Stefan Pfister

Publications (33)242.45 Total impact

• Article: Molecular subgroups of medulloblastoma.

  Paul A Northcott, Adrian M Dubuc, Stefan Pfister, Michael D Taylor
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  ABSTRACT: Recent efforts at stratifying medulloblastomas based on their molecular features have revolutionized our understanding of this morbidity. Collective efforts by multiple independent groups have subdivided medulloblastoma from a single disease into four distinct molecular subgroups characterized by disparate transcriptional signatures, mutational spectra, copy number profiles and, most importantly, clinical features. We present a summary of recent studies that have contributed to our understanding of the core medulloblastoma subgroups, focusing largely on clinically relevant discoveries that have already, and will continue to, shape research.
  Expert Review of Neurotherapeutics 07/2012; 12(7):871-84.
• Article: Subgroup-specific alternative splicing in medulloblastoma.

  Adrian M Dubuc, A Sorana Morrissy, Nanne K Kloosterhof, Paul A Northcott, Emily P Y Yu, David Shih, John Peacock, Wieslawa Grajkowska, Timothy van Meter, Charles G Eberhart, Stefan Pfister, Marco A Marra, William A Weiss, Stephen W Scherer, James T Rutka, Pim J French, Michael D Taylor
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  ABSTRACT: Medulloblastoma comprises four distinct molecular variants: WNT, SHH, Group 3, and Group 4. We analyzed alternative splicing usage in 14 normal cerebellar samples and 103 medulloblastomas of known subgroup. Medulloblastoma samples have a statistically significant increase in alternative splicing as compared to normal fetal cerebella (2.3-times; P < 6.47E-8). Splicing patterns are distinct and specific between molecular subgroups. Unsupervised hierarchical clustering of alternative splicing events accurately assigns medulloblastomas to their correct subgroup. Subgroup-specific splicing and alternative promoter usage was most prevalent in Group 3 (19.4%) and SHH (16.2%) medulloblastomas, while observed less frequently in WNT (3.2%), and Group 4 (9.3%) tumors. Functional annotation of alternatively spliced genes reveals overrepresentation of genes important for neuronal development. Alternative splicing events in medulloblastoma may be regulated in part by the correlative expression of antisense transcripts, suggesting a possible mechanism affecting subgroup-specific alternative splicing. Our results identify additional candidate markers for medulloblastoma subgroup affiliation, further support the existence of distinct subgroups of the disease, and demonstrate an additional level of transcriptional heterogeneity between medulloblastoma subgroups.
  Acta Neuropathologica 02/2012; 123(4):485-99. · 9.32 Impact Factor
• Source

  Available from: Marcel Kool

  Article: Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples.

  Paul A Northcott, David J H Shih, Marc Remke, Yoon-Jae Cho, Marcel Kool, Cynthia Hawkins, Charles G Eberhart, Adrian Dubuc, Toumy Guettouche, Yoslayma Cardentey, Eric Bouffet, Scott L Pomeroy, Marco Marra, David Malkin, James T Rutka, Andrey Korshunov, Stefan Pfister, Michael D Taylor
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  ABSTRACT: The diagnosis of medulloblastoma likely encompasses several distinct entities, with recent evidence for the existence of at least four unique molecular subgroups that exhibit distinct genetic, transcriptional, demographic, and clinical features. Assignment of molecular subgroup through routine profiling of high-quality RNA on expression microarrays is likely impractical in the clinical setting. The planning and execution of medulloblastoma clinical trials that stratify by subgroup, or which are targeted to a specific subgroup requires technologies that can be economically, rapidly, reliably, and reproducibly applied to formalin-fixed paraffin embedded (FFPE) specimens. In the current study, we have developed an assay that accurately measures the expression level of 22 medulloblastoma subgroup-specific signature genes (CodeSet) using nanoString nCounter Technology. Comparison of the nanoString assay with Affymetrix expression array data on a training series of 101 medulloblastomas of known subgroup demonstrated a high concordance (Pearson correlation r = 0.86). The assay was validated on a second set of 130 non-overlapping medulloblastomas of known subgroup, correctly assigning 98% (127/130) of tumors to the appropriate subgroup. Reproducibility was demonstrated by repeating the assay in three independent laboratories in Canada, the United States, and Switzerland. Finally, the nanoString assay could confidently predict subgroup in 88% of recent FFPE cases, of which 100% had accurate subgroup assignment. We present an assay based on nanoString technology that is capable of rapidly, reliably, and reproducibly assigning clinical FFPE medulloblastoma samples to their molecular subgroup, and which is highly suited for future medulloblastoma clinical trials.
  Acta Neuropathologica 11/2011; 123(4):615-26. · 9.32 Impact Factor
• Article: Genome-wide molecular characterization of central nervous system primitive neuroectodermal tumor and pineoblastoma.

