X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • American Association for Cancer Research (AACR)  (54)
  • 1
    Online Resource
    Online Resource
    Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Research Vol. 16, No. 10 ( 2018-10-01), p. 1491-1498
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 10 ( 2018-10-01), p. 1491-1498
    Abstract: Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are extremely rare tumors that typically arise in infancy; however, these entities have not been well characterized in terms of genetic alterations or clinical outcomes. Here, through a multi-institutional collaboration, the largest cohort of DIG/DIA to date is examined using advanced laboratory and data processing techniques. Targeted DNA exome sequencing and DNA methylation profiling were performed on tumor specimens obtained from different patients (n = 8) diagnosed histologically as DIG/DIGA. Two of these cases clustered with other tumor entities, and were excluded from analysis. The remaining 16 cases were confirmed to be DIG/DIA by histology and by DNA methylation profiling. Somatic BRAF gene mutations were discovered in 7 instances (43.8%); 4 were BRAFV600E mutations, and 3 were BRAFV600D mutations. Three instances of malignant transformation were found, and sequencing of the recurrence demonstrated a new TP53 mutation in one case, new ATRX deletion in one case, and in the third case, the original tumor harbored an EML4–ALK fusion, also present at recurrence. DIG/DIA are distinct pathologic entities that frequently harbor BRAFV600 mutations. Complete surgical resection is the ideal treatment, and overall prognosis is excellent. While, the small sample size and incomplete surgical records limit a definitive conclusion about the risk of tumor recurrence, the risk appears quite low. In rare cases with wild-type BRAF, malignant progression can be observed, frequently with the acquisition of other genetic alterations. Implications: DIG/DIA are a distinct molecular entity, with a subset frequently harboring either BRAFV600E or BRAFV600D mutations. Mol Cancer Res; 16(10); 1491–8. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-17-0507
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2097884-4
    SSG: 12
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 2
    Online Resource
    Online Resource
    Abstract 3646: (Epi-)genomic homogeneity in radiation-induced glioblastoma with recurrent PDGFRA amplification and loss of CDKN2A/B following primary acute lymphatic leukemia and medulloblastoma
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3646-3646
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3646-3646
    Abstract: As an essential pillar of today’s cancer treatment, radiation therapy has led to improved survival rates of patients with childhood malignancies including leukemia and central nervous system (CNS) tumors. However, long-term complications such as radiation-induced malignancies occur in a subset of patients following radiation therapy, especially observed in pediatric patients due to their long follow-up period in case of survival. Radiation-induced glioblastomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). Histopathologically, most RIGs are best described as high-grade gliomas resembling de novo glioblastoma, and histopathological features to distinguish RIGs from their sporadic counterparts are lacking. Recent large-scale genomic and epigenomic analyses have revealed key genetic alterations in various types of CNS tumors. Here, we performed comprehensive (epi-)genomic and gene expression profiling of RIGs following radiation therapy for primary MB (n=24) and ALL (n=8). DNA methylation profiling demonstrates a high similarity of global DNA methylation patterns among RIGs, regardless of the primary malignancy. Known genetic alterations in high-grade gliomas such as PDGFRA amplification (53%, 17/32) and loss of CDKN2A/B (63%, 20/32) occur in RIGs. None of the RIGs harbored somatic hotspot mutations in genes encoding histone variants H3.3 and H3.1/H3.2 or IDH1/2, which are frequently observed in high-grade glioma subtypes of children and young adults. Germline alterations causing cancer predisposition syndromes were not found more frequently in RIG patients than in patients suffering from high-grade gliomas without previous irradiation treatment. The genetic homogeneity of RIGs with the absence of histone 3 and IDH1/2 mutations suggests that RIGs share a common cell of origin, which might be particularly vulnerable to radiation. We performed in vitro drug screens on patient-derived RIG tumor spheres, exhibiting amplified and overexpressed PDGFRA, alongside with non-PDGFRA-amplified GBM cell lines to assess the potential efficacy of RTK inhibitors. The median latency time between cranial irradiation and RIG occurrence was 4.5 years (range: 2.5-15). Patients treated for ALL were diagnosed with RIG at age 9-14 years, exposing a particularly vulnerable but narrow time frame for RIG occurrence in ALL patients, in contrast to RIG patients treated for MB (range: 3-39 years). In summary, our study uncovers diagnostic biomarkers and potential targetable alterations in RIG, which could become relevant for the stratification into future clinical trials with e.g. specific RTK inhibitors, with the objective of improving the outcome of survivors of childhood cancer. Citation Format: Maximilian Y. Deng, Dominik Sturm, Elke Pfaff, Gnana P. Balasubramanian, Jens Schittenhelm, Martin Ebinger, Martin U. Schuhmann, Andrey Korshunov, Andreas von Deimling, Olaf Witt, Stefan M. Pfister, David T. Jones. (Epi-)genomic homogeneity in radiation-induced glioblastoma with recurrent PDGFRA amplification and loss of CDKN2A/B following primary acute lymphatic leukemia and medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3646.