Johnson R, Wright KD, Gilbertson RJ.. Molecular profiling of pediatric brain tumors: insight into biology and treatment. Curr Oncol Rep 11: 68-72
Departments of Developmental Neurobiology and Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA. Current Oncology Reports
(Impact Factor: 2.89).
02/2009; 11(1):68-72. DOI: 10.1007/s11912-009-0011-9
Recent history has witnessed unparalleled advances in our understanding of tumor biology, owing in large part to the publication of the human genome project. Paired with improvements in microarray technologies, the combination of genetic and expression profiles provides a unique opportunity to further enhance our understanding of the underlying mechanisms that drive tumor growth. Thus, integrated analysis of identified molecular changes with clinical and histologic data may further delineate a new risk stratification system for pediatric brain tumors, allowing more patient-tailored therapy and molecular-based therapeutic interventions.
Available from: Caterina Baldi
- "pHGGs are less frequent than adult high-grade gliomas (aHGGs);3,4 nevertheless, they account for 15% of all pediatric brain tumors and show, for the most part, a similarly ominous clinical outcome with high mortality and morbidity.2 Recent studies based on high-resolution analysis of copy number and gene expression signatures demonstrated that pediatric and adult HGGs represent a related spectrum of disease distinguished by differences in the frequency of copy number changes, specific gene expression signatures, and IDH1 hotspot mutations only in aHGG.5–7 In pHGG, several genes within the p53, PI3K/RTK, and RB pathways are targeted by focal gain or loss, but other alterations were found only at low frequency except for PDGFRA and CDKN2A.8,9 "
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High-grade gliomas (HGGs) account for 15% of all pediatric brain tumors and are a leading cause of cancer-related mortality and morbidity. Pediatric HGGs (pHGGs) are histologically indistinguishable from their counterpart in adulthood. However, recent investigations indicate that differences occur at the molecular level, thus suggesting that the molecular path to gliomagenesis in childhood is distinct from that of adults. MicroRNAs (miRNAs) have been identified as key molecules in gene expression regulation, both in development and in cancer. miRNAs have been investigated in adult high-grade gliomas (aHGGs), but scant information is available for pHGGs.Methods
We explored the differences in microRNAs between pHGG and aHGG, in both fresh-frozen and paraffin-embedded tissue, by high-throughput miRNA profiling. We also evaluated the biological effects of miR-17-92 cluster silencing on a pHGG cell line.ResultsComparison of miRNA expression patterns in formalin versus frozen specimens resulted in high correlation between both types of samples. The analysis of miRNA profiling revealed a specific microRNA pattern in pHGG with an overexpression and a proliferative role of the miR-17-92 cluster. Moreover, we highlighted a possible quenching function of miR-17-92 cluster on its target gene PTEN, together with an activation of tumorigenic signaling such as sonic hedgehog in pHGG.Conclusions
Our results suggest that microRNA profiling represents a tool to distinguishing pediatric from adult HGG and that miR-17-92 cluster sustains pHGG.
Available from: Carole Cummins
- "Diagnosis remains the most important determinant of treatment and whilst this is available from a major surgical resection in many cases, in others, a diagnosis is made from a small biopsy or on clinical and imaging appearances alone. Molecular tests on the tumour tissue are providing new prognostic markers4,5 and these are starting to be incorporated into clinical management strategies. Novel non-invasive biomarkers would add to this improved tumour characterisation and would have the advantage of being available for cases where surgery was not performed. "
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Brain tumours cause the highest mortality and morbidity rate of all childhood tumour groups and new methods are required to improve clinical management. 1H magnetic resonance spectroscopy (MRS) allows non-invasive concentration measurements of small molecules present in tumour tissue, providing clinically useful imaging biomarkers. The primary aim of this study was to investigate whether MRS detectable molecules can predict the survival of paediatric brain tumour patients.
Patients and methods
Short echo time (30 ms) single voxel 1H MRS was performed on children attending Birmingham Children’s Hospital with a suspected brain tumour and 115 patients were included in the survival analysis. Patients were followed-up for a median period of 35 months and Cox-Regression was used to establish the prognostic value of individual MRS detectable molecules. A multivariate model of survival was also investigated to improve prognostic power.
Lipids and scyllo-inositol predicted poor survival whilst glutamine and N-acetyl aspartate predicted improved survival (p < 0.05). A multivariate model of survival based on three MRS biomarkers predicted survival with a similar accuracy to histologic grading (p < 5e–5). A negative correlation between lipids and glutamine was found, suggesting a functional link between these molecules.
MRS detectable biomolecules have been identified that predict survival of paediatric brain tumour patients across a range of tumour types. The evaluation of these biomarkers in large prospective studies of specific tumour types should be undertaken. The correlation between lipids and glutamine provides new insight into paediatric brain tumour metabolism that may present novel targets for therapy.
Available from: Thomas J Anchordoquy
- "This survival rate comes at significant cognitive, behavioral, and general physical cost to the surviving patients, as the developmental sequelae are often devastating , . Clearly, we need a better understanding of the biology of these tumors, and while great efforts have gone into the molecular genetics of medulloblastomas , one area that remains completely unstudied is that of medulloblastoma exosomes. "
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ABSTRACT: Medulloblastomas are the most prevalent malignant pediatric brain tumors. Survival for these patients has remained largely the same for approximately 20 years, and our therapies for these cancers cause significant health, cognitive, behavioral and developmental sequelae for those who survive the tumor and their treatments. We obviously need a better understanding of the biology of these tumors, particularly with regard to their migratory/invasive behaviors, their proliferative propensity, and their abilities to deflect immune responses. Exosomes, virus-sized membrane vesicles released extracellularly from cells after formation in, and transit thru, the endosomal pathway, may play roles in medulloblastoma pathogenesis but are as yet unstudied in this disease. Here we characterized exosomes from a medulloblastoma cell line with biochemical and proteomic analyses, and included characterization of patient serum exosomes. Further scrutiny of the proteomic data suggested functional properties of the exosomes that are relevant to medulloblastoma tumor biology, including their roles as proliferation stimulants, their activities as attractants for tumor cell migration, and their immune modulatory impacts on lymphocytes. Aspects of this held true for exosomes from other medulloblastoma cell lines as well. Additionally, pathway analyses suggested a possible role for the transcription factor hepatocyte nuclear factor 4 alpha (HNF4A); however, inhibition of the protein's activity actually increased D283MED cell proliferation/clonogenecity, suggesting that HNF4A may act as a tumor suppressor in this cell line. Our work demonstrates that relevant functional properties of exosomes may be derived from appropriate proteomic analyses, which translate into mechanisms of tumor pathophysiology harbored in these extracellular vesicles.
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