Dataset Information

The role of the WNT/?-catenin pathway in central nervous system primitive neuroectodermal tumours (CNS PNETs).

ABSTRACT: BACKGROUND: Central nervous system primitive neuroectodermal tumours (CNS PNETs) are embryonal tumours occurring predominantly in children. Current lack of knowledge regarding their underlying biology hinders development of more effective treatments. We previously identified WNT/?-catenin pathway activation in one-third of CNS PNETs, which was potentially linked to a better prognosis. In this study, we have extended our cohort, achieving a statistically significant correlation with prognosis. We additionally investigated the biological effects of WNT/?-catenin pathway activation in tumour pathogenesis. METHODS: A total of 42 primary and 8 recurrent CNS PNETs were analysed for WNT/?-catenin pathway status using ?-catenin immunohistochemistry. Genomic copy number and mRNA expression data were analysed to identify a molecular profile linked to WNT/?-catenin pathway activation. RESULTS: Pathway activation was seen in 26% of CNS PNETs and was significantly associated with longer overall survival. Genes displaying a significant difference in expression levels, between tumours with and without WNT/?-catenin pathway activation, included several involved in normal CNS development suggesting aberrant pathway activation may be disrupting this process. CONCLUSION: We have identified WNT/?-catenin pathway status as a marker, which could potentially be used to stratify disease risk for patients with CNS PNET. Gene expression data suggest pathway activation is disrupting normal differentiation in the CNS.

SUBMITTER: Rogers HA

PROVIDER: S-EPMC3670474 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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The role of the WNT/β-catenin pathway in central nervous system primitive neuroectodermal tumours (CNS PNETs).

Rogers H A HA Ward J H JH Miller S S Lowe J J Coyle B B Grundy R G RG

British journal of cancer 20130416 10

<h4>Background</h4>Central nervous system primitive neuroectodermal tumours (CNS PNETs) are embryonal tumours occurring predominantly in children. Current lack of knowledge regarding their underlying biology hinders development of more effective treatments. We previously identified WNT/β-catenin pathway activation in one-third of CNS PNETs, which was potentially linked to a better prognosis. In this study, we have extended our cohort, achieving a statistically significant correlation with progno ...[more]

PMID: 23591193

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Project description:Central nervous system primitive neuroectodermal tumor (CNS PNET) and pineoblastoma are highly malignant embryonal brain tumors with poor prognoses. Current therapies are based on the treatment of pediatric medulloblastoma, even though these tumors are distinct at both the anatomical and molecular level. CNS PNET and pineoblastoma have a worse clinical outcome than medulloblastoma; thus, improved therapies based on an understanding of the underlying biology of CNS PNET and pineoblastoma are needed. To this end, we characterized the genomic alterations of 36 pediatric CNS PNETs and 8 pineoblastomas using Affymetrix single nucleotide polymorphism arrays. Overall, the majority of CNS PNETs contained a greater degree of genomic imbalance than pineoblastomas, with gain of 19p (8 [27.6%] of 29), 2p (7 [24.1%] of 29), and 1q (6 [20.7%] of 29) common events in primary CNS PNETs. Novel gene copy number alterations were identified and corroborated by Genomic Identification of Significant Targets In Cancer (GISTIC) analysis: gain of PCDHGA3, 5q31.3 in 62.1% of primary CNS PNETs and all primary pineoblastomas and FAM129A, 1q25 in 55.2% of primary CNS PNETs and 50% of primary pineoblastomas. Comparison of our GISTIC data with publically available data for medulloblastoma confirmed these CNS PNET-specific copy number alterations. With use of the collection of 5 primary and recurrent CNS PNET pairs, we found that gain of 2p21 was maintained at relapse in 80% of cases. Novel gene copy number losses included OR4C12, 11p11.12 in 48.2% of primary CNS PNETs and 50% of primary pineoblastomas. Loss of CDKN2A/B (9p21.3) was identified in 14% of primary CNS PNETs and was significantly associated with older age among children (P = .05). CADPS, 3p14.2 was lost in 27.6% of primary CNS PNETs and was associated with poor prognosis (P = .043). This genome-wide analysis revealed the marked molecular heterogeneity of CNS PNETs and enabled the identification of novel genes and clinical associations potentially involved in the pathogenesis of these tumors.

