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1. JS01.3.A EPIGENETICALLY DEFINED ANGIOCENTRIC GLIOMAS MAY LACK ANGIOCENTRIC GROWTH AND INSTEAD SHOW A VARIETY OF GROWTH PATTERNS

Author

Stegat, L, primary, Rohwer, J L, additional, Stichel, D, additional, Schrimpf, D, additional, Coras, R, additional, Pagès, M, additional, Tauziède-Espariat, A, additional, Varlet, P, additional, Hans, V H, additional, Meyer, J, additional, Schittenhelm, J, additional, Staszewski, O, additional, Cheesman, E, additional, Glatzel, M, additional, Schmid, S, additional, Wesseling, P, additional, Korshunov, A, additional, Sexton-Oates, A, additional, Schüller, U, additional, Kõrgvee, L, additional, Mueller, S, additional, Olar, A, additional, Snuderl, M, additional, Schweizer, L, additional, Aronica, E, additional, Sahm, F, additional, von Deimling, A, additional, Blumcke, I, additional, Jones, D T W, additional, Capper, D, additional, and Wefers, A K, additional

Published
2023
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2. Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial

Author

Wirsching, H.-G., Tabatabai, G., Roelcke, U., Hottinger, A.F., Jörger, F., Schmid, A., Plasswilm, L., Schrimpf, D., Mancao, C., Capper, D., Conen, K., Hundsberger, T., Caparrotti, F., von Moos, R., Riklin, C., Felsberg, J., Roth, P., Jones, D.T.W., Pfister, S., Rushing, E.J., Abrey, L., Reifenberger, G., Held, L., von Deimling, A., Ochsenbein, A., and Weller, M.

Published
2018
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3. Genomic characterization of DICER1-associated neoplasms uncovers molecular classes.

Author

Kommoss, F.K.F., Chong, A.S., Chong, A.L., Pfaff, E., Jones, D.T.W., Hiemcke-Jiwa, L.S., Kester, L.A., Flucke, U.E., Gessler, M., Schrimpf, D., Sahm, F., Clarke, B.A., Stewart, C.J.R., Wang, Yemin, Gilks, C.B., Kommoss, F., Huntsman, D.G., Schüller, U., Koelsche, C., Glenn McCluggage, W., Deimling, A. von, Foulkes, W.D., Kommoss, F.K.F., Chong, A.S., Chong, A.L., Pfaff, E., Jones, D.T.W., Hiemcke-Jiwa, L.S., Kester, L.A., Flucke, U.E., Gessler, M., Schrimpf, D., Sahm, F., Clarke, B.A., Stewart, C.J.R., Wang, Yemin, Gilks, C.B., Kommoss, F., Huntsman, D.G., Schüller, U., Koelsche, C., Glenn McCluggage, W., Deimling, A. von, and Foulkes, W.D.

Abstract

Item does not contain fulltext, DICER1 syndrome is a tumor predisposition syndrome that is associated with up to 30 different neoplastic lesions, usually affecting children and adolescents. Here we identify a group of mesenchymal tumors which is highly associated with DICER1 syndrome, and molecularly distinct from other DICER1-associated tumors. This group of DICER1-associated mesenchymal tumors encompasses multiple well-established clinicopathological tumor entities and can be further divided into three clinically meaningful classes designated "low-grade mesenchymal tumor with DICER1 alteration" (LGMT DICER1), "sarcoma with DICER1 alteration" (SARC DICER1), and primary intracranial sarcoma with DICER1 alteration (PIS DICER1). Our study not only provides a combined approach to classify DICER1-associated neoplasms for improved clinical management but also suggests a role for global hypomethylation and other recurrent molecular events in sarcomatous differentiation in mesenchymal tumors with DICER1 alteration. Our results will facilitate future investigations into prognostication and therapeutic approaches for affected patients.

