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1. Current Molecular and Clinical Landscape of ATRT – The Link to Future Therapies

Author

Gastberger K, Fincke VE, Mucha M, Siebert R, Hasselblatt M, and Frühwald MC

Subjects
swi/snf related matrix associated, actin dependent regulator of chromatin, subfamily b, member 1, smarcb1, atypical teratoid rhabdoid tumor, atrt, central nervous system, cns, treatment, pediatric, cell cycle, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Katharina Gastberger,1,2 Victoria E Fincke,1,2 Marlena Mucha,1,2 Reiner Siebert,3 Martin Hasselblatt,4 Michael C Frühwald1,2 1Pediatrics and Adolescent Medicine, Swabian Children’s Cancer Center, University Medical Center Augsburg, Augsburg, Germany; 2Bavarian Cancer Research Center (BZKF), Augsburg, Germany; 3Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm, Germany; 4Institute of Neuropathology, University Hospital Münster, Münster, GermanyCorrespondence: Michael C Frühwald, EU-RHAB Center, Swabian Children’s Cancer Center, Pediatrics and Adolescent Medicine, University Medical Center Augsburg, and Bavarian Cancer Research Center (BZKF), Stenglinstr. 2, Augsburg, 86156, Germany, Tel +49 821 400 9340, Fax +49 821 400 179201, Email michael.fruehwald@uk-augsburg.deAbstract: ATRT is a highly aggressive and rare pediatric CNS tumor of very young children. Its genetic hallmark is bi-allelic inactivation of SMARCB1 encoding INI1. Rarely SMARCA4 encoding BRG1 is affected. Up to 30% are associated with constitutional heterozygous pathogenic variants in one of the two genes, giving rise to the Rhabdoid-Tumor-Predisposition-Syndromes (RTPS) 1 and 2. Characteristic DNA methylation profiles distinguish ATRT from other SMARCB1-deficient entities. Three distinct subtypes ATRT-MYC, -TYR, and -SHH are on record. ATRT-SHH may be further divided into the subgroups ATRT-SHH1A, -SHH1B, and -SHH2. The cure of ATRT remains challenging, notwithstanding an increasing understanding of molecular pathomechanisms and genetic background. The implementation of multimodal institutional treatment protocols has improved prognosis. Regardless of treatment approaches, clinical risk factors such as age, metastases, and DNA methylation subtype affect survival probability. We provide a critical appraisal of current conventional multimodal regimens and emerging targeted treatment approaches investigated in clinical trials and entity-specific registries. Intense treatment approaches featuring radiotherapy (RT) and high-dose chemotherapy (HDCT) face the difficulty of balancing tumor control and treatment-related toxicity. Current approaches focus on minimizing radiation fields by proton beam therapy or to withhold RT in HDCT-only approaches. Still, a 40– 75% relapse rate upon first-line treatment reveals the need for novel treatment strategies in primary and even more in recurrent/refractory (r/r) disease. Among targeted treatments, immune checkpoint inhibitors and epigenetically active agents appear most promising. Success remains limited in single agent approaches. We hypothesize that mechanism-informed combination therapy will enhance response, as the low mutational burden of ATRT may contribute to acquiring resistance to single targeted agents. As DNA methylation group-specific gene expression profiles appear to influence response to distinct agents, the future treatment of ATRT should respect clinical and biological heterogeneity in risk group adjusted treatment protocols.Keywords: SWI/SNF related matrix associated, actin dependent regulator of chromatin, subfamily b, member 1, SMARCB1, atypical teratoid rhabdoid tumor, ATRT, central nervous system, CNS, treatment, pediatric, cell cycle

Published
2023

2. Histone H3.3 K27M and K36M mutations de-repress transposable elements through perturbation of antagonistic chromatin marks

Author

Chaouch, A., Berlandi, J., Chen, C.C., Frey, F., Badini, S., Harutyunyan, Ashot S., Chen, Xiao, Krug, B., Hébert, S., Jeibmann, A., Lu, C., Kleinman, C.L., Hasselblatt, M., Lasko, P.F., Shirinian, M., Jabado, N., Chaouch, A., Berlandi, J., Chen, C.C., Frey, F., Badini, S., Harutyunyan, Ashot S., Chen, Xiao, Krug, B., Hébert, S., Jeibmann, A., Lu, C., Kleinman, C.L., Hasselblatt, M., Lasko, P.F., Shirinian, M., and Jabado, N.

Abstract

Item does not contain fulltext

Published
2021

3. Clear cell meningiomas are defined by a highly distinct DNA methylation profile and mutations in SMARCE1

Author

Sievers, P., Sill, M., Blume, C., Tauziede-Espariat, A., Schrimpf, D., Stichel, D., Reuss, D.E., Dogan, H., Hartmann, C., Mawrin, C., Hasselblatt, M., Stummer, W., Schick, U., Hench, J., Frank, S., Ketter, R., Schweizer, L., Schittenhelm, J., Puget, S., Brandner, S., Jaunmuktane, Z., Kusters, B., Abdullaev, Z., Pekmezci, M., Snuderl, M., Ratliff, M., Herold-Mende, C., Unterberg, A., Aldape, K., Ellison, D.W., Wesseling, P., Reifenberger, G., Wick, W., Perry, A., Varlet, P., Pfister, S.M., Jones, D.T.W., Deimling, A. von, Sahm, F., Sievers, P., Sill, M., Blume, C., Tauziede-Espariat, A., Schrimpf, D., Stichel, D., Reuss, D.E., Dogan, H., Hartmann, C., Mawrin, C., Hasselblatt, M., Stummer, W., Schick, U., Hench, J., Frank, S., Ketter, R., Schweizer, L., Schittenhelm, J., Puget, S., Brandner, S., Jaunmuktane, Z., Kusters, B., Abdullaev, Z., Pekmezci, M., Snuderl, M., Ratliff, M., Herold-Mende, C., Unterberg, A., Aldape, K., Ellison, D.W., Wesseling, P., Reifenberger, G., Wick, W., Perry, A., Varlet, P., Pfister, S.M., Jones, D.T.W., Deimling, A. von, and Sahm, F.

Abstract

Contains fulltext : 232881.pdf (Publisher’s version ) (Open Access), Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.

Published
2021

4. Sarcoma classification by DNA methylation profiling

Author

Koelsche, C, Schrimpf, D, Stichel, D, Sill, M, Sahm, F, Reuss, DE, Blattner, M, Worst, B, Heilig, CE, Beck, K, Horak, P, Kreutzfeldt, S, Paff, E, Stark, S, Johann, P, Selt, F, Ecker, J, Sturm, D, Pajtler, K W, Reinhardt, A, Wefers, AK, Sievers, P, Ebrahimi, A, Suwala, A, Fernandez-Klett, F, Casalini, B, Korshunov, A, Hovestadt, V, Kommoss, FKF, Kriegsmann, M, Schick, M, Bewerunge-Hudler, M, Milde, T, Witt, O, Kulozik, AE, Kool, M, Romero-Perez, L, Grunewald, TGP, Kirchner, T, Wick, W, Platten, M, Unterberg, A, Uhl, M, Abdollahi, A, Debus, J, Lehner, B, Thomas, C, Hasselblatt, M, Paulus, W, Hartmann, C, Staszewski, O, Prinz, M, Hench, J, Frank, S, Versleijen-Jonkers, YMH, Weidema, ME, Mentzel, T, Griewank, K, Alava, E, Martin, JD, Gastearena, MAI, Chang, KTE, Low, SYY, Cuevas-Bourdier, A, Mittelbronn, M, Mynarek, M, Rutkowski, S, Schuller, U, Mautner, VF, Schittenhelm, J, Serrano, J, Snuderl, M, Buttner, R, Klingebiel, T, Buslei, R, Gessler, M, Wesseling, P, Dinjens, Winand, Brandner, S, Jaunmuktane, Z, Lyskjaer, I, Schirmacher, P, Stenzinger, A, Brors, B, Glimm, H, Heining, C, Tirado, OM, Sainz-Jaspeado, M, Mora, J, Alonso, J, del Muro, XG, Moran, S, Esteller, M, Benhamida, JK, Ladanyi, M, Wardelmann, E, Antonescu, C, Flanagan, A, Dirksen, U, Hohenberger, P, Baumhoer, D, Hartmann, W, Vokuhl, C, Flucke, U, Petersen, I, Mechtersheimer, G, Capper, D, Jones, DT, Frohling, S, Pfister, SM, von Deimling, A, Koelsche, C, Schrimpf, D, Stichel, D, Sill, M, Sahm, F, Reuss, DE, Blattner, M, Worst, B, Heilig, CE, Beck, K, Horak, P, Kreutzfeldt, S, Paff, E, Stark, S, Johann, P, Selt, F, Ecker, J, Sturm, D, Pajtler, K W, Reinhardt, A, Wefers, AK, Sievers, P, Ebrahimi, A, Suwala, A, Fernandez-Klett, F, Casalini, B, Korshunov, A, Hovestadt, V, Kommoss, FKF, Kriegsmann, M, Schick, M, Bewerunge-Hudler, M, Milde, T, Witt, O, Kulozik, AE, Kool, M, Romero-Perez, L, Grunewald, TGP, Kirchner, T, Wick, W, Platten, M, Unterberg, A, Uhl, M, Abdollahi, A, Debus, J, Lehner, B, Thomas, C, Hasselblatt, M, Paulus, W, Hartmann, C, Staszewski, O, Prinz, M, Hench, J, Frank, S, Versleijen-Jonkers, YMH, Weidema, ME, Mentzel, T, Griewank, K, Alava, E, Martin, JD, Gastearena, MAI, Chang, KTE, Low, SYY, Cuevas-Bourdier, A, Mittelbronn, M, Mynarek, M, Rutkowski, S, Schuller, U, Mautner, VF, Schittenhelm, J, Serrano, J, Snuderl, M, Buttner, R, Klingebiel, T, Buslei, R, Gessler, M, Wesseling, P, Dinjens, Winand, Brandner, S, Jaunmuktane, Z, Lyskjaer, I, Schirmacher, P, Stenzinger, A, Brors, B, Glimm, H, Heining, C, Tirado, OM, Sainz-Jaspeado, M, Mora, J, Alonso, J, del Muro, XG, Moran, S, Esteller, M, Benhamida, JK, Ladanyi, M, Wardelmann, E, Antonescu, C, Flanagan, A, Dirksen, U, Hohenberger, P, Baumhoer, D, Hartmann, W, Vokuhl, C, Flucke, U, Petersen, I, Mechtersheimer, G, Capper, D, Jones, DT, Frohling, S, Pfister, SM, and von Deimling, A

Abstract

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.

Published
2021

7. DNA methylation-based classification of central nervous system tumours

Author

Capper, D, Jones, DTW, Sill, M, Hovestadt, V, Schrimpf, D, Sturm, D, Koelsche, C, Sahm, F, Chavez, L, Reuss, DE, Kratz, A, Wefers, AK, Huang, K, Pajtler, KW, Schweizer, L, Stichel, D, Olar, A, Engel, NW, Lindenberg, K, Harter, PN, Braczynski, AK, Plate, KH, Dohmen, H, Garvalov, BK, Coras, R, Hoelsken, A, Hewer, E, Bewerunge-Hudler, M, Schick, M, Fischer, R, Beschorner, R, Schittenhelm, J, Staszewski, O, Wani, K, Varlet, P, Pages, M, Temming, P, Lohmann, D, Selt, F, Witt, H, Milde, T, Witt, O, Aronica, E, Giangaspero, F, Rushing, E, Scheurlen, W, Geisenberger, C, Rodriguez, FJ, Becker, A, Preusser, M, Haberler, C, Bjerkvig, R, Cryan, J, Farrell, M, Deckert, M, Hench, J, Frank, S, Serrano, J, Kannan, K, Tsirigos, A, Brueck, W, Hofer, S, Brehmer, S, Seiz-Rosenhagen, M, Haenggi, D, Hans, V, Rozsnoki, S, Hansford, JR, Kohlhof, P, Kristensen, BW, Lechner, M, Lopes, B, Mawrin, C, Ketter, R, Kulozik, A, Khatib, Z, Heppner, F, Koch, A, Jouvet, A, Keohane, C, Muehleisen, H, Mueller, W, Pohl, U, Prinz, M, Benner, A, Zapatka, M, Gottardo, NG, Driever, PH, Kramm, CM, Mueller, HL, Rutkowski, S, von Hoff, K, Fruehwald, MC, Gnekow, A, Fleischhack, G, Tippelt, S, Calaminus, G, Monoranu, C-M, Perry, A, Jones, C, Jacques, TS, Radlwimmer, B, Gessi, M, Pietsch, T, Schramm, J, Schackert, G, Westphal, M, Reifenberger, G, Wesseling, P, Weller, M, Collins, VP, Bluemcke, I, Bendszus, M, Debus, J, Huang, A, Jabado, N, Northcott, PA, Paulus, W, Gajjar, A, Robinson, GW, Taylor, MD, Jaunmuktane, Z, Ryzhova, M, Platten, M, Unterberg, A, Wick, W, Karajannis, MA, Mittelbronn, M, Acker, T, Hartmann, C, Aldape, K, Schueller, U, Buslei, R, Lichter, P, Kool, M, Herold-Mende, C, Ellison, DW, Hasselblatt, M, Snuderl, M, Brandner, S, Korshunov, A, von Deimling, A, Pfister, SM, Capper, D, Jones, DTW, Sill, M, Hovestadt, V, Schrimpf, D, Sturm, D, Koelsche, C, Sahm, F, Chavez, L, Reuss, DE, Kratz, A, Wefers, AK, Huang, K, Pajtler, KW, Schweizer, L, Stichel, D, Olar, A, Engel, NW, Lindenberg, K, Harter, PN, Braczynski, AK, Plate, KH, Dohmen, H, Garvalov, BK, Coras, R, Hoelsken, A, Hewer, E, Bewerunge-Hudler, M, Schick, M, Fischer, R, Beschorner, R, Schittenhelm, J, Staszewski, O, Wani, K, Varlet, P, Pages, M, Temming, P, Lohmann, D, Selt, F, Witt, H, Milde, T, Witt, O, Aronica, E, Giangaspero, F, Rushing, E, Scheurlen, W, Geisenberger, C, Rodriguez, FJ, Becker, A, Preusser, M, Haberler, C, Bjerkvig, R, Cryan, J, Farrell, M, Deckert, M, Hench, J, Frank, S, Serrano, J, Kannan, K, Tsirigos, A, Brueck, W, Hofer, S, Brehmer, S, Seiz-Rosenhagen, M, Haenggi, D, Hans, V, Rozsnoki, S, Hansford, JR, Kohlhof, P, Kristensen, BW, Lechner, M, Lopes, B, Mawrin, C, Ketter, R, Kulozik, A, Khatib, Z, Heppner, F, Koch, A, Jouvet, A, Keohane, C, Muehleisen, H, Mueller, W, Pohl, U, Prinz, M, Benner, A, Zapatka, M, Gottardo, NG, Driever, PH, Kramm, CM, Mueller, HL, Rutkowski, S, von Hoff, K, Fruehwald, MC, Gnekow, A, Fleischhack, G, Tippelt, S, Calaminus, G, Monoranu, C-M, Perry, A, Jones, C, Jacques, TS, Radlwimmer, B, Gessi, M, Pietsch, T, Schramm, J, Schackert, G, Westphal, M, Reifenberger, G, Wesseling, P, Weller, M, Collins, VP, Bluemcke, I, Bendszus, M, Debus, J, Huang, A, Jabado, N, Northcott, PA, Paulus, W, Gajjar, A, Robinson, GW, Taylor, MD, Jaunmuktane, Z, Ryzhova, M, Platten, M, Unterberg, A, Wick, W, Karajannis, MA, Mittelbronn, M, Acker, T, Hartmann, C, Aldape, K, Schueller, U, Buslei, R, Lichter, P, Kool, M, Herold-Mende, C, Ellison, DW, Hasselblatt, M, Snuderl, M, Brandner, S, Korshunov, A, von Deimling, A, and Pfister, SM

Abstract

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

Published
2018

8. Is ALA-induced fluorescence a novel and independent biomarker of inherent malignant degeneration in low-grade gliomas?

Author

Jaber, M, Ewelt, C, Wölfer, J, Hasselblatt, M, and Stummer, W

Subjects
5ALA, ddc: 610, biomarker, Glioma, 610 Medical sciences, Medicine
Abstract

Objective: Approximately only a small fraction of low-grade gliomas (LGGs) displays visible PPIX fluorescence during surgery, after 5-ALA administration. We wanted to determine if PPIX positive LGGs differed in prognosis from non-PPIX positive LGGs and whether this was reflected by molecular factors,[for full text, please go to the a.m. URL], 67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS)

Published
2016
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9. Molecular and clinical impact of hTERT promoter methylation in 100 pituitary adenomas

Author

Köchling, M, Ewelt, C, Stummer, W, Hasselblatt, M, Paulus, W, and Brokinkel, B

Subjects
ddc: 610, Pituitary Adenoma, Epigenetics, 610 Medical sciences, Medicine, hTERT
Abstract

Objective: Telomerase activation and expression are considered one of the key features in tumorigenesis. Currently, methylations and hotspot mutations of the promoter of the catalytic subunit of the Telomerase (hTERT, human Telomerase Reverse Transcriptase) are discussed as main potential underlying[for full text, please go to the a.m. URL], 66. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

Published
2015
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10. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

Author

Sturm, D., Orr, B.A., Toprak, U.H., Hovestadt, V., Jones, D.T., Capper, D., Sill, M., Buchhalter, I., Northcott, P.A., Leis, I., Ryzhova, M., Koelsche, C., Pfaff, E., Allen, S.J., Balasubramanian, G., Worst, B.C., Pajtler, K.W., Brabetz, S., Johann, P.D., Sahm, F., Reimand, J., Mackay, A., Carvalho, D.M., Remke, M., Phillips, J.J., Perry, A., Cowdrey, C., Drissi, R., Fouladi, M., Giangaspero, F., Lastowska, M., Grajkowska, W., Scheurlen, W., Pietsch, T., Hagel, C., Gojo, J., Lotsch, D., Berger, W., Slavc, I., Haberler, C., Jouvet, A., Holm, S., Hofer, S., Prinz, M., Keohane, C., Fried, I., Mawrin, C., Scheie, D., Mobley, B.C., Schniederjan, M.J., Santi, M., Buccoliero, A.M., Dahiya, S., Kramm, C.M., Bueren, A.O. von, Hoff, K. von, Rutkowski, S., Herold-Mende, C., Fruhwald, M.C., Milde, T., Hasselblatt, M., Wesseling, P., Rossler, J., Schuller, U., Ebinger, M., Schittenhelm, J., Frank, S., Grobholz, R., Vajtai, I., Hans, V., Schneppenheim, R., Zitterbart, K., Collins, V.P., Aronica, E., Varlet, P., Puget, S., Dufour, C., Grill, J., Figarella-Branger, D., Wolter, M., Schuhmann, M.U., Shalaby, T., Grotzer, M., Meter, T. van, Monoranu, C.M., Felsberg, J., Reifenberger, G., Snuderl, M., Forrester, L.A., Koster, J., Versteeg, R., Volckmann, R., Sluis, P. van, Wolf, S., Mikkelsen, T., Gajjar, A., Aldape, K., Moore, A.S., Taylor, M.D., Jones, C., et al., Sturm, D., Orr, B.A., Toprak, U.H., Hovestadt, V., Jones, D.T., Capper, D., Sill, M., Buchhalter, I., Northcott, P.A., Leis, I., Ryzhova, M., Koelsche, C., Pfaff, E., Allen, S.J., Balasubramanian, G., Worst, B.C., Pajtler, K.W., Brabetz, S., Johann, P.D., Sahm, F., Reimand, J., Mackay, A., Carvalho, D.M., Remke, M., Phillips, J.J., Perry, A., Cowdrey, C., Drissi, R., Fouladi, M., Giangaspero, F., Lastowska, M., Grajkowska, W., Scheurlen, W., Pietsch, T., Hagel, C., Gojo, J., Lotsch, D., Berger, W., Slavc, I., Haberler, C., Jouvet, A., Holm, S., Hofer, S., Prinz, M., Keohane, C., Fried, I., Mawrin, C., Scheie, D., Mobley, B.C., Schniederjan, M.J., Santi, M., Buccoliero, A.M., Dahiya, S., Kramm, C.M., Bueren, A.O. von, Hoff, K. von, Rutkowski, S., Herold-Mende, C., Fruhwald, M.C., Milde, T., Hasselblatt, M., Wesseling, P., Rossler, J., Schuller, U., Ebinger, M., Schittenhelm, J., Frank, S., Grobholz, R., Vajtai, I., Hans, V., Schneppenheim, R., Zitterbart, K., Collins, V.P., Aronica, E., Varlet, P., Puget, S., Dufour, C., Grill, J., Figarella-Branger, D., Wolter, M., Schuhmann, M.U., Shalaby, T., Grotzer, M., Meter, T. van, Monoranu, C.M., Felsberg, J., Reifenberger, G., Snuderl, M., Forrester, L.A., Koster, J., Versteeg, R., Volckmann, R., Sluis, P. van, Wolf, S., Mikkelsen, T., Gajjar, A., Aldape, K., Moore, A.S., Taylor, M.D., Jones, C., and et al.

Abstract

Item does not contain fulltext, Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

Published
2016

11. Papillary Tumor of the Pineal Region: A Distinct Molecular Entity

Author

Heim, S., Sill, M., Jones, D.T., Vasiljevic, A., Jouvet, A., Fevre-Montange, M., Wesseling, P., Beschorner, R., Mittelbronn, M., Kohlhof, P., Hovestadt, V., Johann, P., Kool, M., Pajtler, K.W., Korshunov, A., Ruland, V., Sperveslage, J., Thomas, C., Witt, H., Deimling, A. von, Paulus, W., Pfister, S.M., Capper, D., Hasselblatt, M., Heim, S., Sill, M., Jones, D.T., Vasiljevic, A., Jouvet, A., Fevre-Montange, M., Wesseling, P., Beschorner, R., Mittelbronn, M., Kohlhof, P., Hovestadt, V., Johann, P., Kool, M., Pajtler, K.W., Korshunov, A., Ruland, V., Sperveslage, J., Thomas, C., Witt, H., Deimling, A. von, Paulus, W., Pfister, S.M., Capper, D., and Hasselblatt, M.

Abstract

Item does not contain fulltext, Papillary tumor of the pineal region (PTPR) is a neuroepithelial brain tumor, which might pose diagnostic difficulties and recurs often. Little is known about underlying molecular alterations. We therefore investigated chromosomal copy number alterations, DNA methylation patterns and mRNA expression profiles in a series of 24 PTPRs. Losses of chromosome 10 were identified in all 13 PTPRs examined. Losses of chromosomes 3 and 22q (54%) as well as gains of chromosomes 8p (62%) and 12 (46%) were also common. DNA methylation profiling using Illumina 450k arrays reliably distinguished PTPR from ependymomas and pineal parenchymal tumors of intermediate differentiation. PTPR could be divided into two subgroups based on methylation pattern, PTPR group 2 showing higher global methylation and a tendency toward shorter progression-free survival (P = 0.06). Genes overexpressed in PTPR as compared with ependymal tumors included SPDEF, known to be expressed in the rodent subcommissural organ. Notable SPDEF protein expression was encountered in 15/19 PTPRs as compared with only 2/36 ependymal tumors, 2/19 choroid plexus tumors and 0/23 samples of other central nervous system (CNS) tumor entities. In conclusion, PTPRs show typical chromosomal alterations as well as distinct DNA methylation and expression profiles, which might serve as useful diagnostic tools.

Published
2016

12. Targeting Primary Ciliogenesis in Atypical Teratoid/Rhabdoid Tumors

Author

Bluemel, L., Kerl, K., Picard, D., Malzkorn, B., Johann, P. D., Erkek, S., Fruehwald, M. C., Pfister, S. M., Kool, M., Liebau, M. C., Borkhardt, A., Reifenberger, G., Hasselblatt, M., Remke, M., Bluemel, L., Kerl, K., Picard, D., Malzkorn, B., Johann, P. D., Erkek, S., Fruehwald, M. C., Pfister, S. M., Kool, M., Liebau, M. C., Borkhardt, A., Reifenberger, G., Hasselblatt, M., and Remke, M.

Published
2016

13. Correlation of 5-ALA derived porphyrins to contrast enhancement in MRI, Amino acid-PET, IDH1 mutation, 1p19q deletion and MGMT promoter methylation in gliomas

Author

Jaber, M, Ewelt, C, Holling, M, Hasselblatt, M, and Stummer, W

Subjects
ddc: 610, Glioma, 5-ALA, 610 Medical sciences, Medicine, MGMT, humanities
Abstract

Objective: The aim of this study was to assess histological and imaging factors associated with the intraoperative accumulation of 5-aminolaevulinic acid (5-ALA) derived porphyrins in gliomas. Method: Retrospectively, we analyzed the data of patients operated at our department between 01/2012[for full text, please go to the a.m. URL], 65. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

Published
2014
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15. Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age

Author

Fontebasso, AM, Shirinian, M, Khuong-Quang, D-A, Bechet, D, Gayden, T, Kool, M, De Jay, N, Jacob, K, Gerges, N, Hutter, B, Seker-Cin, H, Witt, H, Montpetit, A, Brunet, S, Lepage, P, Bourret, G, Klekner, A, Bognar, L, Hauser, P, Garami, M, Farmer, J-P, Montes, J-L, Atkinson, J, Lambert, S, Kwan, T, Korshunov, A, Tabori, U, Collins, VP, Albrecht, S, Faury, D, Pfister, SM, Paulus, W, Hasselblatt, M, Jones, DTW, Jabado, N, Fontebasso, AM, Shirinian, M, Khuong-Quang, D-A, Bechet, D, Gayden, T, Kool, M, De Jay, N, Jacob, K, Gerges, N, Hutter, B, Seker-Cin, H, Witt, H, Montpetit, A, Brunet, S, Lepage, P, Bourret, G, Klekner, A, Bognar, L, Hauser, P, Garami, M, Farmer, J-P, Montes, J-L, Atkinson, J, Lambert, S, Kwan, T, Korshunov, A, Tabori, U, Collins, VP, Albrecht, S, Faury, D, Pfister, SM, Paulus, W, Hasselblatt, M, Jones, DTW, and Jabado, N

Abstract

Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.

Published
2015

16. Papillary tumor of the pineal region: A distinct molecular entity

Author

Heim, S, Sill, M, Jones, DTW, Vasiljevic, A, Jouvet, A, Fèvre-Montange, M, Wesseling, P, Beschorner, R, Mittelbronn, M, Kohlhof, P, Hovestadt, V, Johann, P, Kool, M, Pajtler, KW, Korshunov, A, Ruland, V, Thomas, C, Witt, H, von Deimling, A, Paulus, W, Pfister, SM, Capper, D, Hasselblatt, M, Heim, S, Sill, M, Jones, DTW, Vasiljevic, A, Jouvet, A, Fèvre-Montange, M, Wesseling, P, Beschorner, R, Mittelbronn, M, Kohlhof, P, Hovestadt, V, Johann, P, Kool, M, Pajtler, KW, Korshunov, A, Ruland, V, Thomas, C, Witt, H, von Deimling, A, Paulus, W, Pfister, SM, Capper, D, and Hasselblatt, M

Published
2015

17. DNA methylation array-based molecular profiling for brain tumor classification

Author

Capper, D, Jones, DTW, Sill, M, Hovestadt, V, Schrimpf, D, Reuss, D, Sahm, F, Kölsche, C, Kratz, A, Mittelbronn, M, Schittenhelm, J, Olar, A, Buslei, R, Hartmann, C, Kohlhof, P, Hasselblatt, M, Schick, M, Bewerunge-Hudler, M, Korshunov, A, Aldape, K, von Deimling, A, Pfister, SM, Capper, D, Jones, DTW, Sill, M, Hovestadt, V, Schrimpf, D, Reuss, D, Sahm, F, Kölsche, C, Kratz, A, Mittelbronn, M, Schittenhelm, J, Olar, A, Buslei, R, Hartmann, C, Kohlhof, P, Hasselblatt, M, Schick, M, Bewerunge-Hudler, M, Korshunov, A, Aldape, K, von Deimling, A, and Pfister, SM

Published
2015

19. Leitfähigkeitsstudien

Author

Jones, G., Bollinger, G. M., Parker, H. C., Wien, M., Joos, G., Blumentritt, M., Debye, P., Hückel, E., Kraus, C. A., Morgan, J. L. R., Lammert, O. M., Stamm, A. J., and Hasselblatt, M.

Published
1932
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20. Allgemeine Apparate

Author

Zschacke, F. H., Ray, F. E., Hume, J., Frerichs, G., Lochte, H. L., Hoover, Anna, Whitnah, C. H., Jackson, J., Dietz, A., Guttmann, E., Dunbar, R. E., Freye, H. A., Wirth, C., Sperry, W. A., Hasselblatt, M., Burschkies, K., Gollnow, G., How, A., Trültzsch, Mayer, F., Thiessen, G. W., Wertz, J. E., Szeszich, L. v., Vollbrecht, H., Hilpert, S., Hofmeier, H., Thompso, P. F., Frantz, Th., Churchill, H. V., Zabe, R. M., Danckwortt, P. W., and N. Gerbers Co. m. b. H.

Published
1934
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21. EU-RHAB: Ergebnisse des europäischen Verbundprojektes zur Erfassung und Behandlung von Kindern mit Rhabdoiden Tumoren

Author

Bartelheim, K, Warmuth-Metz, M, Hasselblatt, M, Leuschner, I, Timmermann, B, Kortmann, RD, Siebert, R, Schneppenheim, R, Gerss, J, and Frühwald, M

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Fragestellung: Maligne rhabdoide Tumoren sind seltene, aggressive Tumoren, die vor allem Patienten unter 3 Jahren betreffen und eine ungünstige Prognose aufweisen. Als derzeitiger Therapiestandard gilt ein multimodales Therapiekonzept, das Chirurgie, Bestrahlung und Chemotherapie, teilweise Hochdosischemotherapie[for full text, please go to the a.m. URL], Süddeutsche Tage der Kinder- und Jugendmedizin; 61. Jahrestagung der Süddeutschen Gesellschaft für Kinder- und Jugendmedizin und der Süddeutschen Gesellschaft für Kinderchirurgie und dem Berufsverband für Kinder- und Jugendärzte – Landesverband Bayern

Published
2012
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22. MGMT promoter methylation status in anaplastic meningiomas

Author

Brokinkel, B, Fischer, BR, Stummer, W, Paulus, W, and Hasselblatt, M

Subjects
ddc: 610, 610 Medical sciences, Medicine, neoplasms
Abstract

Objective: Anaplastic meningioma (grade III WHO) is characterized by aggressive biological behavior. After surgical resection, effective adjuvant chemotherapeutic concepts are lacking. Hypermethylation of the MGMT (O6-methylguanine-DNA methyltransferase) promoter is an important prognostic marker and[for full text, please go to the a.m. URL], 62. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgen (PNCH)

Published
2011
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24. SIOP choroid plexus tumor study 2000 update

Author

Kordes, U, Kutluk, T, Hasselblatt, M, Mahajan, A, Pietsch, T, Thall, P, and Wolff, JE

Subjects
ddc: 610, 610 Medical sciences, Medicine, health care economics and organizations
Abstract

Objective: Presentation of the updated interim analyis of the CPT-SIOP-2000 study Methods: Interim analyis of the CPT-SIOP-2000 study Results: Very rare tumors such as choroid plexus tumors require large referral populations to generate meaningful clinical data. In the year 2000, the international[for full text, please go to the a.m. URL], 62. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgen (PNCH)

Published
2011
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25. Claudin-6 is of limited sensitivity and specificity for the diagnosis of atypical teratoid/rhabdoid tumors

Author

Antonelli, Massimo, Hasselblatt, M, Haberler, C, Di Giannatale, Angela, Garre', Ml, Donofrio, V, Lauriola, Libero, Ridola, Vita, Arcella, A, Früwald, M, and Giangaspero, Felice

Subjects
Male, Chromosomal Proteins, Non-Histone, Kaplan-Meier Estimate, Pediatrics, Sensitivity and Specificity, Germany, Humans, teratoid, Rhabdoid Tumor, Research Articles, ini1 protein, rhabdoid, baf47, Chi-Square Distribution, claudin-6 protein, Settore MED/08 - ANATOMIA PATOLOGICA, atypical teratoid/rhabdoid tumor, brain tumor, atrt cldn6 immunoistochemistry, Brain Neoplasms, SMARCB1 Protein, DNA-Binding Proteins, Austria, Claudins, Female, Follow-Up Studies, Transcription Factors
Abstract

Recent gene expression microarray analyses have indicated that claudin‐6 is specifically expressed in atypical teratoid rhabdoid tumors (AT/RTs), suggesting a role as a positive diagnostic marker in addition to SMARCB1 (INI1) loss, which is encountered in the majority of AT/RTs. In order to investigate the potential of claudin‐6 as a diagnostic marker, expression was investigated in 59 AT/RTs and 60 other primary central nervous system (CNS) tumors, including primitive neuroectodermal tumors, medulloblastomas, choroid plexus tumors, and both pediatric and adult low‐ and high‐grade gliomas using immunohistochemistry. Claudin‐6 was expressed in 17/59 AT/RTs (29%), but also in a variety of other primary CNS tumors, including 60% of medulloblastomas and 21% of malignant gliomas. Even though high staining scores (2+ or 3+) were more often encountered in AT/RTs (Chi‐square 4.177; P = 0.041), the overall frequency of claudin‐6 staining was not significantly higher in AT/RTs as compared with the other tumors (17/59 vs. 16/60; Chi‐square = 0.328; P = 0.567). In a subgroup of 43 AT/RT patients, of which follow‐up data were available, claudin‐6 expression did not show any correlation with survival. In conclusion, claudin‐6 immunohistochemistry is of limited sensitivity and specificity for the diagnosis of AT/RT and does not correlate with clinical behavior.

Published
2011

26. AT-03 * ATYPICAL TERATOID/RHABDOID TUMOUR IS A GENETICALLY HOMOGENEOUS BUT EPIGENETICALLY HETEROGENEOUS DISEASE THAT IS DEFINED BY SUBGROUP SPECIFIC SUPER-ENHANCERS

Author

Johann, P., primary, Erkek, S., additional, Zapatka, M., additional, Kerl, K., additional, Buchhalter, I., additional, Hovestadt, V., additional, Korshunov, A., additional, Rhyzova, M., additional, Jones, D. T. W., additional, Northcott, P. A., additional, Fruhwald, M. C., additional, Hasselblatt, M., additional, Gajjar, A., additional, Pfister, S. M., additional, and Kool, M., additional

Published
2015
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30. ATYPICAL TERATOID RHABDOID TUMOR (ATRT)

Author

Hasselblatt, M., primary, Kordes, U., additional, Wolff, J., additional, Jeibmann, A., additional, Fruhwald, M., additional, Paulus, W., additional, Hasselblatt, M., additional, Isken, S., additional, Siebert, R., additional, Schneppenheim, R., additional, Benesch, M., additional, Fleischhack, G., additional, Gruhn, B., additional, Schlegel, P.-G., additional, Witt, O., additional, Holter, W., additional, Reiter, A., additional, Urban, C., additional, Fruhwald, M. C., additional, Lafay-Cousin, L., additional, Huang, A., additional, Hawkins, C., additional, Fryer, C., additional, Bouffet, E., additional, Kruchko, C., additional, Propp, J., additional, McCarthy, B., additional, Dolecek, T., additional, Kerl, K., additional, Unland, R., additional, Jurgens, H., additional, Kieran, M. W., additional, Roberts, C. W. M., additional, Biegel, J. A., additional, MacConaill, L. E., additional, Rich, B. E., additional, Ligon, K. L., additional, Chi, S., additional, Kondo, A., additional, Shimoji, K., additional, Ogino, I., additional, Junya, F., additional, Sakaguchi, S., additional, Miyajima, M., additional, Arai, H., additional, Alimova, I., additional, Knipstein, J., additional, Harris, P., additional, Venkataraman, S., additional, Marquez, V., additional, Birks, D., additional, Foreman, N., additional, Vibhakar, R., additional, Bartelheim, K., additional, Warmuth-Metz, M., additional, Kortmann, R.-D., additional, Gerss, J., additional, Rizzo, D., additional, Freneaux, P., additional, Brisse, H., additional, Parfait, B., additional, Doz, F., additional, Dufour, C., additional, Stephan, J.-L., additional, Edan, C., additional, Ranchere-Vince, D., additional, Peuchmaur, M., additional, Delattre, O., additional, Bourdeaut, F., additional, Soh, S. Y., additional, Chan, M. Y., additional, Seow, W. T., additional, Chang, K., additional, Ng, W. H., additional, Tan, A. M., additional, Yamasaki, K., additional, Tanaka, C., additional, Okada, K., additional, Fujisaki, H., additional, Osugi, Y., additional, Hara, J., additional, Matsusaka, Y., additional, Sakamoto, H., additional, Inoue, T., additional, Batchelder, P., additional, DeMasters, B. K., additional, Handler, M., additional, Sumerauer, D., additional, Vasovcak, P., additional, Puchmajerova, A., additional, Zapotocky, M., additional, Vicha, A., additional, Kyncl, M., additional, Zamecnik, J., additional, Sedlacek, Z., additional, Kodet, R., additional, Geludkova, O., additional, Kumirova, E., additional, Korshunov, A., additional, Kushel, Y., additional, Melikyan, A., additional, Shishkina, L., additional, Ryzhova, M., additional, Ozerova, V., additional, Gorbatyh, S., additional, Popov, V., additional, Pavlova, E., additional, Scherbenko, O., additional, Borodina, I., additional, Donson, A., additional, Dunham, C., additional, Algar, E., additional, Popovski, D., additional, Muscat, A., additional, Ashley, D., additional, Modena, P., additional, Sardi, I., additional, Brenca, M., additional, Giunti, L., additional, Maestro, R., additional, Buccoliero, A. M., additional, Pollo, B., additional, Genitori, L., additional, Giangaspero, F., additional, Massimino, M., additional, Amani, V., additional, Griesinger, A., additional, Bemis, L., additional, Schittone, S., additional, Puccetti, D., additional, Wargowski, D., additional, Messiaen, L., additional, Patel, N., additional, Salamat, S., additional, Rusinak, D., additional, Iskandar, B., additional, Lun, X., additional, Jayanthan, A., additional, Forsyth, P., additional, and Narendran, A., additional

Published
2012
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33. RESULTS OF THE INTERNATIONAL INTERLABORATORY COMPARISON OF MGMT PROMOTER METHYLATION ANALYSIS INVOLVING TWENTY-THREE ACADEMIC CENTERS IN GERMANY, AUSTRIA AND THE NETHERLANDS

Author

Reifenberger, G., primary, Malzkorn, B., additional, Acker, T., additional, Bettstetter, M., additional, Buslei, R., additional, von Deimling, A., additional, Dietmaier, W., additional, Dubbink, H. J., additional, Eigenbrod, S., additional, Garvalov, B. K., additional, Gerstenmaier, U., additional, Giese, A., additional, Haase, D., additional, Hasselblatt, M., additional, Kirches, E., additional, Koch, A., additional, Marienfeld, R., additional, Mittelbronn, M., additional, Montesinos-Rongen, M., additional, Pagenstecher, A., additional, Riemenschneider, M. J., additional, Prinz, M., additional, Romeike, B., additional, Roos, A., additional, Spiegl-Kreinecker, S., additional, Schittenhelm, J., additional, Schlegel, J., additional, Thal, D. R., additional, Tops, B. B. J., additional, Weis, J., additional, Westphal, G., additional, Worm, K., additional, and Felsberg, J., additional

Published
2014
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34. MEDULLOBLASTOMA

Author

Vaidyanathan, G., primary, Gururangan, S., additional, Bigner, D., additional, Zalutsky, M., additional, Morfouace, M., additional, Shelat, A., additional, Megan, J., additional, Freeman, B. B., additional, Robinson, S., additional, Throm, S., additional, Olson, J. M., additional, Li, X.-N., additional, Guy, K. R., additional, Robinson, G., additional, Stewart, C., additional, Gajjar, A., additional, Roussel, M., additional, Sirachainan, N., additional, Pakakasama, S., additional, Anurathapan, U., additional, Hansasuta, A., additional, Dhanachai, M., additional, Khongkhatithum, C., additional, Hongeng, S., additional, Feroze, A., additional, Lee, K.-S., additional, Gholamin, S., additional, Wu, Z., additional, Lu, B., additional, Mitra, S., additional, Cheshier, S., additional, Northcott, P., additional, Lee, C., additional, Zichner, T., additional, Lichter, P., additional, Korbel, J., additional, Wechsler-Reya, R., additional, Pfister, S., additional, Project, I. P. T., additional, Li, K. K.-W., additional, Xia, T., additional, Ma, F. M. T., additional, Zhang, R., additional, Zhou, L., additional, Lau, K.-M., additional, Ng, H.-K., additional, Lafay-Cousin, L., additional, Chi, S., additional, Madden, J., additional, Smith, A., additional, Wells, E., additional, Owens, E., additional, Strother, D., additional, Foreman, N., additional, Packer, R., additional, Bouffet, E., additional, Wataya, T., additional, Peacock, J., additional, Taylor, M. D., additional, Ivanov, D., additional, Garnett, M., additional, Parker, T., additional, Alexander, C., additional, Meijer, L., additional, Grundy, R., additional, Gellert, P., additional, Ashford, M., additional, Walker, D., additional, Brent, J., additional, Cader, F. Z., additional, Ford, D., additional, Kay, A., additional, Walsh, R., additional, Solanki, G., additional, Peet, A., additional, English, M., additional, Shalaby, T., additional, Fiaschetti, G., additional, Baulande, S., additional, Gerber, N., additional, Baumgartner, M., additional, Grotzer, M., additional, Hayase, T., additional, Kawahara, Y., additional, Yagi, M., additional, Minami, T., additional, Kanai, N., additional, Yamaguchi, T., additional, Gomi, A., additional, Morimoto, A., additional, Hill, R., additional, Kuijper, S., additional, Lindsey, J., additional, Schwalbe, E., additional, Barker, K., additional, Boult, J., additional, Williamson, D., additional, Ahmad, Z., additional, Hallsworth, A., additional, Ryan, S., additional, Poon, E., additional, Ruddle, R., additional, Raynaud, F., additional, Howell, L., additional, Kwok, C., additional, Joshi, A., additional, Nicholson, S. L., additional, Crosier, S., additional, Wharton, S., additional, Robson, K., additional, Michalski, A., additional, Hargrave, D., additional, Jacques, T., additional, Pizer, B., additional, Bailey, S., additional, Swartling, F., additional, Petrie, K., additional, Weiss, W., additional, Chesler, L., additional, Clifford, S., additional, Kitanovski, L., additional, Prelog, T., additional, Kotnik, B. F., additional, Debeljak, M., additional, Grotzer, M. A., additional, Gevorgian, A., additional, Morozova, E., additional, Kazantsev, I., additional, Iukhta, T., additional, Safonova, S., additional, Kumirova, E., additional, Punanov, Y., additional, Afanasyev, B., additional, Zheludkova, O., additional, Grajkowska, W., additional, Pronicki, M., additional, Cukrowska, B., additional, Dembowska-Baginska, B., additional, Lastowska, M., additional, Murase, A., additional, Nobusawa, S., additional, Gemma, Y., additional, Yamazaki, F., additional, Masuzawa, A., additional, Uno, T., additional, Osumi, T., additional, Shioda, Y., additional, Kiyotani, C., additional, Mori, T., additional, Matsumoto, K., additional, Ogiwara, H., additional, Morota, N., additional, Hirato, J., additional, Nakazawa, A., additional, Terashima, K., additional, Fay-McClymont, T., additional, Walsh, K., additional, Mabbott, D., additional, Sturm, D., additional, Northcott, P. A., additional, Jones, D. T. W., additional, Korshunov, A., additional, Pfister, S. M., additional, Kool, M., additional, Hooper, C., additional, Hawes, S., additional, Kees, U., additional, Gottardo, N., additional, Dallas, P., additional, Siegfried, A., additional, Bertozzi, A. I., additional, Sevely, A., additional, Loukh, N., additional, Munzer, C., additional, Miquel, C., additional, Bourdeaut, F., additional, Pietsch, T., additional, Dufour, C., additional, Delisle, M. B., additional, Kawauchi, D., additional, Rehg, J., additional, Finkelstein, D., additional, Zindy, F., additional, Phoenix, T., additional, Gilbertson, R., additional, Trubicka, J., additional, Borucka-Mankiewicz, M., additional, Ciara, E., additional, Chrzanowska, K., additional, Perek-Polnik, M., additional, Abramczuk-Piekutowska, D., additional, Jurkiewicz, D., additional, Luczak, S., additional, Kowalski, P., additional, Krajewska-Walasek, M., additional, Sheila, C., additional, Lee, S., additional, Foster, C., additional, Manoranjan, B., additional, Pambit, M., additional, Berns, R., additional, Fotovati, A., additional, Venugopal, C., additional, O'Halloran, K., additional, Narendran, A., additional, Hawkins, C., additional, Ramaswamy, V., additional, Taylor, M., additional, Singhal, A., additional, Hukin, J., additional, Rassekh, R., additional, Yip, S., additional, Singh, S., additional, Duhman, C., additional, Dunn, S., additional, Chen, T., additional, Rush, S., additional, Fuji, H., additional, Ishida, Y., additional, Onoe, T., additional, Kanda, T., additional, Kase, Y., additional, Yamashita, H., additional, Murayama, S., additional, Nakasu, Y., additional, Kurimoto, T., additional, Kondo, A., additional, Sakaguchi, S., additional, Fujimura, J., additional, Saito, M., additional, Arakawa, T., additional, Arai, H., additional, Shimizu, T., additional, Jurkiewicz, E., additional, Daszkiewicz, P., additional, Drogosiewicz, M., additional, Hovestadt, V., additional, Buchhalter, I., additional, Jager, N. N., additional, Stuetz, A., additional, Johann, P., additional, Schmidt, C., additional, Ryzhova, M., additional, Landgraf, P., additional, Hasselblatt, M., additional, Schuller, U., additional, Yaspo, M.-L., additional, von Deimling, A., additional, Eils, R., additional, Modi, A., additional, Patel, M., additional, Berk, M., additional, Wang, L.-x., additional, Plautz, G., additional, Camara-Costa, H., additional, Resch, A., additional, Lalande, C., additional, Kieffer, V., additional, Poggi, G., additional, Kennedy, C., additional, Bull, K., additional, Calaminus, G., additional, Grill, J., additional, Doz, F., additional, Rutkowski, S., additional, Massimino, M., additional, Kortmann, R.-D., additional, Lannering, B., additional, Dellatolas, G., additional, Chevignard, M., additional, Solecki, D., additional, McKinnon, P., additional, Olson, J., additional, Hayden, J., additional, Ellison, D., additional, Buss, M., additional, Remke, M., additional, Lee, J., additional, Caspary, T., additional, Castellino, R., additional, Sabel, M., additional, Gustafsson, G., additional, Fleischhack, G., additional, Benesch, M., additional, Navajas, A., additional, Reddingius, R., additional, Delisle, M.-B., additional, Lafon, D., additional, Sevenet, N., additional, Pierron, G., additional, Delattre, O., additional, Ecker, J., additional, Oehme, I., additional, Mazitschek, R., additional, Lodrini, M., additional, Deubzer, H. E., additional, Kulozik, A. E., additional, Witt, O., additional, Milde, T., additional, Patmore, D., additional, Boulos, N., additional, Wright, K., additional, Boop, S., additional, Janicki, T., additional, Burzynski, S., additional, Burzynski, G., additional, Marszalek, A., additional, Triscott, J., additional, Green, M., additional, Rassekh, S. R., additional, Toyota, B., additional, Dunham, C., additional, Dunn, S. E., additional, Liu, K.-W., additional, Pei, Y., additional, Genovesi, L., additional, Ji, P., additional, Davis, M., additional, Ng, C. G., additional, Cho, Y.-J., additional, Jenkins, N., additional, Copeland, N., additional, Wainwright, B., additional, Tang, Y., additional, Schubert, S., additional, Nguyen, B., additional, Masoud, S., additional, Lee, A., additional, Willardson, M., additional, Bandopadhayay, P., additional, Bergthold, G., additional, Atwood, S., additional, Whitson, R., additional, Qi, J., additional, Beroukhim, R., additional, Tang, J., additional, Oro, A., additional, Link, B., additional, Bradner, J., additional, Vallero, S. G., additional, Bertin, D., additional, Basso, M. E., additional, Milanaccio, C., additional, Peretta, P., additional, Cama, A., additional, Mussano, A., additional, Barra, S., additional, Morana, G., additional, Morra, I., additional, Nozza, P., additional, Fagioli, F., additional, Garre, M. L., additional, Darabi, A., additional, Sanden, E., additional, Visse, E., additional, Stahl, N., additional, Siesjo, P., additional, Vaka, D., additional, Vasquez, F., additional, Weir, B., additional, Cowley, G., additional, Keller, C., additional, Hahn, W., additional, Gibbs, I. C., additional, Partap, S., additional, Yeom, K., additional, Martinez, M., additional, Vogel, H., additional, Donaldson, S. S., additional, Fisher, P., additional, Perreault, S., additional, Guerrini-Rousseau, L., additional, Pujet, S., additional, Kieffer-Renaux, V., additional, Raquin, M. A., additional, Varlet, P., additional, Longaud, A., additional, Sainte-Rose, C., additional, Valteau-Couanet, D., additional, Staal, J., additional, Lau, L. S., additional, Zhang, H., additional, Ingram, W. J., additional, Cho, Y. J., additional, Hathout, Y., additional, Brown, K., additional, Rood, B. R., additional, Handler, M., additional, Hankinson, T., additional, Kleinschmidt-Demasters, B. K., additional, Hutter, S., additional, Jones, D. T., additional, Kagawa, N., additional, Hirayama, R., additional, Kijima, N., additional, Chiba, Y., additional, Kinoshita, M., additional, Takano, K., additional, Eino, D., additional, Fukuya, S., additional, Yamamoto, F., additional, Nakanishi, K., additional, Hashimoto, N., additional, Hashii, Y., additional, Hara, J., additional, Yoshimine, T., additional, Wang, J., additional, Guo, C., additional, Yang, Q., additional, Chen, Z., additional, Filipek, I., additional, Swieszkowska, E., additional, Tarasinska, M., additional, Perek, D., additional, Kebudi, R., additional, Koc, B., additional, Gorgun, O., additional, Agaoglu, F. Y., additional, Wolff, J., additional, Darendeliler, E., additional, Kerl, K., additional, Gronych, J., additional, McGlade, J., additional, Endersby, R., additional, Hii, H., additional, Johns, T., additional, Sastry, J., additional, Murphy, D., additional, Ronghe, M., additional, Cunningham, C., additional, Cowie, F., additional, Jones, R., additional, Calisto, A., additional, Sangra, M., additional, Mathieson, C., additional, Brown, J., additional, Phuakpet, K., additional, Larouche, V., additional, Bartels, U., additional, Ishida, T., additional, Hasegawa, D., additional, Miyata, K., additional, Ochi, S., additional, Saito, A., additional, Kozaki, A., additional, Yanai, T., additional, Kawasaki, K., additional, Yamamoto, K., additional, Kawamura, A., additional, Nagashima, T., additional, Akasaka, Y., additional, Soejima, T., additional, Yoshida, M., additional, Kosaka, Y., additional, von Bueren, A., additional, Goschzik, T., additional, Kortmann, R., additional, von Hoff, K., additional, Friedrich, C., additional, Muehlen, A. z., additional, Warmuth-Metz, M., additional, Soerensen, N., additional, Deinlein, F., additional, Zwiener, I., additional, Faldum, A., additional, Kuehl, J., additional, KRAMER, K., additional, -Taskar, N. P., additional, Zanzonico, P., additional, Humm, J. L., additional, Wolden, S. L., additional, Cheung, N.-K. V., additional, Venkataraman, S., additional, Alimova, I., additional, Harris, P., additional, Birks, D., additional, Balakrishnan, I., additional, Griesinger, A., additional, Foreman, N. K., additional, Vibhakar, R., additional, Margol, A., additional, Robison, N., additional, Gnanachandran, J., additional, Hung, L., additional, Kennedy, R., additional, Vali, M., additional, Dhall, G., additional, Finlay, J., additional, Erdrich-Epstein, A., additional, Krieger, M., additional, Drissi, R., additional, Fouladi, M., additional, Gilles, F., additional, Judkins, A., additional, Sposto, R., additional, Asgharzadeh, S., additional, Peyrl, A., additional, Chocholous, M., additional, Holm, S., additional, Grillner, P., additional, Blomgren, K., additional, Azizi, A., additional, Czech, T., additional, Gustafsson, B., additional, Dieckmann, K., additional, Leiss, U., additional, Slavc, I., additional, Babelyan, S., additional, Dolgopolov, I., additional, Pimenov, R., additional, Mentkevich, G., additional, Gorelishev, S., additional, Laskov, M., additional, von Bueren, A. O., additional, Nowak, J., additional, Kortmann, R. D., additional, Mynarek, M., additional, Muller, K., additional, Gerber, N. U., additional, Ottensmeier, H., additional, Kwiecien, R., additional, Yankelevich, M., additional, Boyarshinov, V., additional, Glekov, I., additional, Ozerov, S., additional, Gorelyshev, S., additional, Popa, A., additional, Subbotina, N., additional, Martin, A. M., additional, Nirschl, C., additional, Polanczyk, M., additional, Bell, R., additional, Martinez, D., additional, Sullivan, L. M., additional, Santi, M., additional, Burger, P. C., additional, Taube, J. M., additional, Drake, C. G., additional, Pardoll, D. M., additional, Lim, M., additional, Li, L., additional, Wang, W.-G., additional, Pu, J.-X., additional, Sun, H.-D., additional, Ruggieri, R., additional, Symons, M. H., additional, Vanan, M. I., additional, Bolin, S., additional, Schumacher, S., additional, Zeid, R., additional, Yu, F., additional, Vue, N., additional, Gibson, W., additional, Paolella, B., additional, Swartling, F. J., additional, Kieran, M. W., additional, Bradner, J. E., additional, Maher, O., additional, Khatua, S., additional, Tarek, N., additional, Zaky, W., additional, Gupta, T., additional, Mohanty, S., additional, Kannan, S., additional, Jalali, R., additional, Kapitza, E., additional, Denkhaus, D., additional, Muhlen, A. z., additional, van Vuurden, D. G., additional, Garami, M., additional, Fangusaro, J., additional, Davidson, T. B., additional, da Costa, M. J. G., additional, Sterba, J., additional, Clifford, S. C., additional, Finlay, J. L., additional, Schmidt, R., additional, Felsberg, J., additional, Skladny, H., additional, Cremer, F., additional, Reifenberger, G., additional, Kunder, R., additional, Sridhar, E., additional, Moiyadi, A. A., additional, Goel, A., additional, Goel, N., additional, Shirsat, N., additional, Othman, R., additional, Storer, L., additional, Kerr, I., additional, Coyle, B., additional, Law, N., additional, Smith, M. L., additional, Greenberg, M., additional, Laughlin, S., additional, Malkin, D., additional, Liu, F., additional, Moxon-Emre, I., additional, Scantlebury, N., additional, Nasir, A., additional, Onion, D., additional, Lourdusamy, A., additional, Grabowska, A., additional, Cai, Y., additional, Bradshaw, T., additional, de Medeiros, R. S. S., additional, Beaugrand, A., additional, Soares, S., additional, Epelman, S., additional, Wang, W., additional, Sultan, M., additional, Wechsler-Reya, R. J., additional, Zapatka, M., additional, Radlwimmer, B., additional, Alderete, D., additional, Baroni, L., additional, Lubinieki, F., additional, Auad, F., additional, Gonzalez, M. L., additional, Puya, W., additional, Pacheco, P., additional, Aurtenetxe, O., additional, Gaffar, A., additional, Gros, L., additional, Cruz, O., additional, Calvo, C., additional, Shinojima, N., additional, Nakamura, H., additional, Kuratsu, J.-i., additional, Hanaford, A., additional, Eberhart, C., additional, Archer, T., additional, Tamayo, P., additional, Pomeroy, S., additional, Raabe, E., additional, De Braganca, K., additional, Gilheeney, S., additional, Khakoo, Y., additional, Kramer, K., additional, Wolden, S., additional, Dunkel, I., additional, Lulla, R. R., additional, Laskowski, J., additional, Goldman, S., additional, Gopalakrishnan, V., additional, Shih, D., additional, Wang, X., additional, Faria, C., additional, Raybaud, C., additional, Tabori, U., additional, Rutka, J., additional, Jacobs, S., additional, De Vathaire, F., additional, Diallo, I., additional, Llanas, D., additional, Verez, C., additional, Diop, F., additional, Kahlouche, A., additional, Puget, S., additional, Thompson, E., additional, Prince, E., additional, Amani, V., additional, Sin-Chan, P., additional, Lu, M., additional, Kleinman, C., additional, Spence, T., additional, Picard, D., additional, Ho, K. C., additional, Chan, J., additional, Majewski, J., additional, Jabado, N., additional, Dirks, P., additional, Huang, A., additional, Madden, J. R., additional, Donson, A. M., additional, Mirsky, D. M., additional, Dubuc, A., additional, Mack, S., additional, Gendoo, D., additional, Luu, B., additional, MacDonald, T., additional, Van Meter, T., additional, Croul, S., additional, Laureano, A., additional, Brugmann, W., additional, Denman, C., additional, Singh, H., additional, Huls, H., additional, Moyes, J., additional, Sandberg, D., additional, Silla, L., additional, Cooper, L., additional, and Lee, D., additional

Published
2014
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35. ATYPICAL TERATOID RHABDOID TUMOUR

Author

Bertozzi, A. I., primary, Munzer, C., additional, Fouyssac, F., additional, Andre, N., additional, Boetto, S., additional, Leblond, P., additional, Bourdeaut, F., additional, Dufour, C., additional, Deshpande, R. K., additional, Bhat, K. G., additional, Mahalingam, S., additional, Muscat, A., additional, Cain, J., additional, Ferguson, M., additional, Popovski, D., additional, Algar, E., additional, Rossello, F. J., additional, Jayasekara, S., additional, Watkins, D. N., additional, Hodge, J., additional, Ashley, D., additional, Hishii, M., additional, Saito, M., additional, Arai, H., additional, Han, Z. Y., additional, Richer, W., additional, Lucchesi, C., additional, Freneaux, P., additional, Nicolas, A., additional, Grison, C., additional, Pierron, G., additional, Delattre, O., additional, Epari, S., additional, TS, N., additional, Gupta, T., additional, Chinnaswamy, G., additional, Sastri, J. G., additional, Shetty, P., additional, Moiyadi, A., additional, Jalali, R., additional, Fay-McClymont, T., additional, Johnston, D., additional, Janzen, L., additional, Guger, S., additional, Scheinemann, K., additional, Fleming, A., additional, Fryer, C., additional, Hukin, J., additional, Mabbott, D., additional, Huang, A., additional, Bouffet, E., additional, Lafay-Cousin, L., additional, Kawamura, A., additional, Yamamoto, K., additional, Nagashima, T., additional, Bartelheim, K., additional, Benesch, M., additional, Buchner, J., additional, Gerss, J., additional, Hasselblatt, M., additional, Kortmann, R.-D., additional, Fleischack, G., additional, Quiroga, E., additional, Reinhard, H., additional, Schneppenheim, R., additional, Seeringer, A., additional, Siebert, R., additional, Timmermann, B., additional, Warmuth-Metz, M., additional, Schmid, I., additional, Fruhwald, M. C., additional, Kerl, K., additional, Klingebiel, T., additional, Al-Kofide, A., additional, Khafaga, Y., additional, Al-Hindi, H., additional, Dababo, M., additional, Ul-Haq, A., additional, Anas, M., additional, Barria, M. G., additional, Siddiqui, K., additional, Hassounah, M., additional, Ayas, M., additional, Al-Shail, E., additional, Jeibmann, A., additional, Eikmeier, K., additional, Linge, A., additional, Johann, P., additional, Koos, B., additional, Kool, M., additional, Pfister, S. M., additional, Paulus, W., additional, Schuller, U., additional, Junckerstorff, R., additional, Rosenblum, M. K., additional, Alassiri, A. H., additional, Rossi, S., additional, Gottardo, N., additional, Toledano, H., additional, Viscardi, E., additional, Witkowski, L., additional, Nagel, I., additional, Oyen, F., additional, Foulkes, W. D., additional, Schrey, D., additional, Malietzis, G., additional, Chi, S., additional, Marshall, L., additional, Carceller, F., additional, Moreno, L., additional, Zacharoulis, S., additional, Bhardwaj, R., additional, Chakravadhanula, M., additional, Ozals, V., additional, Hampton, C., additional, Metpally, R., additional, Grillner, P., additional, Asmundsson, J., additional, Gustavsson, B., additional, Holm, S., additional, Johann, P. D., additional, Korshunov, A., additional, Ryzhova, M., additional, Milde, T., additional, Witt, O., additional, Jones, D. T. W., additional, Hovestadt, V., additional, Gajjar, A., additional, Fruhwald, M., additional, Pfister, S., additional, Finetti, M., additional, Pons, A. d. C., additional, Selby, M., additional, Smith, A., additional, Crosier, S., additional, Wood, J., additional, Skalkoyannis, B., additional, Bailey, S., additional, Clifford, S., additional, Williamson, D., additional, Rutkowski, S., additional, Kortmann, R. D., additional, Graf, N., additional, Boos, J., additional, Nysom, K., additional, Moreno, N., additional, Holsten, T., additional, Ahlfeld, J., additional, Mertins, J., additional, Hotfilder, M., additional, Schleicher, S., additional, Handgretinger, R., additional, Meisterernst, M., additional, Schmidt, C., additional, Dittmar, S., additional, Chan, G. C. F., additional, Shing, M. M. K., additional, Yuen, H. L., additional, Li, R. C. H., additional, Ling, S. L., additional, Slavc, I., additional, Peyrl, A., additional, Chocholous, M., additional, Azizi, A., additional, Czech, T., additional, Dieckmann, K., additional, Haberler, C., additional, Leiss, U., additional, Gotti, G., additional, Biassoni, V., additional, Schiavello, E., additional, Spreafico, F., additional, Pecori, E., additional, Gandola, L., additional, Massimino, M., additional, Kornelius, K., additional, Yano, H., additional, Nakayama, N., additional, Ohe, N., additional, Ozeki, M., additional, Kanda, K., additional, Kimura, T., additional, Hori, T., additional, Fukao, T., additional, Iwama, T., additional, Weil, A. G., additional, Diaz, A., additional, Gernsback, J., additional, Bhatia, S., additional, Ragheb, J., additional, Niazi, T., additional, Khatib, Z., additional, Zoghbi, A., additional, Meisterernst, a. M., additional, Birks, D., additional, Griesinger, A., additional, Amani, V., additional, Donson, A., additional, Posner, R., additional, Dunham, C., additional, Kleinschmidt-DeMasters, B. K., additional, Handler, M., additional, Vibhakar, R., additional, Foreman, N., additional, Zhou, L., additional, Catchpoole, D., additional, Kakkar, A., additional, Biswas, A., additional, Suri, V., additional, Sharma, M., additional, Kale, S., additional, Mahapatra, A., additional, Sarkar, C., additional, Torchia, J., additional, Picard, D., additional, Ho, K. C., additional, Khuong-Quang, D.-A., additional, Louterneau, L., additional, Bourgey, M., additional, Chan, T., additional, Golbourn, B., additional, Cousin, L.-L., additional, Taylor, M. D., additional, Dirks, P., additional, Rutka, J. T., additional, Hawkins, C., additional, Majewski, J., additional, Kim, S.-K., additional, Jabado, N., additional, Chang, J. H.-C., additional, Confer, M., additional, Chang, A., additional, Goldman, S., additional, Dunn, M., additional, and Hartsell, W., additional

Published
2014
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37. PAX2 is an antiapoptotic molecule with deregulated expression in medulloblastoma

Author

Burger, M C, Brucker, D P, Baumgarten, P, Ronellenfitsch, M W, Wanka, C, Hasselblatt, M, Eccles, M R, Klingebiel, T, Weller, M, Rieger, J, Mittelbronn, M, Steinbach, J P, Burger, M C, Brucker, D P, Baumgarten, P, Ronellenfitsch, M W, Wanka, C, Hasselblatt, M, Eccles, M R, Klingebiel, T, Weller, M, Rieger, J, Mittelbronn, M, and Steinbach, J P

Abstract

PAX2 is a paired box transcription factor possessing a fundamental role in the embryogenesis of hindbrain and urinary tract. PAX genes are proto-oncogenes, PAX2 expression may contribute to the pathogenesis of renal cell carcinoma. Because of the expression of PAX2 in the developing hindbrain and its essential role in cerebellar development, it has been hypothesized that PAX2 may also be involved in medulloblastoma tumorigenesis. We investigated the expression pattern of PAX2 and various genes of the neuronal lineage in medulloblastoma and glioma cell lines. We found high expression of PAX2 mRNA and PAX2 protein in medulloblastoma cells and some glioma cell lines independent of their neuronal lineage gene expression signature. Gene suppression of PAX2 decreased the expression of the PAX2 transcriptional target GDNF in Daoy cells and had a profound cytotoxic effect in vitro on Daoy medulloblastoma and T98G glioma cells. Expression of PAX2 was then assessed in two separate medulloblastoma tissue microarrays with a total of 61 patient samples by immunohistochemistry. PAX2 expression was detected in the majority of medulloblastoma samples and correlated with less differentiated histology. Therefore, PAX2 is a biomarker for a more aggressive medulloblastoma phenotype and may represent a novel therapeutic target.

Published
2012

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

Author

Schindler, G., Capper, D., Meyer, J., Janzarik, W., Omran, H., Herold-Mende, C., Schmieder, K., Wesseling, P., Mawrin, C., Hasselblatt, M., Louis, D.N., Korshunov, A., Pfister, S., Hartmann, C., Paulus, W., Reifenberger, G., Deimling, A. Von, Schindler, G., Capper, D., Meyer, J., Janzarik, W., Omran, H., Herold-Mende, C., Schmieder, K., Wesseling, P., Mawrin, C., Hasselblatt, M., Louis, D.N., Korshunov, A., Pfister, S., Hartmann, C., Paulus, W., Reifenberger, G., and Deimling, A. Von

Abstract

Item does not contain fulltext, 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.

Published
2011

43. RARE TUMORS

Author

Kiyotani, C., primary, Uno, T., additional, Ogiwara, H., additional, Morota, N., additional, Nakazawa, A., additional, Tsutsumi, Y., additional, Masaki, H., additional, Mori, T., additional, Sanz, J. A. S., additional, Guibelalde, M., additional, Tavera, A., additional, Herandez, I., additional, Ibanez, J., additional, Brell, M., additional, Mas, A., additional, Muller, H. L., additional, Gebhardt, U., additional, Warmuth-Metz, M., additional, Pietsch, T., additional, Sorensen, N., additional, Kortmann, R.-D., additional, Stapleton, S., additional, Gonzalez, I., additional, Steinbrueck, S., additional, Rodriguez, L., additional, Tuite, G., additional, Krzyzankova, M., additional, Mertsch, S., additional, Jeibmann, A., additional, Kordes, U., additional, Wolff, J., additional, Paulus, W., additional, Hasselblatt, M., additional, Nonaka, Y., additional, Hara, S., additional, Fukazawa, S., additional, Shimizu, K., additional, Ben-Arush, M., additional, Postovsky, S., additional, Toledano, H., additional, Peretz-Nahum, M., additional, Fujimura, J., additional, Sakaguchi, S., additional, Kondo, A., additional, Saito, Y., additional, Shimoji, K., additional, Ohara, Y., additional, Arakawa, A., additional, Saito, M., additional, Shimizu, T., additional, Benesch, M., additional, von Bueren, A. O., additional, Dantonello, T., additional, von Hoff, K., additional, Leuschner, I., additional, Claviez, A., additional, Bierbach, U., additional, Kropshofer, G., additional, Korinthenberg, R., additional, Graf, N., additional, Suttorp, M., additional, Kortmann, R. D., additional, Friedrich, C., additional, Klingebiel, T., additional, Koscielniak, E., additional, Rutkowski, S., additional, Mesa, M., additional, Sanchez, M., additional, Mejia, J., additional, Pena, G., additional, Dussan, R., additional, Cabeza, M., additional, Storino, A., additional, Dincer, F., additional, Roffidal, T., additional, Powell, M., additional, Berrak, S., additional, Wolff, J. E., additional, Fouyssac, F., additional, Delaunay, C., additional, Vignaud, J.-M., additional, Schmitt, E., additional, Klein, O., additional, Mansuy, L., additional, Chastagner, P., additional, Cruz, O., additional, Guillen, A., additional, Garcia, G., additional, Alamar, M., additional, Candela, S., additional, Roussos, I., additional, Garzon, M., additional, Sunol, M., additional, Muchart, J., additional, Rebollo, M., additional, Mora, J., additional, Diez, B., additional, Muggeri, A., additional, Arakaki, N., additional, Meli, F., additional, Sevlever, G., additional, Tsitouras, V., additional, Pettorini, B., additional, Fellows, G., additional, Blair, J., additional, Didi, M., additional, Daousi, C., additional, Steele, C., additional, Javadpour, M., additional, Sinha, A., additional, Hishii, M., additional, Ishii, H., additional, Miyajima, M., additional, Arai, H., additional, Dvir, R., additional, Sayar, D., additional, Levin, D., additional, Ben-Sirah, L., additional, Constantini, S., additional, Elhasid, R., additional, Gertsch, E., additional, Foreman, N., additional, Valera, E. T., additional, Brassesco, M. S., additional, Machado, H. R., additional, Oliveira, R. S., additional, Santos, A. C., additional, Terra, V. C., additional, Barros, M. V., additional, Scrideli, C. A., additional, Tone, L. G., additional, Merino, D., additional, Pienkowska, M., additional, Shlien, A., additional, Tabori, U., additional, Gilbertson, R., additional, Malkin, D., additional, Jeeva, I., additional, Chang, B., additional, Long, V., additional, Picton, S., additional, Burton, D., additional, Clark, S., additional, Kwok, C., additional, Mokete, B., additional, Rafiq, O., additional, Simmons, I., additional, Shing, M. M. K., additional, Li, C. K., additional, Chan, G. C. F., additional, Ha, S. Y., additional, Yuen, H. L., additional, Luk, C. W., additional, Ling, S. C., additional, Li, R. C. H., additional, Yoon, J. H., additional, Park, H. J., additional, Shin, H. J., additional, Park, B.-K., additional, Kim, J.-Y., additional, Jung, H. L., additional, Ra, Y. S., additional, Ghim, T. T., additional, Hartung, S., additional, Garami, M., additional, Traunecker, H., additional, Thall, P., additional, Mahajan, A., additional, Sumerauer, D., additional, Grillner, P., additional, Orrego, A., additional, Mosskin, M., additional, Gustavsson, B., additional, Holm, S., additional, Peters, N., additional, Rogers, M., additional, Chowdry, S., additional, Selman, W., additional, Mitchell, A., additional, Bangert, B., additional, Ahuja, S., additional, Laschinger, K., additional, Gold, D., additional, Stearns, D., additional, Wright, K., additional, Gupta, K., additional, Klimo, P., additional, Ellison, D., additional, Keating, G., additional, Eckel, L., additional, Giannini, C., additional, Wetjen, N., additional, Patton, A., additional, Zaky, W., additional, McComb, G., additional, Finlay, J., additional, Grimm, J., additional, Wong, K., additional, Dhall, G., additional, Gilles, F., additional, Ormandy, D., additional, Alston, R., additional, Estlin, E., additional, Gattamaneni, R., additional, Birch, J., additional, Kamaly-Asl, I., additional, Hemenway, M., additional, Rush, S., additional, Reginald, Y. A., additional, Nicolin, G., additional, Bartel, U., additional, Buncic, J. R., additional, Aguilera, D., additional, Flamini, R., additional, Mazewski, C., additional, Schniederjan, M., additional, Hayes, L., additional, Boydston, W., additional, MacDonald, T., additional, Fleming, A., additional, Jabado, N., additional, Saint-Martin, C., additional, Albrecht, S., additional, Ramsay, D. A., additional, Farmer, J. P., additional, Bendel, A., additional, Hansen, M., additional, Dugan, S., additional, and Mendelsohn, N., additional

Published
2012
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44. Pediatrics Clinical Research

Author

Wrede, B., primary, Peters, O., additional, Kordes, U., additional, Kutluk, T., additional, Hasselblatt, M., additional, Rytting, M., additional, Rutkowski, S., additional, Mahajan, A., additional, Pietsch, T., additional, Thall, P., additional, Wolff, J. E., additional, Pfister, S., additional, Bingham, R., additional, Vats, T., additional, Rokes, C., additional, Brown, R., additional, Creach, K. M., additional, Rubin, J. B., additional, Leonard, J. R., additional, Limbrick, D. D., additional, Smyth, M. D., additional, Dacey, R. G., additional, Rich, K. M., additional, Dowling, J. L., additional, Linette, G. P., additional, King, A. A., additional, Michalski, J. M., additional, Simpson, J. R., additional, Park, T. S., additional, Perry, A., additional, Mansur, D. B., additional, Gururangan, S., additional, Panandikar, A. P., additional, Broniscer, A., additional, Huang, A., additional, Kellie, S., additional, Ellison, D., additional, Gajjar, A., additional, Aguilera, D., additional, Goldman, S., additional, Tomita, T., additional, Fangusaro, J., additional, Poussaint, T. Y., additional, Onar, A., additional, Gilbertson, R., additional, Packer, R., additional, McClendon, R., additional, Friedman, H., additional, Boyett, J., additional, Baker, J. N., additional, Tagen, M., additional, Onar-Thomas, A., additional, Gilbertson, R. J., additional, Davidoff, A. M., additional, Pai-Panandiker, A., additional, Leung, W., additional, Chin, T. K., additional, Stewart, C. F., additional, Kocak, M., additional, Rowland, C., additional, Merchant, T. E., additional, Kaste, S., additional, Allen, J., additional, Donahue, B., additional, Mathew, J., additional, Kretschmar, C., additional, Pollack, I., additional, Jakacki, R., additional, Massimino, M., additional, Biassoni, V., additional, Gandola, L., additional, Ferroli, P., additional, Bongarzone, I., additional, Spreafico, F., additional, Pecori, E., additional, Schiavello, E., additional, Modena, P., additional, Bach, F., additional, Potepan, P., additional, Slavc, I., additional, Peyrl, A., additional, Czech, T., additional, Haberler, C., additional, Dieckmann, K., additional, Brown, R. J., additional, Dhall, G., additional, Marachelian, A., additional, Gozali, A., additional, Butturini, A., additional, Gilles, F., additional, Thompson, S. J., additional, Gardner, S., additional, Finlay, J. L., additional, Eisenstat, D. D., additional, and Evans, A., additional

Published
2010
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45. Erythropoietin: a candidate compound for neuroprotection in schizophrenia

Author

Ehrenreich, H, primary, Degner, D, additional, Meller, J, additional, Brines, M, additional, Béhé, M, additional, Hasselblatt, M, additional, Woldt, H, additional, Falkai, P, additional, Knerlich, F, additional, Jacob, S, additional, von Ahsen, N, additional, Maier, W, additional, Brück, W, additional, Rüther, E, additional, Cerami, A, additional, Becker, W, additional, and Sirén, A-L, additional

Published
2003
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47. Structure determination of the (√3 × √3)R30° boron phase on the Si(111) surface using photoelectron diffraction

Author

Baumgärtel, P., Paggel, J. J., Hasselblatt, M., Horn, K., Fernandez, V., Schaff, O., Weaver, J. H., Bradshaw, A. M., David Phillip Woodruff, Rotenberg, E., and Denlinger, J.

Abstract

A quantitative structural analysis of the system Si(111)(√3×√3)R30°−B has been performed using photoelectron diffraction in the scanned energy mode. We confirm that the substitutional S5 adsorption site is occupied and show that the interatomic separations to the three nearest-neighbor Si atoms are 1.98(±0.04)Å, 2.14(±0.13)Å, and 2.21(±0.12)Å. These correspond to the silicon atom immediately below the boron atom, the adatom immediately above, and the three atoms to which it is coordinated symmetrically in the first layer.

48. Genetic and epigenetic characterization of posterior pituitary tumors

Author

Carsten Dittmayer, Caterina Giannini, M. Beatriz S. Lopes, Annekathrin Reinhardt, David Capper, Jens Schittenhelm, Roland Coras, Anne Thieme, Martin Hasselblatt, Werner Paulus, Bette K. Kleinschmidt-DeMasters, David A. Solomon, Damian Stichel, Rolf Buslei, Eilís Perez, Ozgur Mete, Arie Perry, Simone Schmid, David T.W. Jones, Christin Siewert, Christoph Nagel, Elisabeth J. Rushing, Arend Koch, Sylvia L. Asa, Andreas von Deimling, Patrick N. Harter, Jürgen Honegger, Stefan M. Pfister, Schmid S., Solomon D.A., Perez E., Thieme A., Kleinschmidt-DeMasters B.K., Giannini C., Reinhardt A., Asa S.L., Mete O., Stichel D., Siewert C., Dittmayer C., Hasselblatt M., Paulus W., Nagel C., Harter P.N., Schittenhelm J., Honegger J., Rushing E., Coras R., Pfister S.M., Buslei R., Koch A., Perry A., Jones D.T.W., von Deimling A., Capper D., and Lopes M.B.

Subjects
Adenoma, Molecular neuropathology, Clinical Sciences, Brain tumor, Copy number analysis, Biology, medicine.disease_cause, Epigenesis, Genetic, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Genetic, medicine, Genetics, Adenoma, Oxyphilic, Humans, 2.1 Biological and endogenous factors, Pituitary Neoplasms, HRAS, Epigenetics, ddc:610, Aetiology, Pituicytoma, Epigenomics, Posterior pituitary gland neoplasms, Cancer, Original Paper, Mutation, Neurology & Neurosurgery, Granular cell tumor, Oxyphilic, Human Genome, Neurosciences, medicine.disease, Posterior pituitary gland neoplasm, DNA methylation, Cancer research, Neurology (clinical), Spindle cell oncocytoma, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, Epigenesis
Abstract

Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.

Published
2021

49. Desmoplastic myxoid tumor, SMARCB1-mutant: clinical, histopathological and molecular characterization of a pineal region tumor encountered in adolescents and adults

Author

Werner Paulus, Martin Sill, Annika K. Wefers, Susanne Bens, Fanny Burel-Vandenbos, Christian Thomas, Michael C. Frühwald, Torsten Pietsch, Francesca Brett, Florian Oyen, Abbas Agaimy, Marcel Kool, Karolina Nemes, Silke Vogelgesang, Guido Reifenberger, Frantz Rom Poulsen, Reiner Siebert, Fausto J. Rodriguez, Roger E. McLendon, Caterina Giannini, Pascal Johann, Eric S. Lipp, Stefan Tippelt, Kathy Keyvani, Klaus Kuchelmeister, Martin Hasselblatt, Andreas von Deimling, Uwe Kordes, Istvan Bodi, Thomas C., Wefers A., Bens S., Nemes K., Agaimy A., Oyen F., Vogelgesang S., Rodriguez F.J., Brett F.M., McLendon R., Bodi I., Burel-Vandenbos F., Keyvani K., Tippelt S., Poulsen F.R., Lipp E.S., Giannini C., Reifenberger G., Kuchelmeister K., Pietsch T., Kordes U., Siebert R., Fruhwald M.C., Johann P.D., Sill M., Kool M., von Deimling A., Paulus W., and Hasselblatt M.

Subjects
0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Proliferation index, Adolescent, Medizin, Brain tumor, Biology, Pineal Gland, Pathology and Forensic Medicine, Frameshift mutation, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, 0302 clinical medicine, Atypical teratoid/rhabdoid tumor (ATRT), myxoid stroma, pineal region, medicine, Humans, SMARCB1, Rhabdoid Tumor, Brain Neoplasms, Myxoid tumor, Age Factors, SMARCB1 Protein, Middle Aged, medicine.disease, Survival Rate, 030104 developmental biology, Tumor progression, Atypical teratoid rhabdoid tumor, Mutation, Atypical teratoid/rhabdoid tumor, SMARCB1 gene, pineal, Female, Neurology (clinical), Epithelioid cell, 030217 neurology & neurosurgery
Abstract

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40years (range 15–61years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.

Published
2020
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50. FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma

Author

Roland Coras, Elisabeth J. Rushing, Rudi Beschorner, Kristian W. Pajtler, David E. Reuss, Walter Stummer, Daniel Schrimpf, Andreas von Deimling, Stefan M. Pfister, Caterina Giannini, Christian Hagel, Felice Giangaspero, Philipp Sievers, Uta Schick, Christel Herold-Mende, Annika K. Wefers, Azadeh Ebrahimi, Patricia Kohlhof, Kristin Huang, Andrey Korshunov, Ori Staszewski, Francesca Diomedi-Camassei, David T.W. Jones, Christian Koelsche, Guido Reifenberger, Felix Sahm, Yanghao Hou, Damian Stichel, Annekathrin Reinhardt, Christian Hartmann, Martin Hasselblatt, Kathy Keyvani, Sievers P., Stichel D., Schrimpf D., Sahm F., Koelsche C., Reuss D.E., Wefers A.K., Reinhardt A., Huang K., Ebrahimi A., Hou Y., Pajtler K.W., Pfister S.M., Hasselblatt M., Stummer W., Schick U., Hartmann C., Hagel C., Staszewski O., Reifenberger G., Beschorner R., Coras R., Keyvani K., Kohlhof P., Diomedi-Camassei F., Herold-Mende C., Giangaspero F., Rushing E., Giannini C., Korshunov A., Jones D.T.W., von Deimling A., University of Zurich, and von Deimling, Andreas

Subjects
Fetal Proteins, Male, 0301 basic medicine, Pathology, Oncogene Proteins, Fusion, 2804 Cellular and Molecular Neuroscience, Medizin, Kaplan-Meier Estimate, DNA methylation profile, Histones, 0302 clinical medicine, Retrospective Studie, Neurocytoma, Nuclear Protein, Brain Neoplasms, FGFR, Nuclear Proteins, Methylation, Isocitrate Dehydrogenase, Histone, 2728 Neurology (clinical), Extraventricular neurocytoma, Molecular classification, DNA methylation, Female, Microtubule-Associated Proteins, Human, medicine.medical_specialty, 10208 Institute of Neuropathology, Clinical Neurology, Brain tumor, Copy number analysis, 610 Medicine & health, Biology, Pathology and Forensic Medicine, Brain Neoplasm, 03 medical and health sciences, Cellular and Molecular Neuroscience, Text mining, Fetal Protein, Parenchyma, medicine, Central neurocytoma, Humans, Receptor, Fibroblast Growth Factor, Type 1, Epigenetics, Fusion, Retrospective Studies, business.industry, Microtubule-Associated Protein, DNA Methylation, medicine.disease, FGFR1–TACC1, 2734 Pathology and Forensic Medicine, Ki-67 Antigen, 030104 developmental biology, 570 Life sciences, biology, brain tumor, extraventricular neurocytoma, fusion, molecular classification, Neurology (clinical), Transcriptome, business, 030217 neurology & neurosurgery
Abstract

Extraventricular neurocytoma (EVN) is a rare primary brain tumor occurring in brain parenchyma outside the ventricular system. Histopathological characteristics resemble those of central neurocytoma but exhibit a wider morphologic spectrum. Accurate diagnosis of these histologically heterogeneous tumors is often challenging because of the overlapping morphological features and the lack of defining molecular markers. Here, we explored the molecular landscape of 40 tumors diagnosed histologically as EVN by investigating copy number profiles and DNA methylation array data. DNA methylation profiles were compared with those of relevant differential diagnoses of EVN and with a broader spectrum of diverse brain tumor entities. Based on this, our tumor cohort segregated into different groups. While a large fraction (n = 22) formed a separate epigenetic group clearly distinct from established DNA methylation profiles of other entities, a subset (n = 14) of histologically diagnosed EVN grouped with clusters of other defined entities. Three cases formed a small group close to but separated from the epigenetically distinct EVN cases, and one sample clustered with non-neoplastic brain tissue. Four additional samples originally diagnosed otherwise were found to molecularly resemble EVN. Thus, our results highlight a distinct DNA methylation pattern for the majority of tumors diagnosed as EVN, but also indicate that approximately onethird of morphological diagnoses of EVN epigenetically correspond to other brain tumor entities. Copy number analysis and confirmation through RNA sequencing revealed FGFR1–TACC1 fusion as a distinctive, recurrent feature within the EVN methylation group (60%), in addition to a small number of other FGFR rearrangements (13%). In conclusion, our data demonstrate a specific epigenetic signature of EVN suitable for characterization of these tumors as a molecularly distinct entity, and reveal a high frequency of potentially druggable FGFR pathway activation in this tumor group.

Published
2018

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