No evidence for involvement of SDHD in neuroblastoma pathogenesis

BACKGROUND: Deletions in the long arm of chromosome 11 are observed in a subgroup of advanced stage neuroblastomas with poor outcome. The deleted region harbours the tumour suppressor gene SDHD that is frequently mutated in paraganglioma and pheochromocytoma, which are, like neuroblastoma, tumours originating from the neural crest. In this study, we sought for evidence for involvement of SDHD in neuroblastoma. METHODS: SDHD was investigated on the genome, transcriptome and proteome level using mutation screening, methylation specific PCR, real-time quantitative PCR based homozygous deletion screening and mRNA expression profiling, immunoblotting, functional protein analysis and ultrastructural imaging of the mitochondria. RESULTS: Analysis at the genomic level of 67 tumour samples and 37 cell lines revealed at least 2 bona-fide mutations in cell lines without allelic loss at 11q23: a 4bp-deletion causing skip of exon 3 resulting in a premature stop codon in cell line N206, and a Y93C mutation in cell line NMB located in a region affected by germline SDHD mutations causing hereditary paraganglioma. No evidence for hypermethylation of the SDHD promotor region was observed, nor could we detect homozygous deletions. Interestingly, SDHD mRNA expression was significantly reduced in SDHD mutated cell lines and cell lines with 11q allelic loss as compared to both cell lines without 11q allelic loss and normal foetal neuroblast cells. However, protein analyses and assessment of mitochondrial morphology presently do not provide clues as to the possible effect of reduced SDHD expression on the neuroblastoma tumour phenotype. CONCLUSIONS: Our study provides no indications for 2-hit involvement of SDHD in the pathogenesis of neuroblastoma. Also, although a haplo-insufficient mechanism for SDHD involvement in advanced stage neuroblastoma could be considered, the present data do not provide consistent evidence for this hypothesis

Placental Types and Effective Perinatal Management of Vasa Previa: Lessons from 55 Cases in a Single Institution

Background: We aimed to identify clinical characteristics and outcomes for each placental type of vasa previa (VP). Methods: Placental types of vasa previa were defined as follows: Type 1, vasa previa with velamentous cord insertion and non-type 1, vasa previa with a multilobed or succenturiate placenta and vasa previa with vessels branching out from the placental surface and returning to the placental cotyledons. Results: A total of 55 cases of vasa previa were included in this study, with 35 cases of type 1 and 20 cases of non-type 1. Vasa previa with type 1 showed a significantly higher association with assisted reproductive technology, compared with non-type 1 (p = 0.024, 60.0% and 25.0%, respectively). The diagnosis was significantly earlier in the type 1 group than in the non-Type 1 group (p = 0.027, 21.4 weeks and 28.6 weeks, respectively). Moreover, the Ward technique for anterior placentation to avoid injury of the placenta and/or fetal vessels was more frequently required in non-type 1 cases (p < 0.001, 60.0%, compared with 14.3% for type 1). Conclusion: The concept of defining placental types of vasa previa will provide useful information for the screening of this serious complication, improve its clinical management and operative strategy, and achieve more preferable perinatal outcomes