Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amplified region (amplicon) around MLL gene is closely linked to the 11q23.3 commonly deleted region of neuroblastoma, which includes cancer-associated genes such as PHLDB1 (LL5A), BCL9L, FOXN5 (FOXR1), CBL, MFRP, and PVRL1 (Nectin) genes. FOXN6 (FOXR2) gene at human chromosome Xp11.21 is generated due to retrotransposition of ancestral Foxn5 gene during evolution. FOXN5 and FOXN6 orthologs share the common domain structure consisting of FN56 and Forhead-box (FOX) domains. Here, we identified and characterized mouse Foxn5 gene by using bioinformatics. Mouse Foxn5, consisting of six exons, was located within mouse genome sequences AC122428.4 and AC125129.5. Foxn5 locus at mouse chromosome 9B was synthenic to rat chromosome 8q22 and human chromosome 11q23.3. Mouse Foxn5 (180 aa) was C-terminally truncated compared with rat Foxn5 and human FOXN5. Mouse 'Foxn5' protein without FOX domain was generated due to a frame shift introduced by germ-line one-base deletion within exon 3. Mouse Foxn5 mRNA was expressed in embryonic germ cells and fertilized eggs. Germ-line mutation of Foxn5 gene in the mouse lineage might lead to divergent scenario of early embryogenesis between mouse and rat through the deregulation of Foxn5 target genes in mouse early embryos, and explain the difficulty in manipulation of rat embryonic stem (ES) cells based on the mouse equivalent system. This is the first report on identification and characterization of mouse Foxn5 gene as well as on species specific germ-line mutation of the Fox family gene.
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PMID:Germ-line mutation of Foxn5 gene in mouse lineage. 1528 1

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.
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PMID:New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. 2691 24

Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. SIGNIFICANCE: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.
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PMID:Sleeping Beauty Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors. 3067 30

Four molecular types of rare central nervous system (CNS) tumors have been recently identified by gene methylation profiling: CNS Neuroblastoma with FOXR2 activation (CNS NB-FOXR2), CNS Ewing Sarcoma Family Tumor with CIC alteration (CNS EFT-CIC), CNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) and CNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). Although they are not represented in 2016 updated WHO classification of CNS tumors, their diagnostic recognition is important because of clinical consequences. We have introduced a diagnostic method based on transcription profiling of tumor specific signature genes from formalin-fixed, paraffin-embedded tumor blocks using NanoString nCounter Technology. Altogether, 14 out of 187 (7.4%) high grade pediatric brain tumors were diagnosed with either of four new CNS categories. Histopathological examination of the tumors confirmed, that they demonstrate a spectrum of morphology mimicking other CNS high grade tumors. However, they also exhibit some suggestive histopathological and immunohistochemical features that allow for a presumptive diagnosis prior to molecular assessment. Clinical characteristics of patients corroborated with the previous findings for CNS EFT-CIC, CNS NB-FOXR2 and CNS HGNET-MN1 patients, with a favorable survival rate for the latter two groups. Among six CNS HGNET-BCOR patients, three patients are long term survivors, suggesting possible heterogeneity within this molecular category of tumors. In summary, we confirmed the effectiveness of NanoString method using a single, multi-gene tumor specific signature and recommend this novel approach for identification of either one of the four newly described CNS tumor entities.
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PMID:Molecular identification of CNS NB-FOXR2, CNS EFT-CIC, CNS HGNET-MN1 and CNS HGNET-BCOR pediatric brain tumors using tumor-specific signature genes. 3265 Aug 33

Central nervous system neuroblastoma with FOXR2 activation (CNS NB FOXR2) has recently been described as a class of brain tumors sharing common genetic events and a highly similar DNA methylation profile. Most of these tumors have previously been diagnosed as primitive neuroectodermal tumor (PNET). Whereas the entity of PNET has been removed from the WHO classification of brain tumors in its current edition, CNS neuroblastoma was kept as an entity, but still lacks any molecular detail. Here, we describe 8 cases of CNS NB FOXR2 focusing on histomorphological and immunohistochemical features and include magnetic resonance imaging (MRI) for 2 of these cases. MRI revealed large supratentorial masses in superficial location with prominent cysts and necrosis, but little edema. Diffusion and enhancement characteristics were variable. Histological analyses showed that most of the cases displayed neuronal differentiation with necrosis, endothelial proliferation, and high vascularity. Immunohistochemistry revealed strong expression of synaptophysin, MAP2, and OLIG2 as well as moderate proliferation. These findings suggest that tumors with the molecular diagnosis of CNS NB FOXR2 may fit well into the WHO entity of CNS neuroblastoma. Our findings may be helpful when establishing an integrated diagnosis and may be indispensable if molecular data are unavailable.
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PMID:Detailed Clinical and Histopathological Description of 8 Cases of Molecularly Defined CNS Neuroblastomas. 3327 Aug 65