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  • 1
    Online-Ressource
    Online-Ressource
    Abstract 3936: Identifying molecular subgroups of gliomas in formalin fixed paraffin embedded material
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3936-3936
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3936-3936
    Kurzfassung: Gliomas are the most common primary brain tumors with heterogeneous morphology and variable prognosis. Histological classification, combined with the patients’ prognostic features, often guides treatment decisions. Unfortunately, differences in histology are subtle and therefore, diagnosis is subject to a large interobserver variability. To improve classification, we did expression profiling on fresh frozen tumor material of 276 glioma samples of all histological subtypes. This resulted in seven molecular subgroups, which correlated significantly better with survival than histology. When validated in prospective studies these molecular clusters could contribute to clinical decision making. However, there is a lack of fresh frozen glioma material, and until now clinical studies have been performed on formalin fixed paraffin embedded (FFPE) material. Therefore, we would like to see whether our molecular clusters are reproducible in FFPE material. Expression profiling was performed on 57 paired snap-frozen/FFPE glioma samples of all histological and molecular subtypes and three non-diseased brain samples. We collected FFPE material from the same patients that were included in our previous study (Gravendeel et al. Cancer Res 2009). FFPE expression profiling was performed using Hu_Ex_1.0_st “exon” arrays (Affymetrix) in combination with Nugen WT-Ovation technology (FFPE V2 and Exon modules). FFPE expression profiles were assigned to a molecular cluster based on its nearest centroid using the 20.000 most variably expressed exons. Preliminary analysis indicates that approximately 75% of all samples were assigned to the correct molecular cluster. Survival data confirmed that the molecular clusters identified using FFPE material retained significant prognostic value, similar to those obtained using fresh frozen material (p=0.0016). Our data indicate that exon arrays in combination with Nugen WT technology are a suitable platform to perform expression profiling on FFPE samples. We are currently expanding our dataset to include FFPE samples from a large phase III European trial. 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 3936. doi:10.1158/1538-7445.AM2011-3936
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3936
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2011
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    Integrated genomic profiling identifies candidate genes implicated in glioma-genesis and a novel LEO1 - SLC12A1 fusion gene
    Wiley ; 2010
    In:  Genes, Chromosomes and Cancer ( 2010), p. NA-NA
    Details
    In: Genes, Chromosomes and Cancer, Wiley, ( 2010), p. NA-NA
    Materialart: Online-Ressource
    ISSN: 1045-2257 , 1098-2264
    URL: Article
    DOI: 10.1002/gcc.20760
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2010
    ZDB Id: 1018988-9
    ZDB Id: 1492641-6
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 3
    Online-Ressource
    Online-Ressource
    Abstract 3932: Tetraploid gliomas share molecular features with pilocytic astrocytomas
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3932-3932
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3932-3932
    Kurzfassung: We have performed expression profiling on 276 glioma samples of all histological subtypes, which resulted in the identification of seven distinct molecular subgroups. Interestingly, pilocytic astrocytomas (PAs) (n=6; adults) were assigned to one specific molecular cluster, together with four other, more malignant, gliomas. All the non-PAs were histologically diagnosed as higher grade gliomas with pilocytic features. Interestingly, there was a dramatic difference between survival of PAs and gliomas of other histological subtypes in this molecular cluster ( & gt;10.6 years vs. 3.4 (avg.) years; p = 0.03). Validation with an external dataset containing only PAs (GSE12907) showed that PAs are virtually always assigned to this molecular cluster, confirming the stability of the cluster. However, similar to our dataset, a subset of samples of both the REMBRANDT (8%) and TCGA (1%) datasets was also assigned to this molecular cluster. To further explore the differences between PAs and non-PAs in this molecular cluster, we performed genotyping using SNP 6.0 chip arrays. As reported previously, all PAs have only one larger genetic aberration; a focal amplification on locus 7q34, which is indicative for the presence of the tandem duplication KIAA1549-BRAF. One of the four samples of other histology also had this identical genetic aberration as PAs. The other (3/4) non-PA gliomas showed more genetic aberrations than the PAs. All patients harboring the KIAA1549-BRAF duplication were still alive (“survivors”) at the moment of writing this abstract (survival 10.6-19.6 years), whereas the remaining patients (“non-survivors”) all died within 0.44-2.7 years. High copy EGFR amplification was seen in none of the survivors but all of the other tumors. None of the samples in this cluster showed an IDH1-132H mutation. Closer inspection of the SNP arrays indicated that all non-survivors are tetraploid, whilst tumors of all survivors are near diploid (except for 3n on 7q34). The ploidy of all samples is currently validated using Fluorescence In Situ Hybridization (FISH). Polyploidy was not observed in any of the other molecular clusters. Validation with the REMBRANDT and the TCGA datasets showed that non-PAs assigned to this molecular cluster had a poor survival, similar to the non-PAs in our dataset. Interestingly, tetraploidy and EGFR amplification were also seen in the GBM samples from the TCGA that were assigned to this cluster. Gliomas from other molecular subtypes did not show tetraploidy on SNP chip data. In conclusion, we have discovered and validated a glioma subtype that shares molecular (RNA expression profile) and histological features with PAs. In spite of these similarities (and in contrast to the PAs), such tumors have a relatively poor prognosis. They are characterized by EGFR amplification and a near tetraploid cytogenetic profile. Identification of this specific subtype may have important therapeutic consequences. 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 3932. doi:10.1158/1538-7445.AM2011-3932