  Suzanne Miller, Hazel A Rogers, Paul Lyon, Vikki Rand, Martyna Adamowicz-Brice, Steven C Clifford, James T Hayden, Sara Dyer, Stefan Pfister, Andrey Korshunov, Marie-Anne Brundler, James Lowe, Beth Coyle, Richard G Grundy
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  ABSTRACT: Central nervous system primitive neuroectodermal tumor (CNS PNET) and pineoblastoma are highly malignant embryonal brain tumors with poor prognoses. Current therapies are based on the treatment of pediatric medulloblastoma, even though these tumors are distinct at both the anatomical and molecular level. CNS PNET and pineoblastoma have a worse clinical outcome than medulloblastoma; thus, improved therapies based on an understanding of the underlying biology of CNS PNET and pineoblastoma are needed. To this end, we characterized the genomic alterations of 36 pediatric CNS PNETs and 8 pineoblastomas using Affymetrix single nucleotide polymorphism arrays. Overall, the majority of CNS PNETs contained a greater degree of genomic imbalance than pineoblastomas, with gain of 19p (8 [27.6%] of 29), 2p (7 [24.1%] of 29), and 1q (6 [20.7%] of 29) common events in primary CNS PNETs. Novel gene copy number alterations were identified and corroborated by Genomic Identification of Significant Targets In Cancer (GISTIC) analysis: gain of PCDHGA3, 5q31.3 in 62.1% of primary CNS PNETs and all primary pineoblastomas and FAM129A, 1q25 in 55.2% of primary CNS PNETs and 50% of primary pineoblastomas. Comparison of our GISTIC data with publically available data for medulloblastoma confirmed these CNS PNET-specific copy number alterations. With use of the collection of 5 primary and recurrent CNS PNET pairs, we found that gain of 2p21 was maintained at relapse in 80% of cases. Novel gene copy number losses included OR4C12, 11p11.12 in 48.2% of primary CNS PNETs and 50% of primary pineoblastomas. Loss of CDKN2A/B (9p21.3) was identified in 14% of primary CNS PNETs and was significantly associated with older age among children (P = .05). CADPS, 3p14.2 was lost in 27.6% of primary CNS PNETs and was associated with poor prognosis (P = .043). This genome-wide analysis revealed the marked molecular heterogeneity of CNS PNETs and enabled the identification of novel genes and clinical associations potentially involved in the pathogenesis of these tumors.
  Neuro-Oncology 08/2011; 13(8):866-79. · 5.72 Impact Factor
• Article: Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct.

