Subtype-specific expression and genetic alterations of the chemokinereceptor gene CXCR4 in medulloblastomas

Int J Cancer. 2005 Oct 20;117(1):82-9. doi: 10.1002/ijc.21116.

Abstract

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.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Substitution
  • Basic Helix-Loop-Helix Transcription Factors
  • Cerebellar Neoplasms / classification
  • Cerebellar Neoplasms / genetics*
  • Cerebellar Neoplasms / metabolism
  • Child
  • Child, Preschool
  • DNA / genetics
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Infant
  • Medulloblastoma / classification
  • Medulloblastoma / genetics*
  • Medulloblastoma / metabolism
  • Middle Aged
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Polymorphism, Single-Stranded Conformational
  • RNA / genetics
  • RNA, Messenger / analysis
  • Receptor, Nerve Growth Factor
  • Receptors, CXCR4 / genetics*
  • Receptors, CXCR4 / metabolism
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trans-Activators
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Zinc Finger Protein GLI1

Substances

  • ATOH1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • Nerve Tissue Proteins
  • Oncogene Proteins
  • RNA, Messenger
  • Receptor, Nerve Growth Factor
  • Receptors, CXCR4
  • Receptors, Nerve Growth Factor
  • Trans-Activators
  • Transcription Factors
  • Zinc Finger Protein GLI1
  • RNA
  • DNA