Rare Occurrence of PHOX2b Mutations in Sporadic Neuroblastomas

Serra, Alexandre; Häberle, Beate; König, Inke R.; Kappler, Roland; Suttorp, Meinolf; Schackert, Hans K.; Roesner, D.; Fitze, Guido

doi:10.1097/mph.0b013e3181772141

Cited by 20 publications

(15 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our finding of small cell lung carcinoma pathways enrichment associated with GBM was consistent with the multiple studies that have identified commonalities among these cancers [72]. The most enriched biological process among the AEU genes associated with GBM survival included regulation of small GTPase mediated signal transduction (RSGST), and neuron development that has been associated with neuroblastoma [73]. The enrichment of biological adhesion confirms our focal adhesion results.…”

Section: Resultssupporting

confidence: 89%

Identification and characterization of alternative exon usage linked glioblastoma multiforme survival

et al. 2012

View full text Add to dashboard Cite

BackgroundAlternative exon usage (AEU) is an important component of gene regulation. Exon expression platforms allow the detection of associations between AEU and phenotypes such as cancer. Numerous studies have identified associations between gene expression and the brain cancer glioblastoma multiforme (GBM). The few consistent gene expression biomarkers of GBM that have been reported may be due to the limited consideration of AEU and the analytical approaches used. The objectives of this study were to develop a model that accounts for the variations in expression present between the exons within a gene and to identify AEU biomarkers of GBM survival.MethodsThe expression of exons corresponding to 25,403 genes was related to the survival of 250 individuals diagnosed with GBM in a training data set. Genes exhibiting AEU in the training data set were confirmed in an independent validation data set of 78 patients. A hierarchical mixed model that allows the consideration of covariation between exons within a gene and of the effect of the epidemiological characteristics of the patients was developed to identify associations between exon expression and patient survival. This general model describes all three possible scenarios: multi-exon genes with and without AEU, and single-exon genes.ResultsAEU associated with GBM survival was identified on 2477 genes (P-value < 5.0E-04 or FDR-adjusted P-value < 0.05). G-protein coupled receptor 98 (Gpr98) and epidermal growth factor (Egf) were among the genes exhibiting AEU with 30 and 9 exons associated with GBM survival, respectively. Pathways enriched among the AEU genes included focal adhesion, ECM-receptor interaction, ABC transporters and pathways in cancer. In addition, 24 multi-exon genes without AEU and 8 single-exon genes were associated with GBM survival (FDR-adjusted P-value < 0.05).ConclusionsThe inferred patterns of AEU were consistent with in silico AS models. The hierarchical model used offered a flexible and simple way to interpret and identify associations between survival that accommodates multi-exon genes with or without AEU and single exon genes. Our results indicate that differential expression of AEU could be used as biomarker for GBM and potentially other cancers.

show abstract

Section: Resultssupporting

confidence: 89%

Identification and characterization of alternative exon usage linked glioblastoma multiforme survival

et al. 2012

View full text Add to dashboard Cite

show abstract

“…c.1810T allele has been detected in 8.7% of sporadic tumours, which is a similar frequency to the mutations observed for the two known familial NB susceptibility genes ( ALK = 12.4%, PHOX2b = 4.3%) [24,25]. Presence of c.1810T allele correlated with inferior 5-year OS and EFS and with more frequent relapse of the disease.…”

