Peter Lichter

Publications of Peter Lichter

• Corrigendum: Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.

  Authors: Jeremy Schwartzentruber, Andrey Korshunov, Xiao-Yang Liu, David T W Jones, Elke Pfaff, Karine Jacob, Dominik Sturm, Adam M Fontebasso, Dong-Anh Khuong Quang, Martje Tönjes [......] Olaf Witt, Cindy Zhang, Pedro Castelo-Branco, Peter Lichter, Damien Faury, Uri Tabori, Christoph Plass, Jacek Majewski, Stefan M Pfister, Nada Jabado

  Nature. 03/2012;

• Expression of podoplanin in human astrocytic brain tumors is controlled by the PI3K-AKT-AP-1 signaling pathway and promoter methylation.

  Authors: Heike Peterziel, Julia Müller, Andreas Danner, Sebastian Barbus, Hai-Kun Liu, Bernhard Radlwimmer, Torsten Pietsch, Peter Lichter, Günther Schütz, Jochen Hess, Peter Angel

  Neuro-oncology. 03/2012; 14(4):426-39.

  Recently, we found strong overexpression of the mucin-type glycoprotein podoplanin (PDPN) in human astrocytic brain tumors, specifically in primary glioblastoma multiforme (GB). In the current study,Recently, we found strong overexpression of the mucin-type glycoprotein podoplanin (PDPN) in human astrocytic brain tumors, specifically in primary glioblastoma multiforme (GB). In the current study, we show an inverse correlation between PDPN expression and PTEN levels in primary human GB and glioma cell lines, and we report elevated PDPN protein levels in the subventricular zone of brain tissue sections of PTEN-deficient mice. In human glioma cells lacking functional PTEN, reintroduction of wild-type PTEN, inhibition of the PTEN downstream target protein kinase B/AKT, or interference with transcription factor AP-1 function resulted in efficient downregulation of PDPN expression. In addition, we observed hypoxia-dependent PDPN transcriptional control and demonstrated that PDPN expression is subject to negative transcriptional regulation by promoter methylation in human GB and in glioma cell lines. Treatment of PTEN-negative glioma cells with demethylating agents induced expression of PDPN. Together, our findings show that increased PDPN expression in human GB is caused by loss of PTEN function and activation of the PI3K-AKT-AP-1 signaling pathway, accompanied by epigenetic regulation of PDPN promoter activity. Silencing of PDPN expression leads to reduced proliferation and migration of glioma cells, suggesting a functional role of PDPN in glioma progression and malignancy. Thus, specific targeting of PDPN expression and/or function could be a promising strategy for the treatment of patients with primary GB.

• Nos2 inactivation promotes the development of medulloblastoma in ptch1 mice by deregulation of gap43-dependent granule cell precursor migration.

  Authors: Daniel Haag, Petra Zipper, Viola Westrich, Daniela Karra, Karin Pfleger, Grischa Toedt, Frederik Blond, Nicolas Delhomme, Meinhard Hahn, Julia Reifenberger, Guido Reifenberger, Peter Lichter

  PLoS genetics. 03/2012; 8(3):e1002572.

  Medulloblastoma is the most common malignant brain tumor in children. A subset of medulloblastoma originates from granule cell precursors (GCPs) of the developing cerebellum and demonstrates aberrantMedulloblastoma is the most common malignant brain tumor in children. A subset of medulloblastoma originates from granule cell precursors (GCPs) of the developing cerebellum and demonstrates aberrant hedgehog signaling, typically due to inactivating mutations in the receptor PTCH1, a pathomechanism recapitulated in Ptch1(+/-) mice. As nitric oxide may regulate GCP proliferation and differentiation, we crossed Ptch1(+/-) mice with mice lacking inducible nitric oxide synthase (Nos2) to investigate a possible influence on tumorigenesis. We observed a two-fold higher medulloblastoma rate in Ptch1(+/-) Nos2(-/-) mice compared to Ptch1(+/-) Nos2(+/+) mice. To identify the molecular mechanisms underlying this finding, we performed gene expression profiling of medulloblastomas from both genotypes, as well as normal cerebellar tissue samples of different developmental stages and genotypes. Downregulation of hedgehog target genes was observed in postnatal cerebellum from Ptch1(+/+) Nos2(-/-) mice but not from Ptch1(+/-) Nos2(-/-) mice. The most consistent effect of Nos2 deficiency was downregulation of growth-associated protein 43 (Gap43). Functional studies in neuronal progenitor cells demonstrated nitric oxide dependence of Gap43 expression and impaired migration upon Gap43 knock-down. Both effects were confirmed in situ by immunofluorescence analyses on tissue sections of the developing cerebellum. Finally, the number of proliferating GCPs at the cerebellar periphery was decreased in Ptch1(+/+) Nos2(-/-) mice but increased in Ptch1(+/-) Nos2(-/) (-) mice relative to Ptch1(+/-) Nos2(+/+) mice. Taken together, these results indicate that Nos2 deficiency promotes medulloblastoma development in Ptch1(+/-) mice through retention of proliferating GCPs in the external granular layer due to reduced Gap43 expression. This study illustrates a new role of nitric oxide signaling in cerebellar development and demonstrates that the localization of pre-neoplastic cells during morphogenesis is crucial for their malignant progression.

• Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas.

  Authors: Marcel Kool, Andrey Korshunov, Marc Remke, David T W Jones, Maria Schlanstein, Paul A Northcott, Yoon-Jae Cho, Jan Koster, Antoinette Schouten-van Meeteren, Dannis van Vuurden [......] Christine Haberler, Franck Bourdeaut, Olivier Delattre, Francois Doz, David W Ellison, Richard J Gilbertson, Scott L Pomeroy, Michael D Taylor, Peter Lichter, Stefan M Pfister

  Acta neuropathologica. 02/2012; 123(4):473-84.

  Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises aMedulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future.

• miRNA-130a Targets ATG2B and DICER1 to Inhibit Autophagy and Trigger Killing of Chronic Lymphocytic Leukemia Cells.

  Authors: Valentina Kovaleva, Rodrigo Mora, Yoon Jung Park, Christoph Plass, Abhilash I Chiramel, Ralf Bartenschlager, Hartmut Döhner, Stephan Stilgenbauer, Armin Pscherer, Peter Lichter, Martina Seiffert

  Cancer research. 02/2012; 72(7):1763-72.

  Toxicity and relapses from the immunochemotherapy used to treat chronic lymphocytic leukemia (CLL) prompt continued interest in gentle but effective targeted treatment options for the mainly elderlyToxicity and relapses from the immunochemotherapy used to treat chronic lymphocytic leukemia (CLL) prompt continued interest in gentle but effective targeted treatment options for the mainly elderly population suffering from this disease. Here, we report the definition of critical CLL cell survival pathways that can be targeted by ectopic reexpression of the miRNA genes miR-130a and miR-143 which are widely downregulated in CLL. Notably, miR-130a inhibited autophagy by reducing autophagosome formation, an effect mediated by downregulation of the genes ATG2B and DICER1, the latter of which is a major component of the miRNA silencing machinery. In support of the concept of a fundamental connection between miRNA disregulation and altered autophagic flux in this cancer, we showed that RNA interference-mediated knockdown of DICER1 expression was sufficient to reduce autophagy in primary or established cultures of CLL cells. Together, our findings show that miR-130a modulates cell survival programs by regulating autophagic flux, and they define roles for miR-130a and Dicer1 in a regulatory feedback loop that mediates CLL cell survival. Cancer Res; 72(7); 1763-72. ©2012 AACR.

• Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.

  Authors: Jeremy Schwartzentruber, Andrey Korshunov, Xiao-Yang Liu, David T W Jones, Elke Pfaff, Karine Jacob, Dominik Sturm, Adam M Fontebasso, Dong-Anh Khuong Quang, Martje Tönjes [......] Olaf Witt, Cindy Zhang, Pedro Castelo-Branco, Peter Lichter, Damien Faury, Uri Tabori, Christoph Plass, Jacek Majewski, Stefan M Pfister, Nada Jabado

  Nature. 02/2012; 482(7384):226-31.

  Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. ToGlioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.

• Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.

  Authors: Tobias Rausch, David T W Jones, Marc Zapatka, Adrian M Stütz, Thomas Zichner, Joachim Weischenfeldt, Natalie Jäger, Marc Remke, David Shih, Paul A Northcott [......] Jan J Molenaar, Rogier Versteeg, Marcel Kool, Uri Tabori, David Malkin, Andrey Korshunov, Michael D Taylor, Peter Lichter, Stefan M Pfister, Jan O Korbel

  Cell. 01/2012; 148(1-2):59-71.

  Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in aGenomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.

• TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome.

  Authors: Frank G Rücker, Richard F Schlenk, Lars Bullinger, Sabine Kayser, Veronica Teleanu, Helena Kett, Marianne Habdank, Carla-Maria Kugler, Karlheinz Holzmann, Verena I Gaidzik [......] Marie von Lilienfeld-Toal, Michael Lübbert, Stefan Fröhling, Thorsten Zenz, Jürgen Krauter, Brigitte Schlegelberger, Arnold Ganser, Peter Lichter, Konstanze Döhner, Hartmut Döhner

  Blood. 12/2011; 119(9):2114-21.

  To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysisTo assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P < .0001) and by a higher frequency of specific copy number alterations, such as -5/5q-, -7/7q-, -16/16q-, -18/18q-, +1/+1p, and +11/+11q/amp11q13∼25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.

• MAPK pathway activation in pilocytic astrocytoma.

  Authors: David T W Jones, Jan Gronych, Peter Lichter, Olaf Witt, Stefan M Pfister

  Cellular and molecular life sciences : CMLS. 12/2011;

  Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated proteinPilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated protein kinase (MAPK) pathway signaling in the development and behavior of PAs. Several mechanisms lead to activation of this pathway in PA, mostly in a mutually exclusive manner, with constitutive BRAF kinase activation subsequent to gene fusion being the most frequent. The high specificity of this fusion to PA when compared with other CNS tumors has diagnostic utility. In addition, the frequency of alteration of this key pathway provides an opportunity for molecularly targeted therapy in this tumor. Here, we review the current knowledge on mechanisms of MAPK activation in PA and some of the downstream consequences of this activation, which are now starting to be elucidated both in vitro and in vivo, as well as clinical considerations and possible future directions.

• Biological and clinical heterogeneity of MYCN-amplified medulloblastoma.

  Authors: Andrey Korshunov, Marc Remke, Marcel Kool, Thomas Hielscher, Paul A Northcott, Dan Williamson, Elke Pfaff, Hendrik Witt, David T W Jones, Marina Ryzhova [......] William A Weiss, Andreas von Deimling, Wolfram Scheurlen, Andreas E Kulozik, Steven C Clifford, V Peter Collins, Frank Westermann, Michael D Taylor, Peter Lichter, Stefan M Pfister

  Acta neuropathologica. 12/2011;

  Focal high-level amplifications of MYC (or MYCC) define a subset of high-risk medulloblastoma patients. However, the prognostic role of MYCN oncogene amplification remains unresolved. We aimed toFocal high-level amplifications of MYC (or MYCC) define a subset of high-risk medulloblastoma patients. However, the prognostic role of MYCN oncogene amplification remains unresolved. We aimed to evaluate the prognostic value of this alteration alone and in combination with biological modifiers in 67 pediatric medulloblastomas with MYCN amplification (MYCN-MB). Twenty-one MYCN-MB were examined using gene expression profiling and array-CGH, whereas for 46 tumors immunohistochemical analysis and FISH were performed. All 67 tumors were further subjected to mutational analyses. We compared molecular, clinical, and prognostic characteristics both within biological MYCN-MB groups and with non-amplified tumors. Transcriptomic analysis revealed SHH-driven tumorigenesis in a subset of MYCN-MBs indicating a biological dichotomy of MYCN-MB. Activation of SHH was accompanied by variant-specific cytogenetic aberrations including deletion of 9q in SHH tumors. Non-SHH MB were associated with gain of 7q and isochromosome 17q/17q gain. Among clinically relevant variables, SHH subtype and 10q loss for non-SHH tumors comprised the most powerful markers of favorable prognosis in MYCN-MB. In conclusion, we demonstrate considerable heterogeneity within MYCN-MB in terms of genetics, tumor biology, and clinical outcome. Thus, assessment of disease group and 10q copy-number status may improve risk stratification of this group and may delineate MYCN-MB with the same dismal prognosis as MYC amplified tumors. Furthermore, based on the enrichment of MYCN and GLI2 amplifications in SHH-driven medulloblastoma, amplification of these downstream signaling intermediates should be taken into account before a patient is enrolled into a clinical trial using a smoothened inhibitor.

• Exploiting biological diversity and genomic aberrations in chronic lymphocytic leukemia.

  Authors: Martina Seiffert, Sascha Dietrich, Alexander Jethwa, Hanno Glimm, Peter Lichter, Thorsten Zenz

  Leukemia & lymphoma. 12/2011;

  There is remarkable heterogeneity in the clinical course and biological characteristics of patient subgroups with chronic lymphocytic leukemia (CLL). Mutations of key tumor suppressors (ATM,There is remarkable heterogeneity in the clinical course and biological characteristics of patient subgroups with chronic lymphocytic leukemia (CLL). Mutations of key tumor suppressors (ATM, miR-15a/16-1 and TP53) have been identified in CLL, and these aberrations are important "drivers" of the disease and some of its clinical characteristics. While some mutations are associated with poor outcome [particularly del(17p) and TP53 mutation], others are linked to a favorable clinical course [e.g. del(13q) as sole aberration]. In addition to genetic aberrations, antigen drive and microenvironmental interactions contribute to the pathogenesis of CLL. How the genetic aberrations impact on the process of antigen drive or microenvironmental interactions is currently unclear. Our improved understanding of the biology and clinical course of specific genetic subgroups is beginning to be translated into more specific and targeted treatment approaches. As a result, genetic subgroups are treated in distinct protocols. This review summarizes the contribution of the microenvironment and the most important genetic aberrations in CLL and how our improved knowledge of the biology of CLL may translate into improved treatment results.

• Molecular subgroups of medulloblastoma: the current consensus.

  Authors: Michael D Taylor, Paul A Northcott, Andrey Korshunov, Marc Remke, Yoon-Jae Cho, Steven C Clifford, Charles G Eberhart, D Williams Parsons, Stefan Rutkowski, Amar Gajjar, David W Ellison, Peter Lichter, Richard J Gilbertson, Scott L Pomeroy, Marcel Kool, Stefan M Pfister

  Acta neuropathologica. 12/2011;

  Medulloblastoma, a small blue cell malignancy of the cerebellum, is a major cause of morbidity and mortality in pediatric oncology. Current mechanisms for clinical prognostication and stratificationMedulloblastoma, a small blue cell malignancy of the cerebellum, is a major cause of morbidity and mortality in pediatric oncology. Current mechanisms for clinical prognostication and stratification include clinical factors (age, presence of metastases, and extent of resection) as well as histological subgrouping (classic, desmoplastic, and large cell/anaplastic histology). Transcriptional profiling studies of medulloblastoma cohorts from several research groups around the globe have suggested the existence of multiple distinct molecular subgroups that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes. Variations in the number, composition, and nature of the subgroups between studies brought about a consensus conference in Boston in the fall of 2010. Discussants at the conference came to a consensus that the evidence supported the existence of four main subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). Participants outlined the demographic, transcriptional, genetic, and clinical differences between the four subgroups. While it is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, herein we outline the current consensus nomenclature, and the differences between the medulloblastoma subgroups.

• MicroRNA-182 promotes leptomeningeal spread of non-sonic hedgehog-medulloblastoma.

  Authors: Alfa H C Bai, Till Milde, Marc Remke, Claudio G Rolli, Thomas Hielscher, Yoon-Jae Cho, Marcel Kool, Paul A Northcott, Manfred Jugold, Alexandr V Bazhin [......] Andreas E Kulozik, Armin Pscherer, Axel Benner, Michael D Taylor, Scott L Pomeroy, Ralf Kemkemer, Olaf Witt, Andrey Korshunov, Peter Lichter, Stefan M Pfister

  Acta neuropathologica. 12/2011;

  The contribution of microRNAs to the initiation, progression, and metastasis of medulloblastoma (MB) remains poorly understood. Metastatic dissemination at diagnosis is present in about 30% of MBThe contribution of microRNAs to the initiation, progression, and metastasis of medulloblastoma (MB) remains poorly understood. Metastatic dissemination at diagnosis is present in about 30% of MB patients, and is associated with a dismal prognosis. Using microRNA expression profiling, we demonstrate that the retinal miR-183-96-182 cluster on chromosome 7q32 is highly overexpressed in non-sonic hedgehog MBs (non-SHH-MBs). Expression of miR-182 and miR-183 is associated with cerebellar midline localization, and miR-182 is significantly overexpressed in metastatic MB as compared to non-metastatic tumors. Overexpression of miR-182 in non-SHH-MB increases and knockdown of miR-182 decreases cell migration in vitro. Xenografts overexpressing miR-182 invaded adjacent normal tissue and spread to the leptomeninges, phenotypically reminiscent of clinically highly aggressive large cell anaplastic MB. Hence, our study provides strong in vitro and in vivo evidence that miR-182 contributes to leptomeningeal metastatic dissemination in non-SHH-MB. We therefore reason that targeted inhibition of miR-182 may prevent leptomeningeal spread in patients with non-SHH-MB.

• CD24 Ala57Val polymorphism predicts pathologic complete response to sequential anthracycline- and taxane-based neoadjuvant chemotherapy for primary breast cancer.

  Authors: Frederik Marmé, Wiebke Werft, Anne Walter, Sascha Keller, Xiaoli Wang, Axel Benner, Barbara Burwinkel, Peter Sinn, Sarah Hug, Christof Sohn [......] Georgiy M Manikhas, Amparo Ruiz, Pedro Sánchez-Rovira, Armando Santoro, Miguel A Segui, Carlos Villena, Peter Lichter, Glen Kristiansen, Peter Altevogt, Andreas Schneeweiss

  Breast cancer research and treatment. 09/2011;

  Overexpression of CD24 is an independent prognostic factor for breast cancer. Recently, two polymorphisms in the CD24 gene were linked to disease risk and progression in autoimmune diseases. Here, weOverexpression of CD24 is an independent prognostic factor for breast cancer. Recently, two polymorphisms in the CD24 gene were linked to disease risk and progression in autoimmune diseases. Here, we evaluated the clinical relevance of these polymorphisms with respect to their potential to predict a pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) for primary breast cancer (PBC), one of the strongest prognostic factors in this setting. A total of 257 patients were randomized to either doxorubicin/cyclophosphamide (AC) or doxorubicin/pemetrexed (AP), both followed by docetaxel (Doc) as NCT for T2-4 N0-2 M0 PBC as part of an international, multicenter, randomized phase II trial. CD24 polymorphisms were analyzed on germ line DNA and correlated with clinicopathologic variables and pCR. No significant associations were found between either of the polymorphisms and any of the clinicopathologic variables. In a multivariate analysis, CD24 Val/Val genotype was the only significant predictor of pCR (OR: 4.97; P = 0.003). The predictive potential was significant in both treatment arms and in the hormone receptor-positive subgroup. There was no correlation between CD24 3'UTR (TG/Del) genotype and pCR. We did not observe any association between CD24 genotype and CD24 protein expression or in vitro chemosensitivity, but there was a significant correlation between CD24 Val/Val and intratumoral lymphocyte aggregates. In conclusion, CD24 Ala/Val SNP is a strong and independent predictor of pCR after NCT for PBC and may affect immune functions rather than tumor characteristics. Further evaluation of the CD24 function and validation of its predictive potential are clearly warranted.

• FSTL5 is a marker of poor prognosis in non-WNT/non-SHH medulloblastoma.

  Authors: Marc Remke, Thomas Hielscher, Andrey Korshunov, Paul A Northcott, Sebastian Bender, Marcel Kool, Frank Westermann, Axel Benner, Huriye Cin, Marina Ryzhova [......] Andrea Wittmann, Anna Schöttler, André O von Bueren, Andreas von Deimling, Stefan Rutkowski, Wolfram Scheurlen, Andreas E Kulozik, Michael D Taylor, Peter Lichter, Stefan M Pfister

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 09/2011; 29(29):3852-61.

  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 remarkableIntegrated 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. 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. 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. 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.

• Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma.

  Authors: Hendrik Witt, Stephen C Mack, Marina Ryzhova, Sebastian Bender, Martin Sill, Ruth Isserlin, Axel Benner, Thomas Hielscher, Till Milde, Marc Remke [......] Olaf Witt, Gary D Bader, Cynthia E Hawkins, Uri Tabori, Abhijit Guha, James T Rutka, Peter Lichter, Andrey Korshunov, Michael D Taylor, Stefan M Pfister

  Cancer cell. 08/2011; 20(2):143-57.

  Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis.Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochemical (IHC) markers for PF ependymoma subgroups allowed validation of our findings on a third independent cohort, using a human ependymoma tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients.

• Antiapoptotic function of charged multivesicular body protein 5: a potentially relevant gene in acute myeloid leukemia.

  Authors: Maria Shahmoradgoli, Otto Mannherz, Felix Engel, Stefanie Heck, Alwin Krämer, Martina Seiffert, Armin Pscherer, Peter Lichter

  International journal of cancer. Journal international du cancer. 06/2011; 128(12):2865-71.

  In recent years, RNA interference (RNAi) has been widely used to uncover gene function or pathway context of novel genes. In our study, we describe a short-hairpin RNA-based RNAi screening of a setIn recent years, RNA interference (RNAi) has been widely used to uncover gene function or pathway context of novel genes. In our study, we describe a short-hairpin RNA-based RNAi screening of a set of functionally uncharacterized human genes for their possible capability to inhibit apoptosis. We thereby identified a new antiapoptotic function for CHMP5 (charged multivesicular body protein 5), which was confirmed by overexpression and rescue assays. Furthermore, caspase assays showed that CHMP5 silencing induced caspase cascade activation mainly through extrinsic apoptosis pathway. Based on genome-wide expression array profiling, a possible regulatory role of CHMP5 on apoptosis-associated genes and different signaling pathways including nuclear factor kappa B was revealed. In addition, we found significantly higher CHMP5 mRNA levels in acute myeloid leukemia patients. This observation together with the antiapoptotic feature of CHMP5 suggests a possible oncogenic function for this gene in leukemogenesis.

• Adult medulloblastoma comprises three major molecular variants.

  Authors: Marc Remke, Thomas Hielscher, Paul A Northcott, Hendrik Witt, Marina Ryzhova, Andrea Wittmann, Axel Benner, Andreas von Deimling, Wolfram Scheurlen, Arie Perry, Sidney Croul, Andreas E Kulozik, Peter Lichter, Michael D Taylor, Stefan M Pfister, Andrey Korshunov

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 05/2011; 29(19):2717-23.

  Medulloblastoma is a rare primary brain tumor in adults, whereas it constitutes the most common malignant brain tumor in children. Integrated genomics approaches revealed at least four distinctMedulloblastoma is a rare primary brain tumor in adults, whereas it constitutes the most common malignant brain tumor in children. Integrated genomics approaches revealed at least four distinct disease variants in children. The aim of this study was to investigate molecular subtypes and their prognostic implication in a large cohort of adult medulloblastomas as the biology in this age group remains poorly understood. We combined transcriptome and DNA copy number analyses for 28 adult medulloblastomas. Statistical and bioinformatic tools were applied to discover distinct molecular variants. Clinical and molecular characteristics of each biologic subtype were validated using immunohistochemistry on a tissue microarray derived from an independent patient cohort of adult medulloblastomas (n = 103). Gene expression profiles revealed three distinct molecular variants with stable subtype separation using the 300 most varying transcripts. Distinct demographics, genetics, transcriptome, and prognosis were noted for each subtype of adult medulloblastoma. Immunohistochemistry revealed aberrant activation of the sonic hedgehog (SHH) pathway in over half of adult medulloblastomas constituting a promising molecular therapeutic target. In contrast, subtype C tumors, which comprise a robust subtype in childhood medulloblastoma are only exceptionally seen in adult cohorts. Notably, adult subtype D and Wnt/wingless tumors were associated with worse prognosis than pediatric cohorts, whereas survival for SHH tumors was similar for both age groups. The transcriptome of adult medulloblastomas differs considerably from pediatric counterparts, both in terms of tumor biology and prognostic impact. Therefore, age-specific classification is required and must be adapted for use in clinical trials of adult medulloblastoma.

• A gene signature distinguishing CD133hi from CD133- colorectal cancer cells: essential role for EGR1 and downstream factors.

  Authors: Aurélie Ernst, Maximilian Aigner, Susumu Nakata, Felix Engel, Magdalena Schlotter, Matthias Kloor, Karsten Brand, Steffen Schmitt, Gunnar Steinert, Nuh Rahbari, Moritz Koch, Bernhard Radlwimmer, Jürgen Weitz, Peter Lichter

  Pathology. 04/2011; 43(3):220-7.

  In colorectal cancer (CRC), CD133 expression is an independent prognostic marker associated with adverse clinical outcome. The CD133 epitope AC133 allowed isolating stem cells from normal andIn colorectal cancer (CRC), CD133 expression is an independent prognostic marker associated with adverse clinical outcome. The CD133 epitope AC133 allowed isolating stem cells from normal and cancerous tissues, although its use in colon was questioned. We aimed to identify differences between AC133 and AC133 cells. We analysed the gene expression profiles of EpCAM/CEA/AC133 and EpCAM/CEA/AC133 cells from primary CRC and liver metastasis tissues (n = 5). Immunohistochemistry confirmed these results in a validation set. We identified 68 genes differentially expressed between both populations, including genes of notorious importance in CRC pathogenesis, and several candidates not previously shown to play a major role in CRC. Notably, EGR1 belonged to the most highly expressed genes in AC133 cells. In the validation set, the presence of EGR1 and CD133 correlated (r = 0.625). Since EGR1 regulates Wnt through up-regulation of TCF4, which induces stem cell marker LGR5, the potential association between LGR5, EGR1 and CD133 was investigated. The presence of LGR5 correlated with the presence of EGR1 and CD133. Strong signals for LGR5 were detected throughout tumour invasion fronts. The study suggests a connection between CD133 and EGR1 and emphasises the importance of the EGR1/TCF4/CD133/LGR5 network in CRC.

• Association of stem cell-related markers and survival in astrocytic gliomas.

  Authors: Feng Wan, Christel Herold-Mende, Benito Campos, Franz-Simon Centner, Christine Dictus, Natalia Becker, Frauke Devens, Carolin Mogler, Jörg Felsberg, Niels Grabe, Guido Reifenberger, Peter Lichter, Andreas Unterberg, Justo Lorenzo Bermejo, Rezvan Ahmadi

  Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals. 03/2011; 16(2):136-43.

  To study the clinical relevance of undifferentiated tumour cells in astrocytic gliomas we employed a large tumour tissue microarray (n=283) with corresponding clinical data and analyzed theTo study the clinical relevance of undifferentiated tumour cells in astrocytic gliomas we employed a large tumour tissue microarray (n=283) with corresponding clinical data and analyzed the expression of Nestin and Sox-2, which mark undifferentiated stem- and progenitor cells in the normal brain. Both markers were expressed abundantly and staining of nestin significantly increased with WHO grade. Further, nestin and Sox-2 immunoreactivity was significantly associated with tumour cell proliferation and nestin expression was independently associated with poor patient survival. Our findings suggest that immature glioma cells are involved in tumour growth and tumour progression and significantly impact on patient prognosis.