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-3646
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 3
    Online Resource
    Online Resource
    Abstract 509: Genomic profiling of acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 509-509
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 509-509
    Abstract: Recent developments in sequencing technologies lead to the discovery of a novel form of genome instability, termed chromothripsis. This catastrophic genomic event, involved in cancer formation, is characterized by tens to hundreds of locally clustered rearrangements on one chromosome, acquired simultaneously. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, essential guardian of genome stability, would show a higher prevalence for chromothripsis due to the defect in DNA double-strand break repair. Using whole-genome sequencing, fluorescence in situ hybridization and RNA sequencing, we characterized the genomic landscape of Acute Lymphoblastic Leukemia (ALL) in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared to tumors from individuals with other types of DNA repair syndromes (27 cases in total, of which 10 with Ataxia Telangiectasia). Our data show that the genomic landscape of Ataxia Telangiectasia ALL is clearly distinct from that of sporadic ALL. Mechanistically, short telomeres and compromised DNA damage response in cells of Ataxia Telangiectasia patients are linked with frequent chromotripsis. Additionally, we show that ATM loss is associated with increased chromothripsis prevalence in further tumor entities. Citation Format: Manasi Ratnaparkhe, Mario Hlevnjak, Thorsten Kolb, Anna Jauch, Kendra Maass, Frauke Devens, Agata Rode, Volker Hovestadt, Andrey Korshunov, Agata Pastorczak, Wojciech Mlynarski, Stephanie Sungalee, Jan Korbel, Jessica Hoell, Ute Fischer, Till Milde, Christof Kramm, Michaela Nathrath, Krystyna Chrzanowska, Eugen Tausch, Masatoshi Takagi, Takashi Taga, Shlomi Constantini, Jan Loeffen, Jules Meijerink, Stefan Zielen, Gudrun Goehring, Brigitte Schlegelberger, Eberhard Maass, Reiner Siebert, Joachim Kunz, Andreas Kulozik, Barbara Worst, David Jones, Stefan Pfister, Marc Zapatka, Peter Lichter, Aurelie Ernst. Genomic profiling of acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 509. doi:10.1158/1538-7445.AM2017-509
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-509
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 4
    Online Resource
    Online Resource
    Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 1 ( 2015-01-01), p. 134-146
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 1 ( 2015-01-01), p. 134-146
    Abstract: Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)–driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH medulloblastoma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood–brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHH-driven medulloblastoma. Cancer Res; 75(1); 134–46. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-13-3629
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 5
    Online Resource
    Online Resource
    Abstract B71: Molecular heterogeneity and novel oncogenic fusions in RELA- and YAP1- negative supratentorial ependymoma
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 14_Supplement ( 2020-07-15), p. B71-B71
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 14_Supplement ( 2020-07-15), p. B71-B71
    Abstract: Introduction: One of the DNA methylation-based molecular subgroups of supratentorial ependymoma (ST-EPN), designated ST-EPN-RELA, mostly harbors fusions of the uncharacterized gene C11orf95 and RELA (ST-EPN-RELA). Rarely, no C11orf95-RELA fusion is detected in tumors predicted to belong to the ST-EPN-RELA group. With this study we aimed to refine the molecular classification of ST-EPN and to identify alternative oncogenic mechanisms in the absence of a classic fusion type. Methods and Materials: In an unbiased approach, t-Distributed Stochastic Neighbor Embedding was applied to 53,468 DNA methylation profiles from brain tumors, other cancer types, and control tissues. Only samples clustering with a reference set of ST-EPN-RELA were selected for further analyses (n=614), including RNA- and/or DNA-panel sequencing, histopathologic reevaluation, and immunohistochemistry for L1CAM. Fusions were validated using RT-PCR on total RNA and Sanger sequencing. Clinical data were analyzed