Published
2023

4. Integrated Molecular-Morphologic Meningioma Classification: A Multicenter Retrospective Analysis, Retrospectively and Prospectively Validated

Author

Maas, SLN, Stichel, D, Hielscher, T, Sievers, P, Berghoff, AS, Schrimpf, D, Sill, M, Euskirchen, P, Blume, C, Patel, A, Dogan, H, Reuss, D, Dohmen, H, Stein, M, Reinhardt, A, Suwala, AK, Wefers, AK, Baumgarten, P, Ricklefs, F, Rushing, EJ, Bewerunge-Hudler, M, Ketter, R, Schittenhelm, J, Jaunmuktane, Z, Leu, S, Greenway, FEA, Bridges, LR, Jones, T, Grady, C, Serrano, J, Golfinos, J, Sen, C, Mawrin, C, Jungk, C, Hänggi, D, Westphal, M, Lamszus, K, Etminan, N, Jungwirth, G, Herold-Mende, C, Unterberg, A, Harter, PN, Wirsching, H-G, Neidert, MC, Ratliff, M, Platten, M, Snuderl, M, Aldape, KD, Brandner, S, Hench, J, Frank, S, Pfister, SM, Jones, DTW, Reifenberger, G, Acker, T, Wick, W, Weller, M, Preusser, M, von Deimling, A, Sahm, F, and German Consortium on Aggressive Meningiomas (KAM)

Abstract

PURPOSE: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established (CDKN2A/B and TERT), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference P = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.

Published
2021

5. Sarcoma classification by DNA methylation profiling

Author

Koelsche, Christian, Schrimpf, D., Stichel, Damian, Sill, M., Sahm, F., Reuss, D.E., Versleijen-Jonkers, Y.M.H., Weidema, M.E., Jones, D.T.W., Flucke, U.E., Pfister, S.M., Deimling, Andreas von, Koelsche, Christian, Schrimpf, D., Stichel, Damian, Sill, M., Sahm, F., Reuss, D.E., Versleijen-Jonkers, Y.M.H., Weidema, M.E., Jones, D.T.W., Flucke, U.E., Pfister, S.M., and Deimling, Andreas von

Abstract

Contains fulltext : 230614.pdf (publisher's version ) (Open Access)

Published
2021

6. 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

7. 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

10. Genome-wide methylation profiling and copy number analysis in atypical fibroxanthomas and pleomorphic dermal sarcomas indicate a similar molecular phenotype

Author

Koelsche, C., Stichel, D., Griewank, K.G., Schrimpf, D., Reuss, D.E., Bewerunge-Hudler, M., Vokuhl, C., Dinjens, W.N., Petersen, I., Mittelbronn, M., Cuevas-Bourdier, A., Buslei, R., Pfister, S.M., Flucke, U.E., Mechtersheimer, G., Mentzel, T., Deimling, A. von, Koelsche, C., Stichel, D., Griewank, K.G., Schrimpf, D., Reuss, D.E., Bewerunge-Hudler, M., Vokuhl, C., Dinjens, W.N., Petersen, I., Mittelbronn, M., Cuevas-Bourdier, A., Buslei, R., Pfister, S.M., Flucke, U.E., Mechtersheimer, G., Mentzel, T., and Deimling, A. von

Abstract

Contains fulltext : 203163.pdf (publisher's version ) (Open Access), Background: Atypical fibroxanthomas (AFX) and pleomorphic dermal sarcomas (PDS) are lesions of the skin with overlapping histologic features and unspecific molecular traits. PDS behaves aggressive compared to AFX. Thus, a precise delineation, although challenging in some instances, is relevant. Methods: We examined the value of DNA-methylation profiling and copy number analysis for separating these tumors. DNA-methylation data were generated from 17 AFX and 15 PDS using the Illumina EPIC array. These were compared with DNA-methylation data generated from 196 tumors encompassing potential histologic mimics like cutaneous squamous carcinomas (cSCC; n = 19), basal cell carcinomas (n = 10), melanoma metastases originating from the skin (n = 11), leiomyosarcomas (n = 11), angiosarcomas of the skin and soft tissue (n = 11), malignant peripheral nerve sheath tumors (n = 19), dermatofibrosarcomas protuberans (n = 13), extraskeletal myxoid chondrosarcomas (n = 9), myxoid liposarcomas (n = 14), schwannomas (n = 10), neurofibromas (n = 21), alveolar (n = 19) and embryonal (n = 17) rhabdomyosarcomas as well as undifferentiated pleomorphic sarcomas (n = 12). Results: DNA-methylation profiling did not separate AFX from PDS. The DNA-methylation profiles of the other cases, however, were distinct from AFX/PDS. They reliably assigned to subtype-specific DNA-methylation clusters, although overlap occurred between some AFX/PDS and cSCC. Copy number profiling revealed alterations in a similar frequency and distribution between AFX and PDS. They involved losses of 9p (22/32) and 13q (25/32). Gains frequently involved 8q (8/32). Notably, a homozygous deletion of CDKN2A was more frequent in PDS (6/15) than in AFX (2/17), whereas amplifications were non-recurrent and overall rare (5/32). Conclusions: Our findings support the concept that AFX and PDS belong to a common tumor spectrum. We could demonstrate the diagnostic value of DNA-methylation profiling to delineating AFX/PDS from potentia

