Cytogenetic Prognostication Within Medulloblastoma Subgroups
Authors: Shih David J.H. , Northcott Paul A. , Remke Marc , Korshunov Andrey , Ramaswamy Vijay , Kool Marcel , Luu Betty , Yao Yuan , Wang Xin , Dubuc Adrian M. , Garzia Livia , Peacock John , Mack Stephen C. , Wu Xiaochong , Rolider Adi , Morrissy A. Sorana , Cavalli Florence M.G. , Jones David T.W. , Zitterbart Karel , Faria Claudia C. , Schüller Ulrich , Kren Leos , Kumabe Toshihiro , Tominaga Teiji , Shin Ra Young , Garami Miklós , Hauser Peter , Chan Jennifer A. , Robinson Shenandoah , Bognár László , Klekner Almos , Saad Ali G. , Liau Linda M. , Albrecht Steffen , Fontebasso Adam , Cinalli Giuseppe , De Antonellis Pasqualino , Zollo Massimo , Cooper Michael K. , Thompson Reid C. , Bailey Simon , Lindsey Janet C. , Di Rocco Concezio , Massimi Luca , Michiels Erna M.C. , Scherer Stephen W. , Phillips Joanna J. , Gupta Nalin , Fan Xing , Muraszko Karin M. , Vibhakar Rajeev , Eberhart Charles G. , Fouladi Maryam , Lach Boleslaw , Jung Shin , Wechsler-Reya Robert J. , Fèvre-Montange Michelle , Jouvet Anne , Jabado Nada , Pollack Ian F. , Weiss William A. , Lee Ji-Yeoun , Cho Byung-Kyu , Kim Seung-Ki , Wang Kyu-Chang , Leonard Jeffrey R. , Rubin Joshua B. , de Torres Carmen , Lavarino Cinzia , Mora Jaume , Cho Yoon-Jae , Tabori Uri , Olson James M. , Gajjar Amar , Packer Roger J. , Rutkowski Stefan , Pomeroy Scott L. , French Pim J. , Kloosterhof Nanne K. , Kros Johan M. , Van Meir Erwin G. , Clifford Steven C. , Bourdeaut Franck , Delattre Olivier , Doz François F. , Hawkins Cynthia E. , Malkin David , Grajkowska Wieslawa A. , Perek-Polnik Marta , Bouffet Eric , Rutka James T. , Pfister Stefan M. , Taylor Michael D. 
Published: February 2014

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.