Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
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Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%). Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization. In addition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours.
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PMID:Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. 2236 37

Epithelioid glioblastoma (eGBM) and pleomorphic xanthoastrocytoma (PXA) with anaplastically transformed foci (ePXA) show overlapping features. Eleven eGBMs and 5 ePXAs were reviewed and studied immunohistochemically. Fluorescence in situ hybridization for EGFR amplification, PTEN deletion and ODZ3 deletion was also performed, with Ilumina 450 methylome analysis obtained in five cases. The average age for eGBM was 30.9 (range 2-79) years, including five pediatric cases and a M : F ratio of 4.5. The ePXA patients had a M : F ratio of 4 and averaged 21.2 (range 10-38) years in age, including two pediatric cases. Six eGBMs and two ePXAs recurred (median recurrence interval of 12 and 3.3 months, respectively). All tumors were composed of solid sheets of loosely cohesive, "melanoma-like" cells with only limited infiltration. ePXAs showed lower grade foci with classic features of PXA. Both tumor types showed focal expression of epithelial and glial markers, retained INI1 and BRG1 expression, occasional CD34 positivity, and lack of mutant IDH1 (R132H) immunoreactivity. BRAF V600E mutation was present in four eGBMs and four ePXAs. ODZ3 deletion was detected in seven eGBMs and two ePXAs. EGFR amplification was absent. Methylome analysis showed that one ePXA and one eGBM clustered with PXAs, one eGBM clustered with low-grade gliomas, and two eGBMs clustered with pediatric-type glioblastomas. Common histologic, immunohistochemical, molecular and clinical features found in eGBM and ePXA suggest that they are closely related or the same entity. If the latter is true, the nomenclature and WHO grading remains to be resolved.
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PMID:Epithelioid Glioblastomas and Anaplastic Epithelioid Pleomorphic Xanthoastrocytomas--Same Entity or First Cousins? 2623 27

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. Alveolar (ARMS) and embryonal (ERMS) histologies predominate, but rare cases are classified as spindle cell/sclerosing (SRMS). For treatment stratification, RMS is further subclassified as fusion-positive (FP-RMS) or fusion-negative (FN-RMS), depending on whether a gene fusion involving PAX3 or PAX7 is present or not. We investigated 19 cases of pediatric RMS using high resolution single-nucleotide polymorphism (SNP) array. FP-ARMS displayed, on average, more structural rearrangements than ERMS; the single FN-ARMS had a genomic profile similar to ERMS. Apart from previously known amplification (e.g., MYCN, CDK4, and MIR17HG) and deletion (e.g., NF1, CDKN2A, and CDKN2B) targets, amplification of ERBB2 and homozygous loss of ASCC3 or ODZ3 were seen. Combining SNP array with cytogenetic data revealed that most cases were polyploid, with at least one case having started as a near-haploid tumor. Further bioinformatic analysis of the SNP array data disclosed genetic heterogeneity, in the form of subclonal chromosomal imbalances, in five tumors. The outcome was worse for patients with FP-ARMS than ERMS or FN-ARMS (6/8 vs. 1/9 dead of disease), and the only children with ERMS showing intratumor diversity or with MYOD1 mutation-positive SRMS also died of disease. High resolution SNP array can be useful in evaluating genomic imbalances in pediatric RMS.
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PMID:Genetic heterogeneity in rhabdomyosarcoma revealed by SNP array analysis. 2648 21