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  • 1
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    The Shh Receptor Boc Promotes Progression of Early Medulloblastoma to Advanced Tumors
    Elsevier BV ; 2014
    In:  Developmental Cell Vol. 31, No. 1 ( 2014-10), p. 34-47
    Details
    In: Developmental Cell, Elsevier BV, Vol. 31, No. 1 ( 2014-10), p. 34-47
    Type of Medium: Online Resource
    ISSN: 1534-5807
    URL: Article
    DOI: 10.1016/j.devcel.2014.08.010
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
    detail.hit.zdb_id: 2053870-4
    SSG: 12
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  • 2
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    HDAC5 and HDAC9 in Medulloblastoma: Novel Markers for Risk Stratification and Role in Tumor Cell Growth
    American Association for Cancer Research (AACR) ; 2010
    In:  Clinical Cancer Research Vol. 16, No. 12 ( 2010-06-15), p. 3240-3252
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 12 ( 2010-06-15), p. 3240-3252
    Abstract: Purpose: Medulloblastomas are the most common malignant brain tumors in childhood. Survivors suffer from high morbidity because of therapy-related side effects. Thus, therapies targeting tumors in a specific manner with small molecules such as histone deacetylase (HDAC) inhibitors are urgently warranted. This study investigated the expression levels of individual human HDAC family members in primary medulloblastoma samples, their potential as risk stratification markers, and their roles in tumor cell growth. Experimental Design: Gene expression arrays were used to screen for HDAC1 through HDAC11. Using quantitative real time reverse transcriptase-PCR and immunohistochemistry, we studied the expression of HDAC5 and HDAC9 in primary medulloblastoma samples. In addition, we conducted functional studies using siRNA-mediated knockdown of HDAC5 and HDAC9 in medulloblastoma cells. Results: HDAC5 and HDAC9 showed the highest expression in prognostically poor subgroups. This finding was validated in an independent set of medulloblastoma samples. High HDAC5 and HDAC9 expression was significantly associated with poor overall survival, with high HDAC5 and HDAC9 expression posing an independent risk factor. Immunohistochemistry revealed a strong expression of HDAC5 and HDAC9 proteins in most of all primary medulloblastomas investigated. siRNA-mediated knockdown of HDAC5 or HDAC9 in medulloblastoma cells resulted in decreased cell growth and cell viability. Conclusion: HDAC5 and HDAC9 are significantly upregulated in high-risk medulloblastoma in comparison with low-risk medulloblastoma, and their expression is associated with poor survival. Thus, HDAC5 and HDAC9 may be valuable markers for risk stratification. Because our functional studies point toward a role in medulloblastoma cell growth, HDAC5 and HDAC9 may potentially be novel drug targets. Clin Cancer Res; 16(12); 3240–52. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-10-0395
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
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    Abstract 31: Subgroup-specific molecular alterations may explain the tremendous clinical heterogeneity of intracranial ependymoma
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 31-31
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 31-31
    Abstract: Intracranial ependymoma comprises the second most common malignant brain tumor in childhood. The prognosis of these tumors remains generally poor and its biological behavior is unpredictable based on current stratification approaches. Neither clinical variables nor histopathological grading or molecular markers have so far been successful in defining a well circumscribed group of high-risk patients. Thus, an innovative staging model for ependymoma is desperately needed. We studied 122 samples from patients with intracranial ependymoma with a median follow-up of circa 8 years by genome-wide assessment of DNA copy-number aberrations using array-CGH (10K BAC array). Aberrations with a potential prognostic value were validated in an independent cohort of 170 patients by FISH analysis. Consecutively, we investigated genome-wide mRNA expression profiling (Agilent 44k) in 65 primary ependymomas and performed unsupervised clustering to identify potential transcriptome-based subgroups. We compared these findings with the previously identified DNA copy-number profiles. For validation of single molecular markers, selected candidate genes were investigated by QRT-PCR on transcriptional level, and protein expression was measured by immunohistochemistry on tissue microarrays (n=170). We were able to define a novel molecular staging system comprised of three genetically distinct subgroups of ependymoma based on DNA copy-number aberrations: i) a low risk group (34% of patients) including tumors with gain of chromosomes 9, 15q, 18, or loss of chromosome 6, or a combination thereof with patients showing a 5-year OS of 100%; ii) an intermediate risk group (41% of patients) characterized by a balanced cytogenetic profile especially for aberrations of chromosomes 1q, 9, 15q, 18, 6 and without a homozygous deletion of CDKN2A which was associated with a 5-year OS of 77%; iii) a high risk group (25% of patients) defined by tumors harbouring a gain of 1q and/or a homozygous deletion of CDKN2A, which was concurrent with a 5-year OS of only 33%. Interestingly, these cytogenetic risk-groups showed a significant overlap with transcriptome-based subgroups identified by unsupervised clustering. Thus, we aimed at the identification of interesting candidate genes which show subgroup-specific expression and have the potential to be used as surrogate marker for certain biological subgroups. The most robust subgroup-specific molecular markers for poor and good outcome were SHC1 and WDR16, respectively. In summary, we could decipher a novel stratification model for intracranial ependymoma consisting of three subgroups based on cytogenetic aberrations. By integrative genomics looking at DNA aberrations and mRNA levels in a large subset of samples, we were able to identify novel biomarkers in ependymoma, which have high potential to be useful for stratifying patients in future clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 31.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-31
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    Abstract 3458: Activated BRAF induces pilocytic astrocytomas in mice
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3458-3458
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3458-3458
    Abstract: Pilocytic astrocytoma (PA) comprises the most common primary brain tumor in children. Although this WHO grade I neoplasm shows a relatively benign biologic behavior many patients suffer from therapy-related long term neurologic impairment and up to 20% of patients experience tumor recurrence. Due to the slow growing nature of PA, adjuvant radiation and chemotherapy are only moderately effective. In order to pre-clinically evaluate novel therapy approaches, we aimed to establish a murine model of these tumors. Based on our previous work which showed that the MAPK intermediate BRAF is altered by duplication, activating mutation (V600E) or translocation of its kinase domain in a vast majority of cases, we applied somatic gene transfer using the Replication-Competent ASLV long terminal repeat (LTR) with a Splice acceptor (RCAS)/Tv-a technique to ectopically express different BRAF variants in Nestin-positive neural progenitors in the brains of newborn mice. While expression of either the BRAF i) full length wildtype, ii) full length V600E or iii) isolated kinase domain wildtype did not induce neoplastic lesions in mice, expression of the iv) isolated V600E mutated kinase domain induced tumors either in the cerebral hemispheres or in the brainstem depending on the site of injection. Although showing no clinical symptoms after an observation period of 4 months, post mortem analysis revealed presence of tumors in & gt;90% of cases. By histopathologic analysis, presence of strongly GFAP-positive lesions with a proliferation index (Ki67) below 1% could be identified. The slow tumor growth compared to other tumors induced with this technique together with presence of piloid-like tumor cells and eosinophilic structures (Rosenthal fibers) closely recapitulate clinical and biological features of human PA. Further analysis using primary murine Ntv-a astrocytes transduced with either of the four constructs in vitro revealed that expression of the isolated BRAF V600E kinase domain led to a twofold increase in proliferation compared to full length BRAF V600E or wild type BRAF kinase domain, while cells transduced with either full length wild type BRAF or GFP (control) showed almost no proliferation. Furthermore, this increase in proliferation could be markedly decreased by in vitro treatment with the kinase inhibitor Sorafenib at a concentration of 5 µM. This could be correlated with the amount of phosphorylation of the MAP kinases MEK and ERK, the downstream targets of BRAF. Treatment of mice with Sorafenib upon tumor induction is currently being conducted using ultrahigh field magnetic resonance imaging to monitor tumor growth and therapy response. Taken together, our data provide first in vivo evidence for the oncogenic role of BRAF in pediatric pilocytic astrocytomas and it will be of paramount clinical importance to use this first animal model for pre-clinical testing of novel treatment approaches. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3458. doi:10.1158/1538-7445.AM2011-3458
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3458
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
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    Abstract 5050: KCNJ2 constitutes a marker and therapeutic target of high-risk medulloblastomas.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 5050-5050
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 5050-5050
    Abstract: Medulloblastoma comprises the most common malignant brain tumor in children. Non-WNT/SHH tumors define the most refractory medulloblastoma subgroups. Interestingly, 17q gain, the most common genetic aberration in medulloblastoma, comprises a cytogenetic hallmark of these molecular high-risk tumors detected in group 3 (62%), and group 4 (73%). The majority of recurrent tumors harbor 17q gain in the corresponding primary. Virtually all of these tumors develop resistance to current treatment protocols at relapse. The lack of a common molecular target hampers the development of urgently needed novel treatment strategies. Through mRNA expression profiling of 64 primary tumor samples, we identified potassium inwardly-rectifying channel J2 (KCNJ2) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. High KCNJ2 transcript levels were significantly associated with non-WNT/non-SHH grouping, anaplastic histology, metastatic dissemination, and poor clinical outcome. KCNJ2 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n=199), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior prognosis (p & lt;0.0001). To functionally validate the potential role of KCNJ2 in medulloblastoma biology, we performed knockdown experiments by small interfering RNA-mediated silencing in two well-characterized medulloblastoma cell lines. Transient knockdown of KCNJ2 resulted in a reduced proliferation rate and induction of apoptosis. Furthermore, treatment of the medulloblastoma cell lines and medulloblastoma stem cells with amiodarone and gambogic acid, two inhibitors of this class of Kir channels, phenocopied these effects in a time- and dose-dependent manner. Whole cell patch clamp results revealed a nearly complete current blockade upon inhibitor treatment. Subsequently, we showed that pharmacological inhibition of KCNJ2 and knockdown KCNJ2 significantly reduced tumor growth and resulted in prolonged survival in an orthotopic medulloblastoma mouse model. In summary, our data suggest that pharmacological inhibition of KCNJ2 may constitute a new therapeutic option for patients with high-risk medulloblastomas. Citation Format: Francesca Valdora, Florian Freier, Livia Garzia, Vijay Ramaswamy, Claudia Seyler, Thomas Hielscher, Nathan Brady, Paul A. Northcott, Marcel Kool, David TW Jones, Hendrik Witt, Gian Paolo Tonini, Wolfram Scheurlen, Hugo A. Katus, Andreas E. Kulozik, Edgar Zitron, Andrey Korshunov, Peter Lichter, Michael D. Taylor, Stefan M. Pfister, Marc Remke. KCNJ2 constitutes a marker and therapeutic target of high-risk medulloblastomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5050. doi:10.1158/1538-7445.AM2013-5050
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-5050
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Abstract 3552: Subgroup-specific pattern of recurrence in medulloblastoma.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3552-3552
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3552-3552
    Abstract: Background: Medulloblastoma constitutes the most common malignant brain tumor of childhood. Although multimodel treatment strategies, encompassing surgery, chemotherapy, and radiation, results in up to 80% five-year overall survival, recurrent medulloblastoma is almost always uniformly fatal. Recent integrated genomic studies have shown that medulloblastoma comprises 4 clinical and biologically distinct variants. We sought to delineate subgroup-specific differences in recurrent medulloblastoma. Methods: We identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children between 1994-2012, and subgrouped cases using nanoString. Clinical details were ascertained via retrospective chart review. Our findings were confirmed through analysis of an independent validation cohort of 85 recurrences. Primary and recurrent matched pairs were evaluated where possible. Results: Twenty-nine recurrent cases were identified, ten with a local recurrence within the tumor bed only, and 19 recurred with metastases. Notably, SHH tumors recurred more frequently in the tumor bed (8/11, 73%) whereas Group 3 and Group 4 developed with metastatic relapses more frequently (16/18, 89%; p & lt;0.01). Late recurrences were observed more commonly in Group 4 cases with a mean time to recurrence of 3.2 years compared to under two years for both SHH and Group 3 (p & lt;0.004), with a tendency to a prolonged interval to death post-recurrence in Group 4 cases (p=0.07). Spinal metastases in the absence of supratentorial metastases were observed in three non-SHH recurrences. The presence of metastases at diagnosis and histology were not predictive factors of recurrence site. In an independent validation cohort of 85 recurrences, 13 recurrences appeared in the tumor bed only of which nine were SHH and 72 recurred with metastases. Of these metastatic relapses, only three SHH tumors were observed, while 36 and 33 belonged to Group 3 or Group4 (p & lt;0.001), respectively. Strikingly, in all instances where matched primary and recurrent pairs were available, the subgroup affiliation remained stable at recurrence. Conclusions: Significant differences in the pattern of recurrence exist across medulloblastoma subgroups. Longer surveillance periods across the entire neuro-axis may be required for Group 4 patients even in the absence of local tumor bed or supratentorial recurrence. Intensified local therapy should be considered upon initial treatment for SHH patients. Citation Format: Vijay Ramaswamy, Marc Remke, Eric Bouffet, David Shih, Claudia Faria, Ulrich Schüller, Sri Gururangan, Roger McLendon, Nada Jabado, Adam Fontebasso, Sandra Dunn, Joanna Triscott, Cynthia Hawkins, Uri Tabori, Kari Codispoti, Roger Packer, Stefan M. Pfister, Andrey Korshunov, Michael D. Taylor. Subgroup-specific pattern of recurrence in medulloblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3552. doi:10.1158/1538-7445.AM2013-3552
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-3552
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Abstract 4591: Whole genome sequencing of SHH medulloblastomas predicts molecular groups of responders and non-responders to SMO-inhibition .
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4591-4591
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4591-4591
    Abstract: Recently, we and others analyzed large series of pediatric medulloblastomas (MB) and identified a number of recurrent aberrations in each of the four major subgroups (WNT, SHH, Group 3 and Group 4). However, due to their infrequent occurrence not much is known about genetic aberrations in adult MBs. We now have analyzed a large series of adult SHH MBs (age ≥ 16) by whole genome sequencing and compared them with pediatric SHH MBs. We sequenced tumor and blood of 26 adult SHH MBs and compared them with 30 pediatric SHH MBs. A replication cohort of 28 adult and 29 pediatric SHH MBs was sequenced for 414 genes by targeted sequencing. We also performed expression profiling and DNA methylation analyses on most of these cases. Whole genome sequencing revealed a clear correlation between mutation rate and age of the patient (r = 0.69). Furthermore, the genomic data showed that SHH MBs can be split up in three distinct subgroups: infants, children and adults. They all have mutations in the SHH pathway, mostly in PTCH1 (infants and adults), SUFU (infants) and SMO (adults). Children almost completely lack the classical upstream SHH pathway mutations but instead have more downstream aberrations such as MYCN and GLI2 mplifications, and have frequent TP53 mutations, often in the germline, whilst all of these were extraordinarily rare in infants and adults. We also identified several recurrent mutations in adult MBs that were not found in pediatric MBs. Moreover, the three SHH subgroups were different in their transcriptome and methylome with the TP53 mutated SHH MBs in children being more similar to adult MBs. Collectively, this data will help to better understand the biology of pediatric and adult SHH-medulloblastoma, but most importantly may help selecting patients for targeted SHH inhibition and new treatment strategies for TP53 mutated SHH MBs in a clinical setting. Citation Format: Marcel Kool, David TW Jones, Natalie Jaeger, Paul A. Northcott, Volker Hovestadt, Ulrich Schueller, Marc Remke, Yoon-Jae Cho, Scott Pomeroy, Michael D. Taylor, Roland Eils, Andrey Korshunov, Peter Lichter, Stefan M. Pfister. Whole genome sequencing of SHH medulloblastomas predicts molecular groups of responders and non-responders to SMO-inhibition . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4591. doi:10.1158/1538-7445.AM2013-4591
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-4591
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Abstract 3447: FSTL5 improves prognostic subclassification of medulloblastoma
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3447-3447
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3447-3447
    Abstract: Current integrated genomic approaches indicate distinct biological variants in medulloblastoma. Comprehensive molecular classification strategies utilize cytogenetic or immunohistochemical biomarkers to refine risk stratification. Novel complementary markers may ameliorate outcome prediction particularly in intermediate or high-risk medulloblastomas. We combined transcriptome and DNA copy-number analysis for 64 primary tumors. Bioinformatic tools were applied to investigate marker genes of molecular variants. Differentially expressed transcripts were evaluated for prognostic value in the entire screening cohort. Immunohistochemical markers were used to determine molecular subtypes in adult and pediatric medulloblastoma samples (n=235). Immunopositivity of FSTL5 was correlated with molecular and prognostic subgroups for 235 non-overlapping medulloblastoma samples on two independent tissue microarrays (TMA). Unsupervised cluster analyses of transcriptome profiles revealed four distinct molecular variants: WNT, SHH, Group C, and Group D. Stable subgroup separation was achieved using only 300 most varying transcripts. Specific distribution of clinical and molecular characteristics was noted for each cluster. Notably, Group C tumors were exclusively present in pediatric medulloblastomas as determined by immunohistochemistry. Delimited expression patterns of FSTL5 in each molecular subgroup were confirmed by quantitative real-time PCR. FSTL5 transcripts were most up-regulated in Group C and Group D tumors with unfavorable prognosis, whereas WNT medulloblastomas showed marked down-regulation. Immunopositivity of FSTL5 identified a large proportion of patients (84 of 235 patients; 36%) at high risk for relapse and death in particular in patients with WNT/SHH-independent tumors. Multivariate analysis revealed that FSTL5 immunopositivity constitutes an independent prognostic marker in pediatric and adult patient cohorts (p & lt;0.0001). Importantly, adding this biomarker to comprehensive outcome prediction schemes substantially reduced the prediction error of the model. Comprehensive analyses of transcriptome and genetic alterations unravel four distinct disease variants. By addition of FSTL5 immunohistochemistry, existing molecular stratification schemes can effectively be complemented and sub-classification of WNT/SHH-independent tumors substantially optimized. This approach may ultimately define clear risk groups to individualize treatment intensities in future clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3447. doi:10.1158/1538-7445.AM2011-3447
