An investigation of WNT pathway activation and association with survival in central nervous system primitive neuroectodermal tumours (CNS PNET)

Abstract

Central nervous system primitive neuroectodermal tumours (CNS PNET) are high-grade, predominantly paediatric, brain tumours. Previously they have been grouped with medulloblastomas owing to their histological similarities. The WNT/b-catenin pathway has been implicated in many tumour types, including medulloblastoma. On pathway activation b-catenin (CTNNB1) translocates to the nucleus, where it induces transcription of target genes. It is commonly upregulated in tumours by mutations in the key pathway components APC and CTNNB1. WNT/b-catenin pathway status was investigated by immunohistochemical analysis of CTNNB1 and the pathway target cyclin D1 (CCND1) in 49 CNS PNETs and 46 medulloblastomas. The mutational status of APC and CTNNB1 (b-catenin) was investigated in 33 CNS PNETs and 22 medulloblastomas. CTNNB1 nuclear localisation was seen in 36% of CNS PNETs and 27% of medulloblastomas. A significant correlation was found between CTNNB1 nuclear localisation and CCND1 levels. Mutations in CTNNB1 were identified in 4% of CNS PNETs and 20% of medulloblastomas. No mutations were identified in APC. A potential link between the level of nuclear staining and a better prognosis was identified in the CNS PNETs, suggesting that the extent of pathway activation is linked to outcome. The results suggest that the WNT/b-catenin pathway plays an important role in the pathogenesis of CNS PNETs. However, activation is not caused by mutations in CTNNB1 or APC in the majority of CNS PNET cases.

Identification of c-myc-dependent proteins in the medulloblastoma cell line D425Med

“…Amongst the best described are (1) proto-oncogene MYC (c-myc) mRNA expression (2) copy number aberrations of chromosomes 17q, 6q, c-myc and n-myc, (3) ErbB2 and ErbB4 receptor expression, (4) neurotrophin receptor TrkC expression, (5) Beta-catenin mutation and nuclear accumulation and (6) p53 mutation (Das et al 2009;Ellison et al 2005;Fattet et al 2009;Gilbertson et al 2001;Grotzer et al 2001;Herms et al 2000;Pfister et al 2009;Ray et al 2004;Rogers et al 2009;Rutkowski et al 2007;von Hoff et al 2010). Low c-myc mRNA expression was identified as an independent predictor of a favourable survival outcome (Grotzer et al 2001Herms et al 2000).…”

Norcantharidin impairs medulloblastoma growth by inhibition of Wnt/β-catenin signaling

“…In addition to characterizing an independent subgroup of genomic aberrations, Wnt-activated tumors occur in 10% to 15% of MBs and Wnt has recently been described as a marker of favorable patient outcome [10,[15][16][17]. Because of this wide involvement of Wnt signaling in MB, compounds targeting Wnt signaling will not only make treatment more effective, but also enable reduction of neurotoxic therapy.…”

Pleiotropic role forMYCNin medulloblastoma

“…As some MB express markers normally found in ventricular zone stem cells, these cells could represent cells of origin for some MB tumors (Eberhart 2007). Wnt signaling abnormalities were described recently in ;15% of MB, corresponding to a minority of tumors with classic pathology and defining a subset of patients with improved outcome (Clifford et al 2006;Kool et al 2008;Rogers et al 2009). Few molecular hallmarks and signaling abnormalities have been identified as drivers for the majority of aggressive tumors, which show classic or LCA pathology.…”