Summary Medulloblastoma is an aggressively-growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and displays tremendous biological and clinical heterogeneity1. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently discriminated2,3. WNT tumours, displaying activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens4. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis2. Group 3 & 4 tumours are molecularly less well-characterised, and also present the greatest clinical challenges2,3,5. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs. Tetraploidy was identified as a frequent early event in Group 3 & 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA-sequencing confirmed these alterations, and revealed the expression of the first medulloblastoma fusion genes. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 & 4 patients.

Congenital dyserythropoietic anemias (CDAs) constitute a rare group of inherited red-blood-cell disorders associated with dysplastic changes in late erythroid precursors. CDA type I (CDAI [MIM 224120], gene symbol CDAN1) is characterized by erythroid pathological features such as internuclear chromatin bridges, spongy heterochromatin, and invagination of the nuclear membrane, carrying cytoplasmic organelles into the nucleus. A cluster of 45 highly inbred Israeli Bedouin with CDAI enabled the mapping of the CDAN1 disease gene to a 2-Mb interval, now refined to 1.2 Mb, containing 15 candidate genes on human chromosome 15q15 (Tamary et al. 1998). After the characterization and exclusion of 13 of these genes, we identified the CDAN1 gene through 12 different mutations in 9 families with CDAI. This 28-exon gene, which is transcribed ubiquitously into 4738 nt mRNA, was reconstructed on the basis of gene prediction and homology searches. It encodes codanin-1, a putative o-glycosylated protein of 1,226 amino acids, with no obvious transmembrane domains. Codanin-1 has a 150-residue amino-terminal domain with sequence similarity to collagens and two shorter segments that show weak similarities to the microtubule-associated proteins, MAP1B (neuraxin) and synapsin. These findings, and the cellular phenotype, suggest that codanin-1 may be involved in nuclear envelope integrity, conceivably related to microtubule attachments. The specific mechanisms by which codanin-1 underlies normal erythropoiesis remain to be elucidated.

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Identification of stigma experiences and appropriate support may be crucial to enhancing psychological adjustment and quality of life in children with facial disfigurement.

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Two human neuroblastoma (NB) cell lines, SH-SY5Y and Kelly, were found to express the gene for erythropoietin (EPO) in an oxygen (O 2 )-dependent manner. However, NB cells had maximal production of EPO with lower partial pressure of O 2 values than the well-characterized hepatoma cell line HepG2. This maximal EPO expression was preceded by accumulation of the O 2 -sensitive ␣ subunit of the heterodimeric transcription-factor complex hypoxia-inducible factor 1 (HIF-1). Western blot analysis revealed that the amount of the ␤ subunit of HIF-1, identical to aryl hydrocarbon receptor nuclear translocator 1 (ARNT1), and the homolog ARNT2 increased in nuclear extracts from SH-SY5Y cells exposed to anoxia. In neuronal cells, ARNT1 and ARNT2 can form a heterodimer with HIF-1␣, generating a functional HIF-1 complex. Using the hypoxia response element of the human EPO enhancer, we conducted electrophoretic mobility shift assays that showed accumulation and binding of HIF-1 complexes containing both ARNT1 and ARNT2 in NB cells. In addition to the HIF-1 complex, hepatocyte nuclear factor 4␣ (HNF4␣) was found to be indispensable for hypoxiainduced EPO gene expression in hepa- IntroductionHypoxia-inducible expression of the glycoprotein hormone erythropoietin (EPO) is part of the body's response to hypoxia, which includes up-regulation of oxygen (O 2 )-dependent genes involved in vascular tone and growth, metabolic adaptation, and O 2 delivery. 1,2 EPO is produced primarily by the kidneys and liver, but EPO gene expression has also been found in several other tissues, including brain tissue, 3 breast cancer cells, 4 female genital tract tissues, 5 and rat Sertoli cells. 6 EPO gene expression is regulated by the heterodimeric transcription-factor complex hypoxia-inducible factor 1 (HIF-1), which is composed of a 120-kDa O 2 -regulated ␣ subunit and a 91-to 94-kDa constitutively expressed ␤ subunit. 7 Under normoxic conditions, HIF-1␣ is posttranslationally hydroxylated at proline residues 402 and 564, 8 which tags the protein for ubiquitination by the E3 ubiquitin ligase complex containing the von Hippel-Lindau tumor-suppressor protein. 9,10 Subsequently, HIF-1␣ protein is rapidly degraded by the proteasome system. 11 Under hypoxic conditions, the ␣ subunit is stabilized because of the lack of proline hydroxylation and accumulates. Stabilized HIF-1␣ translocates into the nucleus and forms an HIF-1 complex with the almost ubiquitously expressed HIF-1␤ (identical to aryl hydrocarbon receptor nuclear translocator 1 [ARNT1]). The HIF-1 complex binds to hypoxia response elements (HREs) found in enhancers or promoters of hypoxia-inducible genes. 12 In addition to ARNT1, kidney and neuronal cells express the ARNT1 homolog ARNT2, which can form a functional HIF complex with HIF-1␣. 13 The HIF-1 binding site (HBS) in the 3Ј EPO enhancer is one of 3 sites that are important for hypoxia-induced EPO gene transcription. 14 The HBS is the most upstream element and is followed by a 4-base-pair (bp) CACA repeat and finally a direct repeat of ...

FDG-PET is a sensitive and specific method for the detection of BM involvement in pediatric HL. The sensitivity of a BMB appears compromised by the focal pattern of BM involvement. Thus, FDG-PET may safely be substituted for a BMB in routine staging procedures.

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