Project description:BackgroundEwing sarcoma/PNET is managed with treatment paradigms involving combinations of chemotherapy, surgery, and sometimes radiation. Although the 5-year survival rate of non-metastatic disease approaches 70%, those cases that are metastatic and those that recur have 5-year survival rates of less than 20%. Molecularly targeted treatments offer the potential to further improve treatment outcomes.MethodsA PUBMED search was performed from 1997 to 2011. Published literature that included the topic of the Ewing sarcoma/PNET was also referenced.ResultsInsulin-like growth factor-1 receptor (IGF-1R) antagonists have demonstrated modest single agent efficacy in phase I/II clinical trials in Ewing sarcoma/PNET, but have a strong preclinical rationale. Based on in vitro and animal data, treatment using antisense RNA and cDNA oligonucleotides directed at silencing the EWS-FLI chimera that occurs in most Ewing sarcoma/PNET may have potential therapeutic importance. However drug delivery and degradation problems may limit this therapeutic approach. Protein-protein interactions can be targeted by inhibition of RNA helicase A, which binds to EWS/FLI as part of the transcriptional complex. Tumour necrosis factor related apoptosis inducing ligand induction using interferon has been used in preclinical models. Interferons may be incorporated into future chemotherapeutic treatment paradigms. Histone deacetylase inhibitors can restore TGF-β receptor II allowing TFF-β signalling, which appears to inhibit growth of Ewing sarcoma/PNET cell lines in vitro. Immunotherapy using allogeneic natural killer cells has activity in Ewing sarcoma/PNET cell lines and xenograft models. Finally, cyclin dependent kinase inhibitors such as flavopiridol may be clinically efficacious in relapsed Ewing sarcoma/PNET.ConclusionPreclinical evidence exists that targeted therapeutics may be efficacious in the ESFT. IGF-1R antagonists have demonstrated efficacy in phase I/II clinical trials, although predicting responses remains a challenge. The future treatment of Ewing sarcoma/PNET is likely to be improved by these scientific advances.

Project description:Primitive neuro-ectodermal tumours (PNET) of the supratentorial region are rare, highly malignant embryonal brain tumours affecting young children. Although supratentorial PNET (sPNET) are histologically similar to infratentorial PNET/medulloblastoma, sPNET have more aggressive clinical phenotypes, which suggest sPNET represents distinct biological entities. In contrast to considerable progress in understanding the signalling pathways involved in medulloblastoma, little is known about sPNET pathogenesis. Prior low resolution CGH (comparative genomic hybridization) studies indicate sPNET have frequent genomic imbalances and copy number aberrations (CNAs). To define genes involved in sPNET pathogenesis, we utilized the Affymetrix 250K Nsp SNP (single nucleotide polymorphism) analysis to identify genes targeted by recurrent CNAs in primary human sPNET samples. Copy number analysis was conducted on 39 primary PNET samples. Select target genes were validated by genomic and/or RT-PCR. Our analysis revealed frequent CNA across the sPNET genome, encompassing large and focal chromosome segments, and corroborated previous reports that isochromosome 17q, an abnormality found in ~ 30% of medulloblastoma, is rare in sPNET. Keywords: single nucleotide polymorphism array, disease state analysis A total of 56 primary sPNET samples were collected for this study from The Hospital for Sick Children, John Hopkins University, St. Jude Research Hospital, University of Cambridge, Children’s Hospital Boston, Virginia Commonwealth University, Instituto nazionale per lo studio e la cura dei tumori, and Texas Children’s Hospital, with local Institutional Research Ethics Board approval. Pineoblastoma and rhaboid tumours were specifically excluded, leaving 52 samples, 39 of which had good quality DNA available. These samples, in addition to 28 diploid reference samples (a gift from Dr. S. Scherer, University of Toronto), were analyzed on the Affymetrix GeneChip Mapping 250K Nsp SNP array. Due to sample availability at the time the arrays were run, the diploid reference samples analyzed on the Sty arrays are different from reference samples analyzed on the Nsp arrays.

Dataset Information

The role of the WNT/?-catenin pathway in central nervous system primitive neuroectodermal tumours (CNS PNETs).

Publications

The role of the WNT/β-catenin pathway in central nervous system primitive neuroectodermal tumours (CNS PNETs).

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