Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors

Primitive neuroectodermal tumors (PNETs) represent the most frequent malign ant 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 carr ying germline APC gene mutations, The APC gene encodes a central component of the WNT/wingless developmental signaling pathway, It regulates the level s of cytoplasmic beta -catenin protein that plays a central role in neural development and cell proliferation, We analyzed 87 sporadic PNETs and 10 PN ET cell lines for mutations of the APC gene and beta -catenin (CTNNBI) gene using single strand conformational polymorphism (SSCP) and sequencing anal ysis. We examined the mutation cluster region of APC (codons1255-1641)for g ermline variants and somatic mutations. The medulloblastoma cell line MHH-M ED-2 carried a Glu1317Gln missense germline variant and a sporadic MB sampl e showed a somatic Prol319Leu substitution, Mutational analysis of exon 3 o f CTNNBI uncovered 4 PNETs (4.8%) with somatic missense mutations. These mu tations caused amino acid substitutions in 3 of 80 medulloblastomas (Ser33P he, Ser33Cys and Ser37Cys) and I of 4 supratentorial PNETs (Gly34Val). All mutations affected GSK-3 beta phosphorylation sites of the degradation targ eting box of beta -catenin and resulted in nuclear beta -catenin protein ac cumulation. Deletions of CTNNBI were not detected by PCR amplification with primers spanning exons 1-5, Our data indicate that inappropriate activatio n of the WNT/wingless signaling pathway by mutations of its components may contribute to the pathogenesis of a subset of PNETs, (C) 2001 Wiley-Liss, I nc.