Published
2019

14. 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

15. The miR-139-5p regulates proliferation of supratentorial paediatric low-grade gliomas by targeting the PI3K/AKT/mTORC1 signalling

Author

Catanzaro, G., Besharat, Z. M., Miele, E., Chiacchiarini, M., Po, A., Carai, A., Marras, C. E., Antonelli, M., Badiali, M., Raso, A., Mascelli, S., Schrimpf, D., Stichel, D., Tartaglia, M., Capper, D., von Deimling, A., Giangaspero, F., Mastronuzzi, A., Locatelli, Franco, Ferretti, E., Locatelli F. (ORCID:0000-0002-7976-3654), Catanzaro, G., Besharat, Z. M., Miele, E., Chiacchiarini, M., Po, A., Carai, A., Marras, C. E., Antonelli, M., Badiali, M., Raso, A., Mascelli, S., Schrimpf, D., Stichel, D., Tartaglia, M., Capper, D., von Deimling, A., Giangaspero, F., Mastronuzzi, A., Locatelli, Franco, Ferretti, E., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Aims: Paediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs. Methods: We performed microRNA profiling on 45 fresh-frozen grade I tumour samples of various histological classes, resected from patients aged ≤16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non-neoplastic brain tissue. Pathway analysis of the microRNAs signature revealed PI3K/AKT signalling as one of the centrally enriched oncogenic signalling. To date, activation of the PI3K/AKT pathway in pLGGs has been reported, although activation mechanisms have not been fully investigated yet. Results: One of the most markedly down-regulated microRNAs in our supratentorial pLGGs cohort was miR-139-5p, whose targets include the gene encoding the PI3K's (phosphatidylinositol 3-kinase) catalytic unit, PIK3CA. We investigated the role of miR-139-5p in regulating PI3K/AKT signalling by the use of human cell cultures derived from supratentorial pLGGs. MiR-139-5p overexpression inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated-p70 S6 kinase (p-p70 S6K), a hallmark of PI3K/AKT/mTORC1 signalling activation. The effect of miR-139-5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002. Conclusions: These findings provide the first evidence that down-regulation of miR-139-5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signalling.

Published
2018

17. Integrated molecular characterization of IDH -mutant glioblastomas

Author

Korshunov, A., primary, Casalini, B., additional, Chavez, L., additional, Hielscher, T., additional, Sill, M., additional, Ryzhova, M., additional, Sharma, T., additional, Schrimpf, D., additional, Stichel, D., additional, Capper, D., additional, Reuss, D. E., additional, Sturm, D., additional, Absalyamova, O., additional, Golanov, A., additional, Lambo, S., additional, Bewerunge-Hudler, M., additional, Lichter, P., additional, Herold-Mende, C., additional, Wick, W., additional, Pfister, S. M., additional, Kool, M., additional, Jones, D. T. W., additional, von Deimling, A., additional, and Sahm, F., additional

Published
2018
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18. BTC1.04 Genomic profiling of IDH-wildtype and IDH-mutant initial and matched recurrent glioblastomas reveals clinically actionable mutations (e.g. BRCA1/2) and resistance signatures

Author

McInerney, C E, primary, Ellis, H P, additional, Schrimpf, D, additional, Sahm, F, additional, Stupnikov, A, additional, Wadsley, M, additional, Wragg, C, additional, White, P, additional, Prise, K M, additional, McArt, D G, additional, and Kurian, K M, additional

Published
2018
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19. The miR‐139‐5p regulates proliferation of supratentorial paediatric low‐grade gliomas by targeting the PI3K/AKT/mTORC1 signalling

Author

Catanzaro, G., primary, Besharat, Z. M., additional, Miele, E., additional, Chiacchiarini, M., additional, Po, A., additional, Carai, A., additional, Marras, C. E., additional, Antonelli, M., additional, Badiali, M., additional, Raso, A., additional, Mascelli, S., additional, Schrimpf, D., additional, Stichel, D., additional, Tartaglia, M., additional, Capper, D., additional, von Deimling, A., additional, Giangaspero, F., additional, Mastronuzzi, A., additional, Locatelli, F., additional, and Ferretti, E., additional

Published
2018
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20. Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases.

Author

Koelsche, C., Schrimpf, D., Tharun, L., Roth, E., Sturm, D., Jones, D.T., Renker, E.K., Sill, M., Baude, A., Sahm, F., Capper, D., Bewerunge-Hudler, M., Hartmann, W., Kulozik, A.E., Petersen, I., Flucke, U.E., Schreuder, H.W.B., Buttner, R., Weber, M.A., Schirmacher, P., Plass, C., Pfister, S.M., Deimling, A. von, Mechtersheimer, G., Koelsche, C., Schrimpf, D., Tharun, L., Roth, E., Sturm, D., Jones, D.T., Renker, E.K., Sill, M., Baude, A., Sahm, F., Capper, D., Bewerunge-Hudler, M., Hartmann, W., Kulozik, A.E., Petersen, I., Flucke, U.E., Schreuder, H.W.B., Buttner, R., Weber, M.A., Schirmacher, P., Plass, C., Pfister, S.M., Deimling, A. von, and Mechtersheimer, G.

Abstract

Contains fulltext : 173988.pdf (publisher's version ) (Open Access), BACKGROUND: Histone 3.3 (H3.3) hotspot mutations in bone tumors occur in the vast majority of giant cell tumors of bone (GCTBs; 96%), chondroblastomas (95%) and in a few cases of osteosarcomas. However, clinical presentation, histopathological features, and additional molecular characteristics of H3.3 mutant osteosarcomas are largely unknown. METHODS: In this multicentre, retrospective study, a total of 106 conventional high-grade osteosarcomas, across all age groups were re-examined for hotspot mutations in the H3.3 coding genes H3F3A and H3F3B. H3.3 mutant osteosarcomas were re-evaluated in a multidisciplinary manner and analyzed for genome-wide DNA-methylation patterns and DNA copy number aberrations alongside H3.3 wild-type osteosarcomas and H3F3A G34W/L mutant GCTBs. RESULTS: Six osteosarcomas (6/106) carried H3F3A hotspot mutations. No mutations were found in H3F3B. All patients with H3F3A mutant osteosarcoma were older than 30 years with a median age of 65 years. Copy number aberrations that are commonly encountered in high-grade osteosarcomas also occurred in H3F3A mutant osteosarcomas. Unlike a single osteosarcoma with a H3F3A K27M mutation, the DNA methylation profiles of H3F3A G34W/R mutant osteosarcomas were clearly different from H3.3 wild-type osteosarcomas, but more closely related to GCTBs. The most differentially methylated promoters between H3F3A G34W/R mutant and H3.3 wild-type osteosarcomas were in KLLN/PTEN (p < 0.00005) and HIST1H2BB (p < 0.0005). CONCLUSIONS: H3.3 mutations in osteosarcomas may occur in H3F3A at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying H3F3A G34W/R mutations are associated with epigenetic dysregulation of KLLN/PTEN and HIST1H2BB.

Published
2017

23. Development and implementation of the open source electronic randomization system RANDI2 and its connectivity to the electronic data capture system (EDCS) OpenClinica

Author

Schrimpf, D and Pilz, L

Subjects
open source, ddc: 610, clinical study, randomization, 610 Medical sciences, Medicine
Abstract

Introduction: In evidence based medicine clinical studies are the gold standard in introducing new treatments to show efficacy and clinical benefit. If possible it should be randomized and an experimental treatment should be tested against a placebo or the established standard. In some medical fields[for full text, please go to the a.m. URL], GMDS 2015; 60. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS)

Published
2015
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24. 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, and Pfister, SM

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Question/methods: Molecular technologies which can complement standard pathology testing have the potential to greatly enhance diagnostic precision. Analysis of DNA methylation, acting as a 'fingerprint' of cellular origin, is one such promising technology for tumor classification. We[for full text, please go to the a.m. URL], 60th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN)

Published
2015
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25. ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an 'integrated' diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma

Author

Reuss, D E, Sahm, F, Schrimpf, D, Wiestler, B, Capper, D, Koelsche, C, Schweizer, L, Korshunov, A, Jones, D T W, Hovestadt, V, Mittelbronn, M, Schittenhelm, J, Herold-Mende, C, Unterberg, A, Platten, M, Weller, M, Wick, W, Pfister, S M, von Deimling, A, University of Zurich, and von Deimling, A

Subjects
2734 Pathology and Forensic Medicine, 2728 Neurology (clinical), 2804 Cellular and Molecular Neuroscience, 610 Medicine & health, 10040 Clinic for Neurology
Published
2015

26. Integrated molecular characterization of IDH‐mutant glioblastomas.

Author

Korshunov, A., Casalini, B., Chavez, L., Hielscher, T., Sill, M., Ryzhova, M., Sharma, T., Schrimpf, D., Stichel, D., Capper, D., Reuss, D. E., Sturm, D., Absalyamova, O., Golanov, A., Lambo, S., Bewerunge‐Hudler, M., Lichter, P., Herold‐Mende, C., Wick, W., and Pfister, S. M.

Subjects
GLIOBLASTOMA multiforme, ISOCITRATE dehydrogenase, DISEASE progression, DNA methylation, DNA fingerprinting
Abstract

Aims: Mutations of isocitrate dehydrogenase (IDH)1/2 affect almost all astrocytomas of WHO grade II and III. A subset of IDH‐mutant astrocytic tumours progresses to IDH‐mutant glioblastoma or presents with the histology of a glioblastoma at first presentation. We set out here to assess the molecular spectrum of IDH‐mutant glioblastomas. Methods: We performed an integrated molecular analysis of a mono‐centric cohort (n = 97); assessed through genome‐wide DNA methylation analysis, copy‐number profiling and targeted next generation sequencing using a neurooncology‐tailored gene panel. Results: Of these 97 IDH‐mutant glioblastomas, 68 had a glioblastoma at first presentation ('de novo' IDH‐mutant glioblastoma) and 29 emerged from a prior low‐grade lesion ('evolved' IDH‐mutant glioblastoma). Unsupervised hierarchical clustering of DNA methylation data disclosed that IDH‐mutant glioblastoma ('de novo' and 'evolved') formed a distinct group separate from other diffuse glioma subtypes. Homozygous deletions of CDKN2A/B were found to be associated with shorter survival. Conclusions: This study demonstrates DNA methylation patterns in IDH‐mutant glioblastoma to be distinct from lower‐grade astrocytic counterparts but homogeneous within de novo and evolved IDH‐mutant glioblastomas, and identifies CDKN2A as a marker for possible genetic sub‐stratification. [ABSTRACT FROM AUTHOR]

Published
2019
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27. Combined alterations in MAPK pathway genes, CDKN2A/B and ATRX characterize anaplastic pilocytic astrocytoma

Author

Kratz, A, Sahm, F, Schrimpf, D, Jones, DT, Reuss, D, Koelsche, C, Huang, K, Wefers, AK, Hovestadt, V, Gramatzki, D, Felsberg, J, Koch, A, Thomale, UW, Reifenberger, G, Becker, A, Hans, V, Prinz, M, Staszewski, O, Acker, T, Dohmen-Scheufler, H, Hartmann, C, Mueller, W, Tuffaha, MSA, Paulus, W, Heß, K, Brokinkel, B, Schittenhelm, J, Monoranu, CM, Kessler, AF, Loehr, M, Buslei, R, Deckert, M, Mawrin, C, Kohlhof, P, Hewer, E, Olar, A, Rodriguez, F, Giannini, C, NageswaraRao, AA, Weller, M, Pohl, U, Brandner, S, Pfister, SM, von Deimling, A, Capper, D, Kratz, A, Sahm, F, Schrimpf, D, Jones, DT, Reuss, D, Koelsche, C, Huang, K, Wefers, AK, Hovestadt, V, Gramatzki, D, Felsberg, J, Koch, A, Thomale, UW, Reifenberger, G, Becker, A, Hans, V, Prinz, M, Staszewski, O, Acker, T, Dohmen-Scheufler, H, Hartmann, C, Mueller, W, Tuffaha, MSA, Paulus, W, Heß, K, Brokinkel, B, Schittenhelm, J, Monoranu, CM, Kessler, AF, Loehr, M, Buslei, R, Deckert, M, Mawrin, C, Kohlhof, P, Hewer, E, Olar, A, Rodriguez, F, Giannini, C, NageswaraRao, AA, Weller, M, Pohl, U, Brandner, S, Pfister, SM, von Deimling, A, and Capper, D

