CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity.
Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.
Division of Hematology-Oncology, Department of Pediatrics, The Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumor Research Centre, Peter Gilgan CRL,686 Bay Street, 17th Floor, 179712, Toronto, ON, M5G0A4, Canada.
Tara
T
Spence
Patrick
P
Sin-Chan
Daniel
D
Picard
Mark
M
Barszczyk
Katharina
K
Hoss
Mei
M
Lu
Seung-Ki
SK
Kim
Young-Shin
YS
Ra
Hideo
H
Nakamura
Jason
J
Fangusaro
Eugene
E
Hwang
Erin
E
Kiehna
Helen
H
Toledano
Yin
Y
Wang
Qing
Q
Shi
Donna
D
Johnston
Jean
J
Michaud
Milena
M
La Spina
Anna Maria
AM
Buccoliero
Dariusz
D
Adamek
Sandra
S
Camelo-Piragua
V
V
Peter Collins
Chris
C
Jones
Nabil
N
Kabbara
Nawaf
N
Jurdi
Pascale
P
Varlet
Arie
A
Perry
David
D
Scharnhorst
Xing
X
Fan
Karin M
KM
Muraszko
Charles G
CG
Eberhart
Ho-Keung
HK
Ng
Sridharan
S
Gururangan
Timothy
T
Van Meter
Marc
M
Remke
Lucie
L
Lafay-Cousin
Jennifer A
JA
Chan
Nongnuch
N
Sirachainan
Scott L
SL
Pomeroy
Steven C
SC
Clifford
Amar
A
Gajjar
Mary
M
Shago
William
W
Halliday
Michael D
MD
Taylor
Richard
R
Grundy
Ching C
CC
Lau
Joanna
J
Phillips
Eric
E
Bouffet
Peter B
PB
Dirks
Cynthia E
CE
Hawkins
Annie
A
Huang
D000293:Adolescent; D017668:Age of Onset; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D003937:Diagnosis, Differential; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D018242:Neuroectodermal Tumors, Primitive / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D016601:RNA-Binding Proteins / Q000378:metabolism*; D000097584:DNA Methyltransferase 3B
D004248:DNA (Cytosine-5-)-Methyltransferases; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D000097584:DNA Methyltransferase 3B; C516326:LIN28B protein, human; C000715187:Lin28A protein, human