retrospectively for 150 patients. Results: We identified one large and four satellite clusters. The large cluster (n=479; designated ST-EPN-RELA 1) and one of the satellite clusters (n=12; ST-EPN-RELA 2) predominantly contained samples with a calibrated score ≥ 0.9 for ST-EPN-RELA based on the current version of the Heidelberg Brain Tumor Classifier. Samples of the three other satellite clusters (n=41, n=17, and n=25 samples) contained 65.9%, 88.2%, and 96.0% of samples with a calibrated score & lt; 0.9 for any methylation class, and were thus predicted as unclassifiable. These clusters were provisionally designated ST-EPN-RELA-like A, B, and C, and initial histologic diagnoses showed a wide spectrum of rare morphologies beside EPN, e.g., sarcoma and teratoma. Within clusters ST-EPN-RELA-like A and C, sequencing revealed fusions of C11orf95 with different partner genes, including MAML2 (n=14), MAML3 (n=2), and NCOA2 (n=7), while ST-EPN-RELA-like B included classic C11orf95-RELA fusions (n=11) in samples with initial diagnoses other than EPN. Copy number variation analysis showed clear differences between the clusters. L1CAM-positivity was observed in all groups. Within the cluster ST-EPN-RELA 1, samples separated according to fusion types, 1 versus 2/3. Analysis of clinical data showed significant differences in overall survival between cases with confirmed C11orf95-RELA fusion type 1 (n=25, median OS=88 months) and type 2/3 (n=20, median OS=67 months). Clinical data collection for the satellite clusters is currently ongoing. Conclusion: Molecular refinement of ST-EPN-RELA revealed novel subgroups harboring fusions of C11orf95 with numerous fusion partners different from RELA, which will be included in the next update of the Heidelberg Classifier. Preliminary analysis suggests differences in clinical outcome related to the fusion type. Findings of this study will improve diagnostic accuracy and clinical management and need to be considered when developing targeted treatment strategies against ST-EPN. Citation Format: D.R. Ghasemi, K. Okonechnikov, A. Korshunov, M. Sill, T. Zheng, J.M. Huebner, K.K. Maass, J. Benzel, M. Snuderl, J. Gojo, U. Schüller, N.U. Gerber, I. Stoler, P. Hernáiz-Driever, T. Milde, D. Sturm, R. Chapman, R.G. Grundy, A. von Deimling, D. Kawauchi, D.T.W. Jones, M. Kool, S.M. Pfister, F. Sahm, K.W. Pajtler. Molecular heterogeneity and novel oncogenic fusions in RELA- and YAP1-negative supratentorial ependymoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B71.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PEDCA19-B71
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 6
    Online Resource
    Online Resource
    The Transcription Factor Evi-1 Is Overexpressed, Promotes Proliferation, and Is Prognostically Unfavorable in Infratentorial Ependymomas
    American Association for Cancer Research (AACR) ; 2011
    In:  Clinical Cancer Research Vol. 17, No. 11 ( 2011-06-01), p. 3631-3637
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 11 ( 2011-06-01), p. 3631-3637
    Abstract: Purpose: Ependymomas are glial tumors of presumably radial glial origin that share morphologic similarities with ependymal cells. The molecular genetics of ependymomas of supratentorial, infratentorial, and spinal location is heterogeneous. We aimed at identifying pathways operative in the development of infratentorial ependymomas. Experimental Design: To do so, gene expression profiles of tumor cells laser microdissected from infratentorial ependymomas (n = 15) were compared with that of nonneoplastic ependymal cells laser microdissected from autopsy tissue (n = 7). Results: Among 31 genes significantly overexpressed ( & gt;5-fold) in ependymomas, transcription factor EVI1 (ecotropic viral integration site 1) showed the highest overexpression (35-fold). Evi-1 protein expression could be confirmed in formalin-fixed, paraffin-embedded samples of 26 of 28 infratentorial ependymomas but only in 7 of 47 nonependymal glial tumors (P & lt; 0.001). Furthermore, MDS1/EVI1 fusion transcripts were detectable in 17 of 28 infratentorial ependymomas and significantly correlated with MGMT (O6-methylguanine-DNA-methyltransferase) promoter hypermethylation (P & lt; 0.05). In primary infratentorial ependymoma cells, transfection with EVI1-specific siRNAs resulted in significant growth inhibition [48 hours: 87% ± 2% and 74% ± 10% as compared with control (mean ± SD; P & lt; 0.001)]. The prognostic role of EVI1 could further be validated in an independent cohort of 39 infratentorial and 26 supratentorial ependymomas on the basis of mRNA expression profiling. Although in supratentorial ependymomas EVI1 expression status had no prognostic impact, in infratentorial ependymomas, high EVI1 expression was associated with shorter overall survival and progression-free survival. Conclusions: To conclude, the transcription factor Evi-1 is overexpressed in infratentorial ependymomas, promotes proliferation of ependymal tumor cells, and is prognostically unfavorable. Clin Cancer Res; 17(11); 3631–7. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-11-0175
