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Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors
Author(s) -
Koch Arend,
Waha Anke,
Tonn Jörg C.,
Sörensen Nils,
Berthold Frank,
Wolter Marietta,
Reifenberger Julia,
Hartmann Wolfgang,
Friedl Waltraut,
Reifenberger Guido,
Wiestler Otmar D.,
Pietsch Torsten
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1342
Subject(s) - biology , missense mutation , medulloblastoma , wnt signaling pathway , exon , germline mutation , genetics , germline , somatic cell , mutation , gene , cancer research , microbiology and biotechnology
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 β‐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 β‐ 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‐3β phosphorylation sites of the degradation targeting box of β‐catenin and resulted in nuclear β‐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. © 2001 Wiley‐Liss, Inc.