Multiple CDK/CYCLIND genes are amplified in medulloblastoma and supratentorial primitive neuroectodermal brain tumor.
Embryonal brain tumors, which include medulloblastoma and the more aggressive supratentorial primitive neuroectodermal tumor (sPNET), comprise one of the largest group of malignant pediatric brain tumors. We observed in high resolution array comparative genomic hybridization and polymerase chain reaction analyses that several different components of the CDK/CYCLIND/pRB regulatory complex, including the CDK4/6 and CCND1/2 loci, are targets of gene amplification in medulloblastoma and sPNET. CDK6 and CCND1 gene amplification were respectively most common and robust, and overall CDK/CYCLIND gene amplification was more commonly observed in sPNET (25%) than medulloblastoma (1-5%). CDK6 overexpression enhanced in vitro and in vivo oncogenicity and endogenous CDK6 or CCND1 knockdown decreased pRB phosphorylation and impaired cell cycle progression in both medulloblastoma and sPNET cell lines. Although animal models implicate the pRB tumor suppressor pathway in medulloblastoma and sPNET, mutations of RB1 or the related INK4 tumor suppressor loci are rare in primary human tumors. Our data suggest that CDK/CYCLIND gene amplification may represent important mechanisms for functional inactivation of pRB in medulloblastoma and sPNET.
Program in Cell Biology, Hospital for Sick Children, Toronto, Canada.
Meihua
M
Li
Will
W
Lockwood
Maria
M
Zielenska
Paul
P
Northcott
Young Shing
YS
Ra
Eric
E
Bouffet
Maisa
M
Yoshimoto
James T
JT
Rutka
Hai
H
Yan
Michael D
MD
Taylor
Charles
C
Eberhart
Cynthia E
CE
Hawkins
Wan
W
Lam
Jeremy A
JA
Squire
Annie
A
Huang
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056741:Cyclin D / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000502:physiology; D018844:Cyclin-Dependent Kinases / Q000235:genetics*; D005784:Gene Amplification; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D016133:Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000235:genetics; D015173:Supratentorial Neoplasms / Q000235:genetics*
C530104:CCND1 protein, human; D056741:Cyclin D; D016160:Retinoblastoma Protein; D019938:Cyclin D1; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases