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  • Bender, Sebastian  (9)
  • Hielscher, Thomas  (9)
  • Witt, Hendrik  (9)
  • 1
    Online Resource
    Online Resource
    Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma
    Elsevier BV ; 2012
    In:  Cancer Cell Vol. 22, No. 4 ( 2012-10), p. 425-437
    Details
    In: Cancer Cell, Elsevier BV, Vol. 22, No. 4 ( 2012-10), p. 425-437
    Type of Medium: Online Resource
    ISSN: 1535-6108
    URL: Article
    DOI: 10.1016/j.ccr.2012.08.024
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2012
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    SSG: 12
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  • 2
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    Delineation of Two Clinically and Molecularly Distinct Subgroups of Posterior Fossa Ependymoma
    Elsevier BV ; 2011
    In:  Cancer Cell Vol. 20, No. 2 ( 2011-08), p. 143-157
    Details
    In: Cancer Cell, Elsevier BV, Vol. 20, No. 2 ( 2011-08), p. 143-157
    Type of Medium: Online Resource
    ISSN: 1535-6108
    URL: Article
    DOI: 10.1016/j.ccr.2011.07.007
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2011
    detail.hit.zdb_id: 2074034-7
    detail.hit.zdb_id: 2078448-X
    SSG: 12
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  • 3
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    Molecular Staging of Intracranial Ependymoma in Children and Adults
    American Society of Clinical Oncology (ASCO) ; 2010
    In:  Journal of Clinical Oncology Vol. 28, No. 19 ( 2010-07-01), p. 3182-3190
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 28, No. 19 ( 2010-07-01), p. 3182-3190
    Abstract: The biologic behavior of intracranial ependymoma is unpredictable on the basis of current staging approaches. We aimed at the identification of recurrent genetic aberrations in ependymoma and evaluated their prognostic significance to develop a molecular staging system that could complement current classification criteria. Patients and Methods As a screening cohort, we studied a cohort of 122 patients with ependymoma before standardized therapy by using array-based comparative genomic hybridization. DNA copy-number aberrations identified as possible prognostic markers were validated in an independent cohort of 170 patients with ependymoma by fluorescence in situ hybridization analysis. Copy-number aberrations were correlated with clinical, histopathologic, and survival data. Results In the screening cohort, age at diagnosis, gain of 1q, and homozygous deletion of CDKN2A comprised the most powerful independent indicators of unfavorable prognosis. In contrast, gains of chromosomes 9, 15q, and 18 and loss of chromosome 6 were associated with excellent survival. On the basis of these findings, we developed a molecular staging system comprised of three genetic risk groups, which was then confirmed in the validation cohort. Likelihood ratio tests and multivariate Cox regression also demonstrated the clear improvement in predictive accuracy after the addition of these novel genetic markers. Conclusion Genomic aberrations in ependymomas are powerful independent markers of disease progression and survival. By adding genetic markers to established clinical and histopathologic variables, outcome prediction can potentially be improved. Because the analyses can be conducted on routine paraffin-embedded material, it will now be possible to prospectively validate these markers in multicenter clinical trials on population-based cohorts.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2009.27.3359
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2010
    detail.hit.zdb_id: 2005181-5
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  • 4
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    FSTL5 Is a Marker of Poor Prognosis in Non-WNT/Non-SHH Medulloblastoma
    American Society of Clinical Oncology (ASCO) ; 2011
    In:  Journal of Clinical Oncology Vol. 29, No. 29 ( 2011-10-10), p. 3852-3861
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 29, No. 29 ( 2011-10-10), p. 3852-3861
    Abstract: Integrated genomics approaches have revealed at least four distinct biologic variants of medulloblastoma: WNT (wingless), SHH (sonic hedgehog), group C, and group D. Because of the remarkable clinical heterogeneity of group D tumors and the dismal prognosis of group C patients, it is vital to identify molecular biomarkers that will allow early and effective treatment stratification in these non-WNT/non-SHH tumors. Patients and Methods We combined transcriptome and DNA copy-number analyses for 64 primary medulloblastomas. Bioinformatic tools were used to discover marker genes of molecular variants. Differentially expressed transcripts were evaluated for prognostic value in the screening cohort. The prognostic power of follistatin-like 5 (FSTL5) immunopositivity was tested for 235 nonoverlapping medulloblastoma samples on two independent tissue microarrays. Results Comprehensive analyses of transcriptomic and genetic alterations delineate four distinct variants of medulloblastoma. Stable subgroup separation was achieved by using the 300 transcripts that varied the most. Distinct expression patterns of FSTL5 in each molecular subgroup were confirmed by quantitative real-time polymerase chain reaction. Immunopositivity of FSTL5 identified a large cohort of patients (84 of 235 patients; 36%) at high risk for relapse and death. Importantly, more than 50% of non-WNT/non-SHH tumors displayed FSTL5 negativity, delineating a large patient cohort with a good prognosis who would otherwise be considered intermediate or high-risk on the basis of current molecular subgrouping. Conclusion FSTL5 expression denoted a dismal prognosis both within and across medulloblastoma subgroups. The addition of FSTL5 immunohistochemistry to existing molecular stratification schemes constitutes a reliable and cost-effective tool for prognostication in future clinical trials of medulloblastoma.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2011.36.2798
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2011
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  • 5
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    Role of LIM and SH3 Protein 1 (LASP1) in the Metastatic Dissemination of Medulloblastoma
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 20 ( 2010-10-15), p. 8003-8014
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 20 ( 2010-10-15), p. 8003-8014
    Abstract: Medulloblastoma is the most common malignant pediatric brain tumor and is one of the leading causes of cancer-related mortality in children. 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 medulloblastoma. Through mRNA expression profiling, we identified LIM and SH3 protein 1 (LASP1) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. In an independent validation cohort of 101 medulloblastoma samples, the abundance of LASP1 mRNA was significantly associated with 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n = 207), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival. In vitro experiments in medulloblastoma cell lines showed a strong reduction of cell migration, increased adhesion, and decreased proliferation upon LASP1 knockdown by small interfering RNA–mediated silencing, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medulloblastoma. Cancer Res; 70(20); 8003–14. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-0592
    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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  • 6
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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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  • 7
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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
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  • 8
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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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  • 9
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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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