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  • 1
    Abstract: PURPOSE: High messenger RNA (mRNA) expression of the tropomyosin receptor kinase C gene (TrkC) has been associated with favorable survival in medulloblastoma patients. Untested is whether it plays a role through modulating the response to therapy or whether it might be a surrogate marker for a favorable molecular subgroup. METHODS: The medulloblastoma-derived cell line DAOY was stably transfected to overexpress TrkC (clone DAOY-TrkC) and compared to a control (clone DAOY-EV, empty vector transfected). Cell viability (MTS assay) was tested after irradiation or incubation with chemotherapeutic drugs. Neuroradiologic response to postoperative chemotherapy or craniospinal irradiation (CSI) of medulloblastoma patients aged 3-21 years with postoperative residual disease treated within the consecutive trials HIT'91/HIT2000 was compared to TrkC mRNA expression in their tumor samples. Five well-characterized independent expression-profiling studies covering together 686 medulloblastoma patients were analyzed for TrkC levels according to the molecular subgroups. RESULTS: Cell viability of DAOY-TrkC compared to DAOY-EV was not different after exposure to increasing doses of irradiation, cisplatin, etoposide, or vincristine. While TrkC mRNA expression tended to be higher in non-responders (n = 5/19) to postoperative CSI (p = 0.03, ratio 15.5, 95% CI 9-267), this was the case in responders (n = 23/43) to chemotherapy (p = 0.04, ratio 6.1, 95% CI 1.1-35), both analyzed with Mann-Whitney U test (not significant after Bonferroni adjustment). The highest TrkC mRNA levels were found in the SHH subgroup across all expression-profiling studies. CONCLUSIONS: High TrkC mRNA expression appears to be frequent in the SHH subgroup and seems not to have a major effect on therapy responsiveness in medulloblastoma patients.
    Type of Publication: Journal article epub ahead of print
    PubMed ID: 28695340
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  • 2
    Keywords: CANCER ; DIAGNOSIS ; GENE-EXPRESSION ; MUTATIONS ; CENTRAL-NERVOUS-SYSTEM ; CHILDREN ; DIFFERENTIAL EXPRESSION ; NEUROENDOCRINE TUMORS ; EARLY-CHILDHOOD MEDULLOBLASTOMA ; POSTOPERATIVE CHEMOTHERAPY
    Abstract: INTRODUCTION: Neuroectodermal tumors in general demonstrate high and dense expression of the somatostatin receptor subtype 2 (sst2). It controls proliferation of both normal and neoplastic cells. sst2 has thus been suggested as a therapeutic target and prognostic marker for certain malignancies. METHODS: To assess global expression patterns of sst 2 mRNA, we evaluated normal (n = 353) and tumor tissues (n = 340) derived from previously published gene expression profiling studies. These analyses demonstrated specific upregulation of sst 2 mRNA in medulloblastoma (p 〈 0.001). sst2 protein was investigated by immunohistochemistry in two independent cohorts. RESULTS: Correlation of sst2 protein expression with clinicopathological variables revealed significantly higher levels in medulloblastoma (p 〈 0.05) compared with CNS-PNET, ependymoma, or pilocytic astrocytoma. The non-SHH medulloblastoma subgroup tumors showed particularly high expression of sst2, when compared to other tumors and normal tissues. Furthermore, we detected a significant survival benefit in children with tumors exhibiting high sst2 expression (p = 0.02) in this screening set. A similar trend was observed in a validation cohort including 240 independent medulloblastoma samples. CONCLUSION: sst2 is highly expressed in medulloblastoma and deserves further evaluation in the setting of prospective trials, given its potential utility as a prognostic marker and a therapeutic target.