  Paul A Northcott, Thomas Hielscher, Adrian Dubuc, Stephen Mack, David Shih, Marc Remke, Hani Al-Halabi, Steffen Albrecht, Nada Jabado, Charles G Eberhart, Wieslawa Grajkowska, William A Weiss, Steven C Clifford, Eric Bouffet, James T Rutka, Andrey Korshunov, Stefan Pfister, Michael D Taylor
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  ABSTRACT: Recent integrative genomic approaches have defined molecular subgroups of medulloblastoma that are genetically and clinically distinct. Sonic hedgehog (Shh) medulloblastomas account for one-third of all cases and comprise the majority of infant and adult medulloblastomas. To discern molecular heterogeneity among Shh-medulloblastomas, we analyzed transcriptional profiles from four independent Shh-medulloblastoma expression datasets (n = 66). Unsupervised clustering analyses demonstrated a clear distinction between infant and adult Shh-medulloblastomas, which was reliably replicated across datasets. Comparison of transcriptomes from infant and adult Shh-medulloblastomas revealed deregulation of multiple gene families, including genes implicated in cellular development, synaptogenesis, and extracellular matrix maintenance. Furthermore, metastatic dissemination is a marker of poor prognosis in adult, but not in pediatric Shh-medulloblastomas. Children with desmoplastic Shh-medulloblastomas have a better prognosis than those with Shh-medulloblastomas and classic histology. Desmoplasia is not prognostic for adult Shh-medulloblastoma. Cytogenetic analysis of a large, non-overlapping cohort of Shh-medulloblastomas (n = 151) revealed significant over-representation of chromosome 10q deletion (P < 0.001) and MYCN amplification (P < 0.05) in pediatric Shh cases compared with adults. Adult Shh-medulloblastomas harboring chromosome 10q deletion, 2 gain, 17p deletion, 17q gain, and/or GLI2 amplification have a much worse prognosis as compared to pediatric cases exhibiting the same aberrations. Collectively, our data demonstrate that pediatric and adult Shh-medulloblastomas are clinically, transcriptionally, genetically, and prognostically distinct.
  Acta Neuropathologica 06/2011; 122(2):231-40. · 9.32 Impact Factor
• Article: The transcription factor evi-1 is overexpressed, promotes proliferation, and is prognostically unfavorable in infratentorial ependymomas.

  Björn Koos, Sebastian Bender, Hendrik Witt, Sonja Mertsch, Jörg Felsberg, Rudi Beschorner, Andrey Korshunov, Barbara Riesmeier, Stefan Pfister, Werner Paulus, Martin Hasselblatt
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  ABSTRACT: 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. 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). Among 31 genes significantly overexpressed (>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 < 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 < 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 < 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. To conclude, the transcription factor Evi-1 is overexpressed in infratentorial ependymomas, promotes proliferation of ependymal tumor cells, and is prognostically unfavorable.
  Clinical Cancer Research 06/2011; 17(11):3631-7. · 7.74 Impact Factor
• Article: Medulloblastoma comprises four distinct molecular variants.

  Paul A Northcott, Andrey Korshunov, Hendrik Witt, Thomas Hielscher, Charles G Eberhart, Stephen Mack, Eric Bouffet, Steven C Clifford, Cynthia E Hawkins, Pim French, James T Rutka, Stefan Pfister, Michael D Taylor
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  ABSTRACT: Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups. We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the data set. Immunohistochemistry for subgroup-specific signature genes was used to determine subgroup affiliation for 294 nonoverlapping medulloblastomas on two independent tissue microarrays. Multiple unsupervised analyses of transcriptional profiles identified the following four distinct, nonoverlapping molecular variants: WNT, SHH, group C, and group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (group C), and KCNA1 (group D) could reliably and uniquely classify formalin-fixed medulloblastomas in approximately 98% of patients. Group C patients (NPR3-positive tumors) exhibited a significantly diminished progression-free and overall survival irrespective of their metastatic status. Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma subclassification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma.
  Journal of Clinical Oncology 04/2011; 29(11):1408-14. · 18.37 Impact Factor
• Article: An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice.

