Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis.
BACKGROUND
Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease.


METHODS
We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers.


RESULTS
We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2·9 years [95% CI 2·4-5·2] for group 1 vs 7·9 years [6·0-9·7] for group 2 and 5·9 years [4·9-7·8] for group 3; p=0·005), and had poorest survival (median survival 0·8 years [95% CI 0·5-1·2] in group 1, 1·8 years [1·4-2·3] in group 2 and 4·3 years [0·8-7·8] in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037).


CONCLUSIONS
LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials.


BACKGROUND
Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust.
Division of Hematology-Oncology, Arthur and Sonia Labatt Brain Tumour Research Centre, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Daniel
D
Picard
Suzanne
S
Miller
Cynthia E
CE
Hawkins
Eric
E
Bouffet
Hazel A
HA
Rogers
Tiffany S Y
TS
Chan
Seung-Ki
SK
Kim
Young-Shin
YS
Ra
Jason
J
Fangusaro
Andrey
A
Korshunov
Helen
H
Toledano
Hideo
H
Nakamura
James T
JT
Hayden
Jennifer
J
Chan
Lucie
L
Lafay-Cousin
Pingzhao
P
Hu
Xing
X
Fan
Karin M
KM
Muraszko
Scott L
SL
Pomeroy
Ching C
CC
Lau
Ho-Keung
HK
Ng
Chris
C
Jones
Timothy
T
Van Meter
Steven C
SC
Clifford
Charles
C
Eberhart
Amar
A
Gajjar
Stefan M
SM
Pfister
Richard G
RG
Grundy
Annie
A
Huang
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D005060:Europe; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D007564:Japan; D053208:Kaplan-Meier Estimate; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018242:Neuroectodermal Tumors, Primitive / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D009656:North America; D000076104:Oligodendrocyte Transcription Factor 2; D025341:Principal Component Analysis; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000235:genetics*; D015203:Reproducibility of Results; D056910:Republic of Korea; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors
D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D016601:RNA-Binding Proteins; C000715187:Lin28A protein, human; C405708:OLIG2 protein, human