    Type of Publication: Journal article published
    PubMed ID: 23677175
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  • 3
    Keywords: CANCER ; radiation ; leukemia ; MUTATIONS ; FREQUENT ; CHILDREN ; METHYLATION ; DECITABINE ; MULTIPLE ; PROTOCADHERIN PCDH10
    Abstract: PURPOSE: The aim of this study was to investigate the genetic and epigenetic mechanisms contributing to PCDH10 down-regulation in medulloblastoma. We examined the role of PCDH10 as a mediator of medulloblastoma cell proliferation, cell cycle progression, and cell migration. METHODS: We identified a focal homozygous deletion of PCDH10 in medulloblastoma by surveying a cohort of 212 tumours by Affymetrix SNP array analysis. PCDH10 expression was assessed by quantitative reverse transcriptase PCR in a series of 26 tumours. The promoter methylation status of PCDH10 was determined using methylation specific PCR and Sequenom MassCLEAVE analysis. Functional studies examining the role of PCDH10 in medulloblastoma development were performed by re-expression of PCDH10 in the DAOY medulloblastoma cell line, and then, cell proliferation, cell cycle distribution, and cell migration assays were performed. RESULTS: We report a very focal homozygous deletion on chromosome 4q28.3 harbouring the PCDH10 gene. We demonstrate that PCDH10 transcription is down-regulated in 19/26 (73%) of medulloblastomas suggesting that other mechanisms also could be involved in gene repression. We found that DNA hypermethylation contributed to the deregulation of PCDH10 in 11/44 (25%) of medulloblastoma cell lines and primary tumours. Using a stable cell line (DAOY) re-expressing PCDH10, we observed that cell migration was impaired upon restoration of PCDH10 expression. CONCLUSIONS: Our findings suggest that genetic and epigenetic deregulation of PCDH10 occurs in a significant portion of medulloblastoma patients. Failure to express PCDH10 may result in loss of inhibition of cell migration, thereby contributing to medulloblastoma progression.
    Type of Publication: Journal article published
    PubMed ID: 21597995
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  • 4
    Keywords: RISK-FACTORS ; RADIATION-THERAPY ; OCCLUSIVE DISEASE ; ARTERIOVENOUS-MALFORMATION ; CAROTID-ARTERY ; neurofibromatosis ; SICKLE-CELL-ANEMIA ; REPUBLIC-OF-CHINA ; DOWN-SYNDROME ; ARTERIAL ISCHEMIC-STROKE
    Abstract: INTRODUCTION: A large variety of inherited or acquired childhood disorders and conditions may present in conjunction with progressive bilateral stenosis and/or occlusion of the terminal segments of the internal carotid artery. In addition, the development of pathological collateral vessels can be observed in the vicinity of the steno-occlusive changes in these patients. This condition is known as moyamoya-like (MML) vasculopathy. The natural history, the angiographic appearance, and the pathology of MML vasculopathy probably differ from those of definite moyamoya disease. Adequate cerebral vascular imaging should be considered in all pediatric patients with inherited or acquired systemic disorders and symptoms attributable to cerebral ischemia. CASES AND DISCUSSION: We present four pediatric cases of MML vasculopathy, and outline the etiology, the current classification, and the therapeutic approaches for this heterogeneous disease entity.
    Type of Publication: Journal article published
    PubMed ID: 15127215
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  • 5
    Abstract: INTRODUCTION: Individuals with Down syndrome (DS) have an increased risk of acute leukemia compared to a markedly decreased incidence of solid tumors. Medulloblastoma, the most common malignant brain tumor of childhood, is particularly rare in the DS population, with only one published case. As demonstrated in a mouse model, DS is associated with cerebellar hypoplasia and a decreased number of cerebellar granule neuron progenitor cells (CGNPs) in the external granule cell layer (EGL). Treatment of these mice with sonic hedgehog signaling pathway (Shh) agonists promote normalization of CGNPs and improved cognitive functioning. CASE REPORT: We describe a 21-month-old male with DS and concurrent desmoplastic/nodular medulloblastoma (DNMB)-a tumor derived from Shh dysregulation and over-activation of CGNPs. Molecular profiling further classified the tumor into the new consensus SHH molecular subgroup. Additional testing revealed a de novo heterozygous germ line mutation in the PTCH1 gene encoding a tumor suppressor protein in the Shh pathway. DISCUSSION: The developmental failure of CGNPs in DS patients offers a plausible explanation for the rarity of medulloblastoma in this population. Conversely, patients with PTCH1 germline mutations experience Shh overstimulation resulting in Gorlin (Nevoid Basal Cell Carcinoma) syndrome and an increased incidence of malignant transformation of CGNPs leading to medulloblastoma formation. This represents the first documented report of an individual with DS simultaneously carrying PTCH1 germline mutation. CONCLUSION: We have observed a highly unusual circumstance in which the PTCH1 mutation appears to "trump" the effects of DS in causation of Shh-activated medulloblastoma.
    Type of Publication: Journal article published
    PubMed ID: 27444290
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