  Jan Gronych, Andrey Korshunov, Josephine Bageritz, Till Milde, Manfred Jugold, Dolores Hambardzumyan, Marc Remke, Christian Hartmann, Hendrik Witt, David T W Jones, Olaf Witt, Sabine Heiland, Martin Bendszus, Eric C Holland, Stefan Pfister, Peter Lichter
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  ABSTRACT: Pilocytic astrocytoma (PA) is the most common type of primary brain tumor in children and the second most frequent cancer in childhood. Children with incompletely resected PA represent a clinically challenging patient cohort for whom conventional adjuvant therapies are only moderately effective. This has produced high clinical demand for testing of new molecularly targeted treatments. However, the development of new therapeutics for PA has been hampered by the lack of an adequate in vivo tumor model. Recent studies have identified activation of MAPK signaling, mainly by oncogenic BRAF activation, as a hallmark genetic event in the pathogenesis of human PA. Using in vivo retroviral somatic gene transfer into mouse neural progenitor cells, we have shown here that ectopic expression of the activated BRAF kinase domain is sufficient to induce PA in mice. Further in vitro analyses demonstrated that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with the kinase inhibitor sorafenib. Our in vivo model for PA shows that the activated BRAF kinase domain is sufficient to induce PA and highlights its role as a potential therapeutic target.
  The Journal of clinical investigation 03/2011; 121(4):1344-8. · 15.39 Impact Factor
• Source

  Available from: Heymut Omran

  Article: Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma.

  Genevieve Schindler, David Capper, Jochen Meyer, Wibke Janzarik, Heymut Omran, Christel Herold-Mende, Kirsten Schmieder, Pieter Wesseling, Christian Mawrin, Martin Hasselblatt, David N Louis, Andrey Korshunov, Stefan Pfister, Christian Hartmann, Werner Paulus, Guido Reifenberger, Andreas von Deimling
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  ABSTRACT: Missense mutations of the V600E type constitute the vast majority of tumor-associated somatic alterations in the v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene. Initially described in melanoma, colon and papillary thyroid carcinoma, these alterations have also been observed in primary nervous system tumors albeit at a low frequency. We analyzed exon 15 of BRAF spanning the V600 locus by direct sequencing in 1,320 adult and pediatric tumors of the nervous system including various types of glial, embryonal, neuronal and glioneuronal, meningeal, adenohypophyseal/sellar, and peripheral nervous system tumors. A total of 96 BRAF mutations were detected; 93 of the V600E type and 3 cases with a three base pair insertion between codons 599 and 600. The highest frequencies of BRAF (V600E) mutations were found in WHO grade II pleomorphic xanthoastrocytomas (42/64; 66%) and pleomorphic xanthoastrocytomas with anaplasia (15/23; 65%), as well as WHO grade I gangliogliomas (14/77; 18%), WHO grade III anaplastic gangliogliomas (3/6) and pilocytic astrocytomas (9/97; 9%). In pilocytic astrocytomas BRAF (V600E) mutation was strongly associated with extra-cerebellar location (p = 0.009) and was most frequent in diencephalic tumors (4/12; 33%). Glioblastomas and other gliomas were characterized by a low frequency or absence of mutations. No mutations were detected in non-glial tumors, including embryonal tumors, meningiomas, nerve sheath tumors and pituitary adenomas. The high mutation frequencies in pleomorphic xanthoastrocytomas, gangliogliomas and extra-cerebellar pilocytic astrocytomas implicate BRAF (V600E) mutation as a valuable diagnostic marker for these rare tumor entities. Future clinical trials should address whether BRAF (V600E) mutant brain tumor patients will benefit from BRAF (V600E)-directed targeted therapies.
  Acta Neuropathologica 03/2011; 121(3):397-405. · 9.32 Impact Factor
• Article: [Reliability of molecular tumour markers in children with medulloblastoma--an example from clinical practice].

  Stefan Pfister
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  ABSTRACT: During the 1960s less than five percent of the children suffering from cancer could be cured. Today we are able to cure approximately three quarters. It is research in molecular biology elucidating the origin of cancer at the level of cells, genes and molecules that has accounted for this success. Research results include, for example, the identification of molecular markers of leukaemia that are able to predict the intensity of therapy necessary for maximum benefit. Furthermore, molecular markers have been identified for paediatric brain tumours which raise the hope for more individualized and targeted therapy.
  Zeitschrift für Evidenz Fortbildung und Qualität im Gesundheitswesen 01/2011; 105(7):511-3.
• Article: Absence of chromosome 19q13.41 amplification in a case of atypical teratoid/rhabdoid tumor with ependymoblastic differentiation.

  Marco Gessi, Stefan Pfister, Volkmar H Hans, Andrey Korshunov, Torsten Pietsch
  Acta Neuropathologica 11/2010; 121(2):283-5. · 9.32 Impact Factor
• Article: Molecular staging of intracranial ependymoma in children and adults.

  Andrey Korshunov, Hendrik Witt, Thomas Hielscher, Axel Benner, Marc Remke, Marina Ryzhova, Till Milde, Sebastian Bender, Andrea Wittmann, Anna Schöttler, Andreas E Kulozik, Olaf Witt, Andreas von Deimling, Peter Lichter, Stefan Pfister
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  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. 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. 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. 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.
  Journal of Clinical Oncology 07/2010; 28(19):3182-90. · 18.37 Impact Factor
• Article: The genetics of pediatric brain tumors.

  Adrian M Dubuc, Paul A Northcott, Stephen Mack, Hendrik Witt, Stefan Pfister, Michael D Taylor
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  ABSTRACT: Brain tumors are the most common childhood solid malignancy and the leading cause of cancer-related death in children. Medulloblastoma, ependymoma, supratentorial primitive neuroectodermal tumors, and pilocytic astrocytoma are the most prevalent types, all of which are clinically, histologically, and genetically heterogeneous. Despite an incomplete molecular understanding of these tumors, we have made significant headway in the past 5 years in identifying and classifying important genetic alterations and pathways central to the disease process. This review summarizes our current state of knowledge, emphasizes recent seminal findings in the field, and proposes future research efforts needed to further characterize the genetic basis of pediatric brain tumors.
  Current Neurology and Neuroscience Reports 05/2010; 10(3):215-23. · 3.45 Impact Factor
• Article: HDAC5 and HDAC9 in medulloblastoma: novel markers for risk stratification and role in tumor cell growth.

  Till Milde, Ina Oehme, Andrey Korshunov, Annette Kopp-Schneider, Marc Remke, Paul Northcott, Hedwig E Deubzer, Marco Lodrini, Michael D Taylor, Andreas von Deimling, Stefan Pfister, Olaf Witt
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  ABSTRACT: 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. 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. 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. 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.
  Clinical Cancer Research 04/2010; 16(12):3240-52. · 7.74 Impact Factor
• Source

  Available from: PubMed Central

  Article: DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells.

  Simone Bork, Stefan Pfister, Hendrik Witt, Patrick Horn, Bernhard Korn, Anthony D Ho, Wolfgang Wagner
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  ABSTRACT: Within 2-3 months of in vitro culture-expansion, mesenchymal stromal cells (MSC) undergo replicative senescence characterized by cell enlargement, loss of differentiation potential and ultimate growth arrest. In this study, we have analyzed DNA methylation changes upon long-term culture of MSC by using the HumanMethylation27 BeadChip microarray assessing 27,578 unique CpG sites. Furthermore, we have compared MSC from young and elderly donors. Overall, methylation patterns were maintained throughout both long-term culture and aging but highly significant differences were observed at specific CpG sites. Many of these differences were observed in homeobox genes and genes involved in cell differentiation. Methylation changes were verified by pyrosequencing after bisulfite conversion and compared to gene expression data. Notably, methylation changes in MSC were overlapping in long-term culture and aging in vivo. This supports the notion that replicative senescence and aging represent developmental processes that are regulated by specific epigenetic modifications.
  Aging cell 11/2009; 9(1):54-63. · 7.55 Impact Factor
• Source

  Available from: rutgers.edu

  Article: Histology and molecular pathology of pediatric brain tumors.

  Stefan Pfister, Christian Hartmann, Andrey Korshunov
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  ABSTRACT: In recent years, brain tumors have become the single most frequent cause of cancer-related mortality in children, although their frequency is approximately 50% less than leukemia. According to the classification of the World Health Organization, histopathological diagnosis is of paramount importance for clinicians to choose the most appropriate treatment option and tailor treatment intensity to disease risk. However, histopathological assessment is often difficult, and adding molecular information to classic neuropathological analyses may help ensure diagnostic accuracy, improve risk stratification of patients within a given tumor entity, and help in identifying novel therapeutic targets for an individualized treatment approach. Therefore, this review focuses both on established histopathology as well as on molecular features in the most important brain tumors in children.
  Journal of child neurology 11/2009; 24(11):1375-86. · 1.59 Impact Factor
• Article: From glioblastoma to gangliocytoma: an unforeseen but welcome shift in biological behavior.

  Astrid Jeibmann, Martin Hasselblatt, Stefan Pfister, Ronald Sträter, Angela Brentrup, Markus Holling, Thomas Niederstadt, Werner Paulus, Michael C Frühwald
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  ABSTRACT: The prognosis in children harboring a glioblastoma multiforme (GBM) is usually poor. Few GBMs in children, however, seem to respond quite well to adjuvant chemotherapy. The biological basis for such chemotherapy sensitivity remains uncertain. In this paper the authors report the case of a 2-month-old girl with a histologically confirmed GBM (WHO Grade IV) in whom chemotherapy was accompanied by differentiation of the malignant primary tumor into a typical gangliocytoma (WHO Grade I) showing ganglioid differentiation and expression of neuronal markers synaptophysin, neurofilament, and NeuN as well as a low Ki 67/MIB-1 proliferation index. Array-comparative genomic hybridization did not reveal genetic alterations in either specimen. Even though the underlying biological mechanisms remain to be elucidated, closer examination of frequency and prognostic significance of neuronal differentiation in pediatric GBMs within ongoing and future clinical trials may be warranted.
  Journal of Neurosurgery Pediatrics 11/2009; 4(5):475-8. · 1.53 Impact Factor
• Article: Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma.

  Andrey Korshunov, Jochen Meyer, David Capper, Arne Christians, Marc Remke, Hendrik Witt, Stefan Pfister, Andreas von Deimling, Christian Hartmann
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  ABSTRACT: Separation of pilocytic astrocytoma from diffuse astrocytomas frequently poses problems mostly related to small sample size. Precise classification and grading are essential due to different therapeutic strategies prompted by diagnoses of pilocytic astrocytoma WHO grade I, diffuse astrocytomas WHO grade II or anaplastic astrocytoma WHO grade III. Recently, genomic aberrations with a high specificity for distinct glioma entities have been described. Pilocytic astrocytomas carry a duplication at chromosome band 7q34 containing a BRAF-KIAA1549 gene fusion in the majority of cases. IDH1 mutations are observed very frequently in adult astrocytomas and IDH2 mutations have been reported in some astrocytomas. We examined a series of 120 astrocytomas including 70 pilocytic astrocytomas WHO grade I and 50 diffuse astrocytomas WHO grade II for both, BRAF-KIAA1549 fusion with a newly developed FISH assay and mutations in IDH1 and IDH2 by direct sequencing. Pilocytic astrocytomas contained the BRAF fusion in 49 cases (70%) but neither IDH1 nor IDH2 mutations. Astrocytomas WHO grade II exhibited IDH1 mutations in 38 cases (76%) but neither IDH2 mutations nor BRAF fusions. Thus, combined molecular analysis of BRAF and IDH1 is a sensitive and highly specific approach to separate pilocytic astrocytoma from diffuse astrocytoma.
  Acta Neuropathologica 07/2009; 118(3):401-5. · 9.32 Impact Factor
• Article: High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-beta and PI3K-AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavorable early treatment response.

  Marc Remke, Stefan Pfister, Corinne Kox, Grischa Toedt, Natalia Becker, Axel Benner, Wiebke Werft, Stephen Breit, Shuangyou Liu, Felix Engel, Andrea Wittmann, Martin Zimmermann, Martin Stanulla, Martin Schrappe, Wolf-Dieter Ludwig, Claus R Bartram, Bernhard Radlwimmer, Martina U Muckenthaler, Peter Lichter, Andreas E Kulozik
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  ABSTRACT: Precursor T-cell acute lymphoblastic leukemia (T-ALL) in children represents a clinical challenge, because relapses are usually fatal. It is thus necessary to identify high-risk patients as early as possible to effectively individualize treatment. We aimed to define novel molecular risk markers in T-ALL and performed array-based comparative genomic hybridization (array-CGH) and expression analyses in 73 patients. We show that DNA copy-number changes are common in T-ALL and affect 70 of 73 (96%) patients. Notably, genomic imbalances predicted to down-regulate the TGF-beta or up-regulate the PI3K-AKT pathways are identified in 25 of 73 (34%) and 21 of 73 (29%) patients, suggesting that these pathways play key roles in T-ALL leukemogenesis. Furthermore, we identified a deletion at 6q15-16.1 in 9 of 73 (12%) of the patients, which predicts poor early treatment response. This deletion includes the CASP8AP2 gene, whose expression is shown to be down-regulated. The interaction of CASP8AP2 with CASP8 plays a crucial role in apoptotic regulation, suggesting a functional link between the clinical effect of the deletion and the molecular mode of action. The data presented here implicate the TGF-beta and PI3K-AKT pathways in T-ALL leukemogenesis and identify a subgroup of patients with CASP8AP2 deletions and poor early treatment response.
  Blood 05/2009; 114(5):1053-62. · 9.90 Impact Factor
• Article: Novel oncogene amplifications in tumors from a family with Li-Fraumeni syndrome.

  Juliane Rieber, Marc Remke, Christian Hartmann, Andrey Korshunov, Birgit Burkhardt, Dominik Sturm, Gunhild Mechtersheimer, Andrea Wittmann, Johann Greil, Claudia Blattmann, Olaf Witt, Wolfgang Behnisch, Marc-Eric Halatsch, Berk Orakcioglu, Andreas von Deimling, Peter Lichter, Andreas Kulozik, Stefan Pfister
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  ABSTRACT: Li-Fraumeni syndrome (LFS) represents an inherited tumor syndrome that is typically caused by germline mutations of the tumor suppressor gene TP53. TP53 dysfunction secondarily disturbs the genetic integrity of the cell. Here, we report a family with LFS harboring a germline TP53 mutation (R248W) located in the functional domain of the protein that binds to the minor groove of the DNA. In this family, tumors of the central nervous system were diagnosed as primary malignancies in all carriers of the mutation. The index patient developed an anaplastic medulloblastoma with unusual genomic profile exhibiting six distinct high-level genomic amplifications, two of them targeting the MYCN and GLI2 genes, respectively. In an extrarenal rhabdoid tumor from the same patient, we found a novel high-level amplification of the MYC oncogene. The father of this patient was diagnosed with myxopapillary ependymoma (WHO degrees I), whereas a brother died from an early relapse of a choroid plexus carcinoma. The analysis of this LFS familiy thus revealed novel oncogene amplifications as different second hits that are likely to also play a role in the pathogenesis of their sporadic counterparts.
  Genes Chromosomes and Cancer 05/2009; 48(7):558-68. · 3.31 Impact Factor