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 7
    Online Resource
    Online Resource
    Genetic Aberrations Leading to MAPK Pathway Activation Mediate Oncogene-Induced Senescence in Sporadic Pilocytic Astrocytomas
    American Association for Cancer Research (AACR) ; 2011
    In:  Clinical Cancer Research Vol. 17, No. 14 ( 2011-07-15), p. 4650-4660
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 14 ( 2011-07-15), p. 4650-4660
    Abstract: Purpose: Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS) through activation of the mitogen-activated protein kinase (MAPK) pathway. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas (PA), the most prevalent brain neoplasm in children. We investigated whether OIS is induced in PA. Experimental Design: We tested expression of established senescence markers in three independent cohorts of sporadic PA. We also assessed for OIS in vitro, using forced expression of wild-type and V600E-mutant BRAF in two astrocytic cell lines: human telomerase reverse transcriptase (hTERT)-immortalized astrocytes and fetal astrocytes. Results: Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic β-galactosidase activity, low KI-67 index, and induction of p16INK4a but not p53 in the majority of 52 PA samples (46 of 52; 88.5%). Overexpression of a number of senescence-associated genes [CDKN2A (p16), CDKN1A (p21), CEBPB, GADD45A, and IGFBP7] was shown at the mRNA level in two independent PA tumor series. In vitro, sustained activation of wild-type or mutant BRAF induced OIS in both astrocytic cell lines. Loss of p16INK4a in immortalized astrocytes abrogated OIS, indicative of the role of this pathway in mediating this phenomenon in astrocytes. OIS is a mechanism of tumor suppression that restricts the progression of benign tumors. We show that it is triggered in PAs through p16INK4a pathway induction following aberrant MAPK activation. Conclusions: OIS may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas, and the high overall survival of affected patients. Clin Cancer Res; 17(14); 4650–60. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-11-0127
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 8
    Online Resource
    Online Resource
    Clinically Tractable Outcome Prediction of Non-WNT/Non-SHH Medulloblastoma Based on TPD52 IHC in a Multicohort Study
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 1 ( 2022-01-01), p. 116-128
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 1 ( 2022-01-01), p. 116-128
    Abstract: International consensus and the 2021 WHO classification recognize eight molecular subgroups among non-WNT/non-SHH (Group 3/4) medulloblastoma, representing approximately 60% of tumors. However, very few clinical centers worldwide possess the technical capabilities to determine DNA methylation profiles or other molecular parameters of high risk for group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an IHC marker as a clinically tractable method for improved medulloblastoma risk stratification. Experimental Design: We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. Results: TPD52 IHC positivity represented a significant independent predictor of early relapse and death for group 3/4 medulloblastoma [HRs between 3.67 and 26.7; 95% confidence interval (CI) between 1.00 and 706.23; P = 0.05, 0.017, and 0.0058]. Cross-validated survival models incorporating TPD52 IHC with clinical features outperformed existing state-of-the-art risk stratification schemes, and reclassified approximately 50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity was a predictive indicator of poor response to chemotherapy [HR, 12.66; 95% CI, 3.53–45.40; P & lt; 0.0001], suggesting important implication for therapeutic choices. Conclusions: This study redefines the approach to risk stratification in group 3/4 medulloblastoma in global practice. Because integration of TPD52 IHC in classification algorithms significantly improved outcome prediction, this test could be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-2057
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 9
    Online Resource
    Online Resource
    Spinal Myxopapillary Ependymomas Demonstrate a Warburg Phenotype
    American Association for Cancer Research (AACR) ; 2015
    In:  Clinical Cancer Research Vol. 21, No. 16 ( 2015-08-15), p. 3750-3758
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 16 ( 2015-08-15), p. 3750-3758
    Abstract: Purpose: Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. Experimental Design: Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production. Results: At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. Conclusions: Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE. Clin Cancer Res; 21(16); 3750–8. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-2650
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 10
    Online Resource
    Online Resource
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
Nothing or not found what you are looking for? Please check your search query or use the Interlibrary Loan Search.
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages