Mutations in PIK3CAare infrequent in neuroblastoma

Dam, Vincent van; Morgan, Brian T; Mazánek, Pavel; Hogarty, Michael D.

doi:10.1186/1471-2407-6-177

Cited by 29 publications

(21 citation statements)

References 36 publications

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“…Gain of function of the a subunit is common in human cancers by overexpression or mutations . In our NB tumour material, we could not identify any mutations in the PIK3CA gene (data not shown) and Dam et al (2006) have reported only infrequent mutations in their NB material. The PI3 kinases are generally considered to function as oncogenes.…”

Section: Discussionmentioning

confidence: 59%

Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours

et al. 2007

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Chromosome 1p is frequently deleted in neuroblastoma (NB) tumours. The commonly deleted region has been narrowed down by loss of heterozygosity studies undertaken by different groups. Based on earlier mapping data, we have focused on a region on 1p36 (chr1: 7 765 595 -11 019 814) and performed an analysis of 30 genes by exploring features such as epigenetic regulation, that is DNA methylation and histone deacetylation, mutations at the DNA level and mRNA expression. Treatment of NB cell lines with the histone deacetylase inhibitor trichostatin A led to increased gene transcription of four of the 30 genes, ERRFI1 (MIG-6), PIK3CD, RBP7 (CRBPIV) and CASZ1, indicating that these genes could be affected by epigenetic downregulation in NBs. Two patients with nonsynonymous mutations in the PIK3CD gene were detected. One patient harboured three variations in the same exon, and p.R188W. The other patient had the variation p.M655I. In addition, synonymous variations and one variation in an intronic sequence were also found. The mRNA expression of this gene is downregulated in unfavourable, compared to favourable, NBs. One nonsynonymous mutation was also identified in the ERRFI1 gene, p.N343S, and one synonymous. None of the variations above were found in healthy control individuals. In conclusion, of the 30 genes analysed, the PIK3CD gene stands out as one of the most interesting for further studies of NB development and progression.

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Section: Discussionmentioning

confidence: 59%

Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours

et al. 2007

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“…Therefore, the effect on kinase activity of these mutations is unknown. (24) We did not identify any PIK3CA mutations in our larger set of NB cases.…”

Section: Discussionmentioning

confidence: 72%

Oncogene Mutation Profiling of Pediatric Solid Tumors Reveals Significant Subsets of Embryonal Rhabdomyosarcoma and Neuroblastoma with Mutated Genes in Growth Signaling Pathways

Shukla

Ameur

Yılmaz

et al. 2012

Clinical Cancer Research

205

175

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Compared to the numerous broad screens for oncogene mutations in adult cancers, very few have been performed in pediatric solid tumors. To identify novel mutations and potential therapeutic targets in pediatric cancers, we performed a high-throughput Sequenom-based analysis in large sets of several major pediatric solid cancers, including neuroblastoma (NB), Ewing sarcoma (ES), rhabdomyosarcoma (RMS), and desmoplastic small round cell tumor (DSRCT). Experimental Design We designed a highly multiplexed Sequenom-based assay to interrogate 275 recurrent mutations across 29 genes. Genomic DNA was extracted from 192 NB, 75 ES, 89 RMS, and 24 DSRCT samples. All mutations were verified by Sanger sequencing. Results Mutations were identified in 13% of NB samples, 4% of ES samples, 21.1% of RMS samples, and no DSRCT samples. ALK mutations were present in 10.4% of NB samples. The remainder of NB mutations involved the BRAF, RAS, and MAP2K1 genes and were absent in samples harboring ALK mutations. Mutations were more common in embryonal RMS (ERMS) samples (28.3%) than alveolar RMS (ARMS) (3.5%). In addition to previously identified RAS and FGFR4 mutations, we report for the first time PIK3CA and CTNNB1 (Beta-Catenin) mutations in 4.9% and 3.3% of ERMS, respectively. Conclusions In ERMS, ES, and NB, we identified novel occurrences of several oncogene mutations recognized as drivers in other cancers. Overall, NB and ERMS contain significant subsets of cases with non-overlapping mutated genes in growth signaling pathways. Tumor profiling can identify a subset of pediatric solid tumor patients as candidates for kinase inhibitors or RAS-targeted therapies.

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“…16). PI3K signaling is not generally hyperactivated by PTEN or PIK3CA deletions or mutations in neuroblastoma (29,30), and, as shown in Supplementary Fig. S2A, PTEN protein was expressed in all the neuroblastoma cell lines studied.…”

Section: Pi3k Differentially Regulates Hif1a and Hif2a Protein Expresmentioning

confidence: 73%

PI3K–mTORC2 but not PI3K–mTORC1 Regulates Transcription of HIF2A/EPAS1 and Vascularization in Neuroblastoma

et al. 2015

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Hypoxia-inducible factor (HIF) is a master regulator of cellular responses to oxygen deprival with a critical role in mediating the angiogenic switch in solid tumors. Differential expression of the HIF subunits HIF1a and HIF2a occurs in many human tumor types, suggesting selective implications to biologic context. For example, high expression of HIF2a that occurs in neuroblastoma is associated with stem cell-like features, disseminated disease, and poor clinical outcomes, suggesting pivotal significance for HIF2 control in neuroblastoma biology. In this study, we provide novel insights into how HIF2a expression is transcriptionally controlled by hypoxia and how this control is abrogated by inhibition of insulin-like growth factor-1R/INSR-driven phosphoinositide 3-kinase (PI3K) signaling. Reducing PI3K activity was sufficient to decrease HIF2a mRNA and protein expression in a manner with smaller and less vascularized tumors in vivo. PI3K-regulated HIF2A mRNA expression was independent of Akt or mTORC1 signaling but relied upon mTORC2 signaling. HIF2A mRNA was induced by hypoxia in neuroblastoma cells isolated from metastatic patient-derived tumor xenografts, where HIF2A levels could be reduced by treatment with PI3K and mTORC2 inhibitors. Our results suggest that targeting PI3K and mTORC2 in aggressive neuroblastomas with an immature phenotype may improve therapeutic efficacy.

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Mutations in PIK3CAare infrequent in neuroblastoma

Cited by 29 publications

References 36 publications

Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours

Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours

Oncogene Mutation Profiling of Pediatric Solid Tumors Reveals Significant Subsets of Embryonal Rhabdomyosarcoma and Neuroblastoma with Mutated Genes in Growth Signaling Pathways

PI3K–mTORC2 but not PI3K–mTORC1 Regulates Transcription of HIF2A/EPAS1 and Vascularization in Neuroblastoma

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