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3932
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2011
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 4
    Online-Ressource
    Online-Ressource
    Intrinsic Molecular Subtypes of Glioma Are Prognostic and Predict Benefit From Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Combination With Other Prognostic Factors in Anaplastic Oligodendroglial Brain Tumors: A Report From EORTC Study 26951
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 3 ( 2013-01-20), p. 328-336
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 3 ( 2013-01-20), p. 328-336
    Kurzfassung: Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can be identified based on unsupervised gene expression analysis. Here, we have evaluated the clinical relevance of these subtypes within European Organisation for Research and Treatment of Cancer (EORTC) 26951, a randomized phase III clinical trial investigating adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study includes gene expression profiles of formalin-fixed, paraffin-embedded (FFPE) clinical trial samples. Patients and Methods Gene expression profiling was performed in 140 samples, 47 fresh frozen samples and 93 FFPE samples, on HU133_Plus_2.0 and HuEx_1.0_st arrays, respectively. Results All previously identified six IGSs are present in EORTC 26951. This confirms that different molecular subtypes are present within a well-defined histologic subtype. Intrinsic subtypes are highly prognostic for overall survival (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance status, and tumor location), molecular (1p/19q loss of heterozygosity [LOH], IDH1 mutation, and MGMT methylation), and histologic parameters. Combining known molecular (1p/19q LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (proportion of explained variation, 30% v 23% for each individual group of factors). Specific genetic changes (IDH1, 1p/19q LOH, and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p/19q LOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone versus 12.8 years after RT/PCV (P = .0349; hazard ratio, 2.18; 95% CI, 1.06 to 4.50). Conclusion Intrinsic subtypes are highly prognostic in EORTC 26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV.
    Materialart: Online-Ressource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2012.44.1444
    RVK:
    XA 52760
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Clinical Oncology (ASCO)
    Publikationsdatum: 2013
    ZDB Id: 2005181-5
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 5
    Online-Ressource
    Online-Ressource
    A Hypermethylated Phenotype Is a Better Predictor of Survival than MGMT Methylation in Anaplastic Oligodendroglial Brain Tumors: A Report from EORTC Study 26951
    American Association for Cancer Research (AACR) ; 2011
    In:  Clinical Cancer Research Vol. 17, No. 22 ( 2011-11-15), p. 7148-7155
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 22 ( 2011-11-15), p. 7148-7155
    Kurzfassung: Purpose: The MGMT promoter methylation status has been suggested to be predictive for outcome to temozolomide chemotherapy in patients with glioblastoma (GBM). Subsequent studies indicated that MGMT promoter methylation is a prognostic marker even in patients treated with radiotherapy alone, both in GBMs and in grade III gliomas. Experimental Design: To help determine the molecular mechanism behind this prognostic effect, we have conducted genome-wide methylation profiling and determined the MGMT promoter methylation status, 1p19q LOH, IDH1 mutation status, and expression profile on a series of oligodendroglial tumors [anaplastic oligodendrogliomas (AOD) and anaplastic oligoastrocytomas (AOA)] within EORTC study 26951. The series was expanded with tumors of the same histology and treatment from our own archive. Results: Methylation profiling identified two main subgroups of oligodendroglial brain tumors of which survival in the CpG island hypermethylation phenotype (CIMP+) subgroup was markedly better than the survival of the unmethylated (CIMP−) subgroup (5.62 vs. 1.24 years; P & lt; 0.0001). CIMP status correlated with survival, MGMT promoter methylation, 1p19q LOH, and IDH1 mutation status. CIMP status strongly increases the predictive accuracy of survival in a model including known clinical prognostic factors such as age and performance score. We validated our results on an independent data set from the Cancer Genome Atlas (TCGA). Conclusion: The strong association between CIMP status and MGMT promoter methylation suggests that the MGMT promoter methylation status is part of a more general, prognostically favorable genome-wide methylation profile. Methylation profiling therefore may help identify AODs and AOAs with improved prognosis. Clin Cancer Res; 17(22); 7148–55. ©2011 AACR.
    Materialart: Online-Ressource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-11-1274
    RVK:
    XA 36791
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2011
    ZDB Id: 1225457-5
    ZDB Id: 2036787-9
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
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