Morrissy Florence M G Cavalli Claudia C Faria Stephen W Scherer Uri Tabori Cynthia E Hawkins David Malkin Eric Bouffet James T Rutka and Michael D Taylor Hospital for Sick Children; David J H Shih Marc Remke Vijay Ramaswamy Yuan Yao Xin Wang Adrian M Dubuc John Peacock Stephen C Mack and Michael D Taylor University of Toronto Toronto; Boleslaw Lach McMaster University Hamilton Ontario; Jennifer A Chan University of Calgary Calgary Alberta; Steffen Albrecht Adam Fontebasso and Nada Jabado McGill University Montreal Quebec Canada; Paul A Northcott Andrey Korshunov Marcel Kool David T W Jones and Stefan M Pfister German Cancer Research Center; Stefan M Pfister University Hospital Heidelberg Heidelberg; Ulrich Schüller Ludwig Maximilians University Munich; Stefan Rutkowski University Medical Center Hamburg Eppendorf Hamburg Germany; Karel Zitterbart Masaryk University School of Medicine; Karel Zitterbart and Leos Kren University Hospital Brno Brno Czech Republic; Toshihiro Kumabe and Teiji Tominaga Tohoku University Graduate School of Medicine Sendai Japan; Young Shin Ra University of Ulsan Asan Medical Center; Ji Yeoun Lee Byung Kyu Cho Seung Ki Kim and Kyu Chang Wang Seoul National University Children's Hospital Seoul; Shin Jung Chonnam National University Research Institute of Medical Sciences Chonnam National University Hwasun Hospital and Medical School Chonnam South Korea; Peter Hauser and Miklós Garami Semmelweis University Budapest; László Bognár and Almos Klekner University of Debrecen Medical and Health Science Centre Debrecen Hungary; Shenandoah Robinson Boston Children's Hospital; Scott L Pomeroy Harvard Medical School Boston MA; Ali G Saad University of Arkansas for Medical Sciences Little

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Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis

Divergent clonal selection dominates medulloblastoma at recurrence