Cytogenetic prognostication within medulloblastoma subgroups.
OBJECTIVE
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.


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.


CONCLUSIONS
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 
David J H
DJ
Shih
Paul A
PA
Northcott
Marc
M
Remke
Andrey
A
Korshunov
Vijay
V
Ramaswamy
Marcel
M
Kool
Betty
B
Luu
Yuan
Y
Yao
Xin
X
Wang
Adrian M
AM
Dubuc
Livia
L
Garzia
John
J
Peacock
Stephen C
SC
Mack
Xiaochong
X
Wu
Adi
A
Rolider
A Sorana
AS
Morrissy
Florence M G
FM
Cavalli
David T W
DT
Jones
Karel
K
Zitterbart
Claudia C
CC
Faria
Ulrich
U
Schüller
Leos
L
Kren
Toshihiro
T
Kumabe
Teiji
T
Tominaga
Young
Y
Shin Ra
Miklós
M
Garami
Peter
P
Hauser
Jennifer A
JA
Chan
Shenandoah
S
Robinson
László
L
Bognár
Almos
A
Klekner
Ali G
AG
Saad
Linda M
LM
Liau
Steffen
S
Albrecht
Adam
A
Fontebasso
Giuseppe
G
Cinalli
Pasqualino
P
De Antonellis
Massimo
M
Zollo
Michael K
MK
Cooper
Reid C
RC
Thompson
Simon
S
Bailey
Janet C
JC
Lindsey
Concezio
C
Di Rocco
Luca
L
Massimi
Erna M C
EM
Michiels
Stephen W
SW
Scherer
Joanna J
JJ
Phillips
Nalin
N
Gupta
Xing
X
Fan
Karin M
KM
Muraszko
Rajeev
R
Vibhakar
Charles G
CG
Eberhart
Maryam
M
Fouladi
Boleslaw
B
Lach
Shin
S
Jung
Robert J
RJ
Wechsler-Reya
Michelle
M
Fèvre-Montange
Anne
A
Jouvet
Nada
N
Jabado
Ian F
IF
Pollack
William A
WA
Weiss
Ji-Yeoun
JY
Lee
Byung-Kyu
BK
Cho
Seung-Ki
SK
Kim
Kyu-Chang
KC
Wang
Jeffrey R
JR
Leonard
Joshua B
JB
Rubin
Carmen
C
de Torres
Cinzia
C
Lavarino
Jaume
J
Mora
Yoon-Jae
YJ
Cho
Uri
U
Tabori
James M
JM
Olson
Amar
A
Gajjar
Roger J
RJ
Packer
Stefan
S
Rutkowski
Scott L
SL
Pomeroy
Pim J
PJ
French
Nanne K
NK
Kloosterhof
Johan M
JM
Kros
Erwin G
EG
Van Meir
Steven C
SC
Clifford
Franck
F
Bourdeaut
Olivier
O
Delattre
François F
FF
Doz
Cynthia E
CE
Hawkins
David
D
Malkin
Wieslawa A
WA
Grajkowska
Marta
M
Perek-Polnik
Eric
E
Bouffet
James T
JT
Rutka
Stefan M
SM
Pfister
Michael D
MD
Taylor
D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D003582:Cytogenetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D009687:Nuclear Proteins / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D046888:Tissue Array Analysis; D051153:Wnt Proteins / Q000235:genetics; D055815:Young Adult; D000075746:Zinc Finger Protein Gli2
D014408:Biomarkers, Tumor; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; C509239:SHH protein, human; D051153:Wnt Proteins; D000075746:Zinc Finger Protein Gli2