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3447
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    Abstract 1424: KCNJ2 comprises a marker of poor prognosis and a therapeutic target in non-WNT/non-SHH medulloblastoma
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1424-1424
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1424-1424
    Abstract: Medulloblastoma comprises the most common malignant brain tumor in childhood. Recently, integrated genomic approaches revealed four major biological disease variants: WNT (wingless), SHH (sonic hedgehog), group 3, and group 4. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk non-WNT/non-SHH medulloblastoma. Thus, novel therapeutic options for these patients are urgently warranted. Through mRNA expression profiling of 64 primary tumor samples, we identified potassium inwardly-rectifying channel J2 (KCNJ2) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. Notably, recent reports have linked deregulation of voltage-dependent ion channels to the development of other types of cancer. We first validated our microarray findings on KCNJ2 transcript levels using quantitative real-time PCR. High KCNJ2 transcript levels were significantly associated with non-WNT/non-SHH grouping, anaplastic histology, metastatic dissemination, and poor clinical outcome. KCNJ2 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n=199), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival (p & lt;0.0001). To functionally validate the potential role of KCNJ2 in medulloblastoma biology, we performed knockdown experiments by small interfering RNA-mediated silencing in two well characterized medulloblastoma cell lines. Knockdown of KCNJ2 resulted in a reduced proliferation rate and induction of apoptosis. Furthermore, treatment of the medulloblastoma cell lines with Amiodarone and SR 59230A, two inhibitors of this class of Kir channels, phenocopied these promising anti-proliferative and pro-apoptotic effects in a time- and dose-dependent manner. Whole cell patch clamp results revealed a remarkable current reduction upon inhibitor treatment with SR 59230A. In summary, we could delineate KCNJ2 immunopositivity as an independent biomarker for medulloblastoma with dismal prognosis. Thus, pharmacological inhibition of this candidate gene may constitute a new therapeutic option for patients with high-risk medulloblastomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1424. doi:1538-7445.AM2012-1424
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-1424
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
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    Abstract 1432: The heterogeneous genomic landscape of posterior fossa ependymoma
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1432-1432
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1432-1432
    Abstract: Brain tumors are the most common cause of cancer-related death in childhood. Ependymomas, are the third most common pediatric brain tumor. The disease remains incurable for about 45% of patients even after gross total resection and radiotherapy. Despite showing a very homogeneous histological picture, ependymomas display distinct molecular behavior, which supports the existence of several independent entities of the disease. We examined two non-overlapping cohorts of 102 and 75 ependymomas by mRNA expression profiling, on two different array platforms (Affymetrix, Agilent). When performing multiple statistical clustering methods (unsupervised consensus NMF and consensus HCL), we could consistently identify three major clusters, including two subgroups of posterior fossa (PF) ependymoma, a variant common in children and associated with heterogeneous clinical outcome. Subgroup-specific chromosome aberrations of PF tumors were detected by aCGH, and biological signaling pathways distinguishing PF subgroups were identified by gene set enrichment analysis and visualized in Cytoscape. We validated the most significantly classifying markers of each subgroup by immunohistochemistry on a tissue microarray containing an independent set of 265 PF ependymomas. Our findings delineate two subgroups of PF ependymoma (groups A and B) which are demographically, transcriptionally, genetically, and clinically distinct. Group A patients are younger, have laterally located tumors with a balanced genome, more frequently develop secondary metastases and are much more likely to have an extremely poor outcome as compared with group B patients. Based on a multi-variate Cox proportional-hazards model, our identified markers have the strongest independent prognostic value among demographic and molecular variables with Hazard ratios of 8.45 (PFS) and 10.55 (OS). Prognostic significance and predictive impact is being validated in the GPOH HIT2000 Ependymoma study. The identification of two distinct subgroups of PF ependymoma, and markers applicable for their clinical distinction, will allow for better prognostication of individual cases, independent of age, level of resection and WHO grade, and also for stratification in future ependymoma clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1432. doi:1538-7445.AM2012-1432
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-1432
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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