title: Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors.
abstract: Primitive neuroectodermal tumors (PNETs) represent the most frequent malignant brain tumors in childhood. The majority of these neoplasms occur in the cerebellum and are classified as medulloblastomas (MB). Most PNETs develop sporadically; however, their incidence is highly elevated in patients carrying germline APC gene mutations. The APC gene encodes a central component of the WNT/wingless developmental signaling pathway. It regulates the levels of cytoplasmic beta-catenin protein that plays a central role in neural development and cell proliferation. We analyzed 87 sporadic PNETs and 10 PNET cell lines for mutations of the APC gene and beta-catenin (CTNNB1) gene using single strand conformational polymorphism (SSCP) and sequencing analysis. We examined the mutation cluster region of APC (codons 1255--1641) for germline variants and somatic mutations. The medulloblastoma cell line MHH-MED-2 carried a Glu1317Gln missense germline variant and a sporadic MB sample showed a somatic Pro1319Leu substitution. Mutational analysis of exon 3 of CTNNB1 uncovered 4 PNETs (4.8%) with somatic missense mutations. These mutations caused amino acid substitutions in 3 of 80 medulloblastomas (Ser33Phe, Ser33Cys and Ser37Cys) and 1 of 4 supratentorial PNETs (Gly34Val). All mutations affected GSK-3 beta phosphorylation sites of the degradation targeting box of beta-catenin and resulted in nuclear beta-catenin protein accumulation. Deletions of CTNNB1 were not detected by PCR amplification with primers spanning exons 1--5. Our data indicate that inappropriate activation of the WNT/wingless signaling pathway by mutations of its components may contribute to the pathogenesis of a subset of PNETs.
authors: Department of Neuropathology, University of Bonn Medical Center; Bonn, Germany.
authors: A
authors: A
authors: Koch
authors: A
authors: A
authors: Waha
authors: J C
authors: JC
authors: Tonn
authors: N
authors: N
authors: Sörensen
authors: F
authors: F
authors: Berthold
authors: M
authors: M
authors: Wolter
authors: J
authors: J
authors: Reifenberger
authors: W
authors: W
authors: Hartmann
authors: W
authors: W
authors: Friedl
authors: G
authors: G
authors: Reifenberger
authors: O D
authors: OD
authors: Wiestler
authors: T
authors: T
authors: Pietsch
mesh_terms: D025601:Adenomatous Polyposis Coli Protein; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D015153:Blotting, Western; D002528:Cerebellar Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D018242:Neuroectodermal Tumors, Primitive / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin