Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma.
We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.
Northcott
Paul A
PA
Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
Nakahara
Yukiko
Y
Wu
Xiaochong
X
Feuk
Lars
L
Ellison
David W
DW
Croul
Sid
S
Mack
Stephen
S
Kongkham
Paul N
PN
Peacock
John
J
Dubuc
Adrian
A
Ra
Young-Shin
YS
Zilberberg
Karen
K
McLeod
Jessica
J
Scherer
Stephen W
SW
Sunil Rao
J
J
Eberhart
Charles G
CG
Grajkowska
Wiesia
W
Gillespie
Yancey
Y
Lach
Boleslaw
B
Grundy
Richard
R
Pollack
Ian F
IF
Hamilton
Ronald L
RL
Van Meter
Timothy
T
Carlotti
Carlos G
CG
Boop
Frederick
F
Bigner
Darrell
D
Gilbertson
Richard J
RJ
Rutka
James T
JT
Taylor
Michael D
MD
D002528:Cerebellar Neoplasms / Q000201:enzymology / Q000235:genetics*; D005784:Gene Amplification; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D015894:Genome, Human; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008527:Medulloblastoma / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017384:Sequence Deletion
D006657:Histones; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine