Subtype-specific expression and genetic alterations of the chemokinereceptor gene CXCR4 in medulloblastomas.
Recent findings indicate that the chemokine receptor Cxcr4 is essential for normal development of the cerebellar cortex. As medulloblastomas (MBs), the most common malignant brain tumors of childhood, are believed to arise from neuronal cerebellar precursors, we asked whether there is a potential role for Cxcr4 in the pathogenesis of MB. RT-PCR and immunohistochemistry revealed expression of Cxcr4 in different variants of MBs. Whereas 18/20 classic MBs showed very low levels of CXCR4 mRNA, high amounts were expressed in 17/18 desmoplastic and 6/7 extensively nodular MBs. In addition, a significant correlation of high CXCR4 mRNA levels and presence of the neurotrophin receptor p75NTR or expression of ATOH1 and GLI1 suggests that CXCR4 is a reliable marker for tumors derived from the cerebellar external granular layer. Because Cxcr4 is important for migration and cell cycle control of granular precursors, we screened for mutations in the coding region by SSCP and gene sequencing. In a series of 90 MBs and 8 MB cell lines, we found one germline and one somatic mutation resulting in amino acid substitutions in the first (Ile53Leu) and second (Asp97Asn) transmembrane regions, respectively. These data suggest that Cxcr4 may be involved in the pathogenesis of MBs.
Schüller
Ulrich
U
Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
Koch
Arend
A
Hartmann
Wolfgang
W
Garrè
Maria L
ML
Goodyer
Cynthia G
CG
Cama
Armando
A
Sörensen
Niels
N
Wiestler
Otmar D
OD
Pietsch
Torsten
T
D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D051792:Basic Helix-Loop-Helix Proteins; D002528:Cerebellar Neoplasms / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D008527:Medulloblastoma / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D018807:Polymorphism, Single-Stranded Conformational; D012313:RNA / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D020800:Receptor, Nerve Growth Factor; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000071676:Zinc Finger Protein GLI1
D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D012313:RNA; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; D019718:Receptors, CXCR4; D017475:Receptors, Nerve Growth Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C500942:ATOH1 protein, human