Section: Discussionsupporting

confidence: 66%

“…Studies of familial cases of NB allowed for identification of two NB susceptibility genes ( ALK , PHOX2B ) yet their mutations are present in about 10% of sporadic tumours [24,25]. Inability to identify a single major specific tumour suppressor gene as a triggering agent of NB initiation [2] points toward the role played by genes involved in normal noradrenergic development.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, even though the study was aimed at detection of constitutional mutations, since the available material collected by both national tissue banks consisted of primary NB tumours, tumour DNA was analysed. A similar approach is applied in studies of other researchers [24,25] because tumour biology is the area of primary interest from the clinical point of view. Besides, tumour samples are the routine material available for molecular assessment in research setting.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

c.1810C>T Polymorphism of NTRK1Gene is associated with reduced Survival in Neuroblastoma Patients

et al. 2009

View full text Add to dashboard Cite

BackgroundTrkA (encoded by NTRK1 gene), the high-affinity tyrosine kinase receptor for neurotrophins, is involved in neural crest cell differentiation. Its expression has been reported to be associated with a favourable prognosis in neuroblastoma. Therefore, the entire coding sequence of NTRK1 gene has been analysed in order to identify mutations and/or polymorphisms which may alter TrkA receptor expression.MethodsDNA was extracted from neuroblastomas of 55 Polish and 114 Italian patients and from peripheral blood leukocytes of 158 healthy controls. Denaturing High-Performance Liquid Chromatography (DHPLC) and Single-Strand Conformation Polymorphism (SSCP) analysis were used to screen for sequence variants. Genetic changes were confirmed by direct sequencing and correlated with biological and clinical data.ResultsThree previously reported and nine new single nucleotide polymorphisms were detected. c.1810C>T polymorphism present in 8.7% of cases was found to be an independent marker of disease recurrence (OR = 13.3; p = 0.009) associated with lower survival rates (HR = 4.45 p = 0.041). c.1810C>T polymorphism's unfavourable prognostic value was most significant in patients under 18 months of age with no MYCN amplification (HR = 26; p = 0.008). In-silico analysis of the c.1810C>T polymorphism suggests that the substitution of the corresponding amino acid residue within the conservative region of the tyrosine kinase domain might theoretically interfere with the functioning of the TrkA protein.ConclusionsNTRK1 c.1810C>T polymorphism appears to be a new independent prognostic factor of poor outcome in neuroblastoma, especially in children under 18 months of age with no MYCN amplification.

show abstract

“…These mutations are believed to interfere with the PHOX2B protein's role in promoting nerve cell differentiation. However, germline mutations of PHOX2B accounted for merely 6.4 % of hereditary neuroblastoma cases and were rarely detected in more common sporadic cases of the disease, indicating that the gene was not the major pathogenic gene [17, 19]. …”

Section: Germline Mutations Of Nbmentioning

confidence: 99%

Research progress of neuroblastoma related gene variations

Cao

Jin

et al. 2016

Oncotarget

View full text Add to dashboard Cite

Neuroblastoma, the most common extracranial solid tumor among children, is an embryonal tumor originating from undifferentiated neural crest cell. Neuroblastomas are highly heterogeneous, represented by the wide range of clinical presentations and likelihood of cure, ranging from spontaneous regression to relentless progression despite rigorous multimodal treatments. Approximately, 50% of cases are high-risk with overall survival rates less than 40%. With the efforts to collect large numbers of clinically annotated specimens and the advancements in technologies, researchers have revealed numerous genetic alterations that may drive tumor growth. However, the most lack mutations in genes that are recurrently mutated, which inspires researchers to identify disrupted pathways instead of single mutated genes to unearth biological systems perturbed in neuroblastoma. Stratification of patients and target therapy based on their molecular signatures have been the center of focus. This review provides a comprehensive summary of the recent advances in identification of candidate genes variations, targeted approaches to high-risk neuroblastoma and evaluates the methods utilized for detection, which will provide new avenues to develop therapies and further genetic researches.

show abstract

Rare Occurrence of PHOX2b Mutations in Sporadic Neuroblastomas

Cited by 20 publications

References 22 publications

Identification and characterization of alternative exon usage linked glioblastoma multiforme survival

Identification and characterization of alternative exon usage linked glioblastoma multiforme survival

c.1810C>T Polymorphism of NTRK1Gene is associated with reduced Survival in Neuroblastoma Patients

Research progress of neuroblastoma related gene variations

Contact Info

Product

Resources

About