Published
2016

30. IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO

Author

Reuss, D.E., Mamatjan, Y., Schrimpf, D., Capper, D., Hovestadt, V., Kratz, A., Sahm, F., Koelsche, C., Korshunov, A., Olar, A., Hartmann, C., Reijneveld, J.C., Wesseling, P., Unterberg, A., Platten, M., Wick, W., Herold-Mende, C., Aldape, K., Deimling, A. von, Reuss, D.E., Mamatjan, Y., Schrimpf, D., Capper, D., Hovestadt, V., Kratz, A., Sahm, F., Koelsche, C., Korshunov, A., Olar, A., Hartmann, C., Reijneveld, J.C., Wesseling, P., Unterberg, A., Platten, M., Wick, W., Herold-Mende, C., Aldape, K., and Deimling, A. von

Abstract

Contains fulltext : 153031.pdf (publisher's version ) (Closed access), The WHO 2007 classification of tumors of the CNS distinguishes between diffuse astrocytoma WHO grade II (A IIWHO2007) and anaplastic astrocytoma WHO grade III (AA III WHO2007). Patients with A II WHO2007 are significantly younger and survive significantly longer than those with AA III WHO2007. So far, classification and grading relies on morphological grounds only and does not yet take into account IDH status, a molecular marker of prognostic relevance. We here demonstrate that WHO 2007 grading performs poorly in predicting prognosis when applied to astrocytoma carrying IDH mutations. Three independent series including a total of 1360 adult diffuse astrocytic gliomas with IDH mutation containing 683 A II IDHmut, 562 AA III IDHmut and 115 GBM IDHmut have been examined for age distribution and survival. In all three series patients with A II IDHmut and AA III IDHmut were of identical age at presentation of disease (36-37 years) and the difference in survival between grades was much less (10.9 years for A II IDHmut, 9.3 years for AA III IDHmut) than that reported for A II WHO2007 versus AA III WHO2007. Our analyses imply that the differences in age and survival between A II WHO2007 and AA III WHO2007 predominantly depend on the fraction of IDH-non-mutant astrocytomas in the cohort. This data poses a substantial challenge for the current practice of astrocytoma grading and risk stratification and is likely to have far-reaching consequences on the management of patients with IDH-mutant astrocytoma.

Published
2015

31. Next-Generation-Sequencing in routine neuropathology diagnostics

Author

Sahm, F, Schrimpf, D, Meyer, J, Jones, D, Reuss, D, Capper, D, Koelsche, C, Kratz, A, Korshunov, A, Zapatka, M, Pfister, S, Unterberg, A, Wick, W, von Deimling, A, Sahm, F, Schrimpf, D, Meyer, J, Jones, D, Reuss, D, Capper, D, Koelsche, C, Kratz, A, Korshunov, A, Zapatka, M, Pfister, S, Unterberg, A, Wick, W, and von Deimling, A

Published
2015

32. Combination of the electronic data capture system (EDCS) OpenClinica and the randomization system (RS) RANDI2

Author

Schrimpf, D and Pilz, L

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Introduction: Today clinical trials are often realized with the assistance of electronic applications. A basic application is an electronic data capture system (EDCS) supporting the data entry and management. The advantage using such systems is the direct control of entered data and the immediate availability[for full text, please go to the a.m. URL], GMDS 2013; 58. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS)

Published
2013
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33. Integration of web-based Randomization- and EDC-Systems

Author

Schrimpf, D and Pilz, L

Subjects
clinical trials, ddc: 610, Electronic data capture, randomization, 610 Medical sciences, Medicine
Abstract

Introduction: Randomization – allocation of patients by chance – is used in clinical trials to reduce unknown influencing effects and to prevent selection bias, essential to guarantee the comparability between treatments. A further development of classical randomization methods are adaptive[for full text, please go to the a.m. URL], GMDS 2012; 57. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS)

Published
2012
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34. Implementierung verschiedener Randomisationsalgorithmen in der web-basierten Anwendung RANDI2 für klinische Studien

Author

Schrimpf, D and Pilz, LR

Subjects
Randomisationsverfahren, ddc: 610, RANDI2, 610 Medical sciences, Medicine, Web-Applikation, Klinische Studien
Abstract

Einleitung/Hintergrund: Das Open Source Projekt RANDI2 stellt eine Plattform für die elektronische Randomisation klinischer Studien zur Verfügung, indem Patienten zufällig den verschiedenen Behandlungsarmen zugeordnet werden können. Realisiert sind zurzeit die Verfahren vollständige[for full text, please go to the a.m. URL], 54. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds)

Published
2009
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39. Possible Combinations of Electronic Data Capture and Randomization Systems.

Author

Schrimpf, D., Haag, M., and Pilz, L R.

Subjects
RANDOMIZATION (Statistics), CLINICAL trials, DATA quality, DATA entry, COMPUTER software development
Abstract

Background: Clinical trials (CT) are in a wider sense experiments to prove and establish clinical benefit of treatments. Nowadays electronic data capture systems (EDCS) are used more often bringing a better data management and higher data quality into clinical practice. Also electronic systems for the randomization are used to assign the patients to the treatments. Objectives: If the mentioned randomization system (RS) and EDCS are used, possibly identical data are collected in both, especially by stratified randomization. This separated data storage may lead to data inconsistency and in general data samples have to be aligned. The article discusses solutions to combine RS and EDCS. In detail one approach is realized and introduced. Methods: Different possible settings of combination of EDCS and RS are determined and the pros and cons for each solution are worked out. For the combination of two independent applications the necessary interfaces for the communication are defined. Thereby, existing standards are considered. An example realization is implemented with the help of open-source applications and state-of-the-art software development procedures. Results: Three possibilities of separate usage or combination of EDCS and RS are presented and assessed: i) the complete independent usage of both systems; ii) realization of one system with both functions; and iii) two separate systems, which communicate via defined interfaces. In addition a realization of our preferred approach, the combination of both systems, is introduced using the open source tools RANDI2 and Open- Clinica. Conclusion: The advantage of a flexible independent development of EDCS and RS is shown based on the fact that these tool are very different featured. In our opinion the combination of both systems via defined interfaces fulfills the requirements of randomization and electronic data capture and is feasible in practice. In addition, the use of such a setting can reduce the training costs and the error-prone duplicated data entry. [ABSTRACT FROM AUTHOR]

Published
2014
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45. 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

46. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations

Author

Camelia M. Monoranu, Andreas von Deimling, Albert J. Becker, Joerg Felsberg, Jens Schittenhelm, Martina Deckert, Marco Prinz, Rolf Buslei, Till Acker, Katharina Heß, Ute Pohl, Volker Hovestadt, Wolf Mueller, Patricia Kohlhof, Dorothee Gramatzki, Muin S. A. Tuffaha, Amulya NageswaraRao, Andrey Korshunov, Benjamin Brokinkel, Daniel Schrimpf, David T.W. Jones, Annekathrin Reinhardt, Ulrich W. Thomale, Werner Paulus, Ekkehard Hewer, Christian Koelsche, Christian Mawrin, Damian Stichel, Ori Staszewski, Wolfgang Wick, David E. Reuss, Almuth F. Kessler, Caterina Giannini, Annika K. Wefers, Michael Platten, Martin Sill, Daniel Hänggi, Kristin Huang, Christian Hartmann, Adriana Olar, David Capper, Volkmar Hans, Andreas Unterberg, Zane Jaunmuktane, Sebastian Brandner, Nuno Miguel Nunes, Christel Herold-Mende, Felix Sahm, Uri Tabori, Guido Reifenberger, Arend Koch, Mario Loehr, Michael Weller, Hildegard Dohmen, Stefan M. Pfister, Fausto J. Rodriguez, Reinhardt A., Stichel D., Schrimpf D., Sahm F., Korshunov A., Reuss D.E., Koelsche C., Huang K., Wefers A.K., Hovestadt V., Sill M., Gramatzki D., Felsberg J., Reifenberger G., Koch A., Thomale U.-W., Becker A., Hans V.H., Prinz M., Staszewski O., Acker T., Dohmen H., Hartmann C., Mueller W., Tuffaha M.S.A., Paulus W., Hess K., Brokinkel B., Schittenhelm J., Monoranu C.-M., Kessler A.F., Loehr M., Buslei R., Deckert M., Mawrin C., Kohlhof P., Hewer E., Olar A., Rodriguez F.J., Giannini C., NageswaraRao A.A., Tabori U., Nunes N.M., Weller M., Pohl U., Jaunmuktane Z., Brandner S., Unterberg A., Hanggi D., Platten M., Pfister S.M., Wick W., Herold-Mende C., Jones D.T.W., von Deimling A., and Capper D.

Subjects
0301 basic medicine, Male, Medizin, Kaplan-Meier Estimate, Mitogen-Activated Protein Kinase Kinase, Histones, 0302 clinical medicine, CDKN2A, Retrospective Studie, Age Factor, 610 Medicine & health, Child, DNA Modification Methylases, Aged, 80 and over, Pilocytic astrocytoma, Brain Neoplasms, DNA Repair Enzyme, Age Factors, CDKN2A/B, Middle Aged, Molecular characterization, Isocitrate Dehydrogenase, Histone, ATRX, Child, Preschool, DNA methylation, Female, MGMT, Human, Signal Transduction, Adult, X-linked Nuclear Protein, IDH1, Adolescent, Panel sequencing, Biology, Astrocytoma, Pathology and Forensic Medicine, BRAF, DNA copy number alteration, Brain Neoplasm, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Glioma, DNA Modification Methylase, medicine, Humans, Gene, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Retrospective Studies, Pilocytic astrocytoma with anaplasia, Aged, Mitogen-Activated Protein Kinase Kinases, Tumor Suppressor Protein, Methylation profile based classification, Tumor Suppressor Proteins, Infant, DNA Methylation, medicine.disease, Anaplastic pilocytic astrocytoma, 030104 developmental biology, DNA Repair Enzymes, FGFR1, NF1, Mutation, Cancer research, 570 Life sciences, biology, Neurology (clinical), 030217 neurology & neurosurgery, Anaplastic astrocytoma
Abstract

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding(t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.

Published
2018

47. Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis

Author

Pascal Johann, Yvonne Crede, Nasir Ud Din, Frank van Landeghem, Volker Hovestadt, David Capper, Annika K. Wefers, Susanne Peetz-Dienhart, Felice Giangaspero, Marcel Kool, Arie Perry, Daniel Schrimpf, Manila Antonelli, Reiner Siebert, Markus J. Riemenschneider, Stefan M. Pfister, David Sumerauer, Hannes Vogel, Christian Thomas, Michael C. Frühwald, Florian Oyen, Caterina Giannini, Susanne Bens, Andrey Korshunov, Peter Hauser, Reinhard Schneppenheim, David T.W. Jones, Marie Christine Bernardo, Kathy Keyvani, Martin Hasselblatt, Hasselblatt M., Thomas C., Hovestadt V., Schrimpf D., Johann P., Bens S., Oyen F., Peetz-Dienhart S., Crede Y., Wefers A., Vogel H., Riemenschneider M.J., Antonelli M., Giangaspero F., Bernardo M.C., Giannini C., Ud Din N., Perry A., Keyvani K., van Landeghem F., Sumerauer D., Hauser P., Capper D., Korshunov A., Jones D.T.W., Pfister S.M., Schneppenheim R., Siebert R., Fruhwald M.C., and Kool M.

Subjects
tumors, Male, DNA Copy Number Variations, Prognosi, neurology (clinical), SMARCB1, cellular and molecular neuroscience, chordomas, skull base and spine, Medizin, Pathology and Forensic Medicine, Brain Neoplasm, Diagnosis, Differential, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Biomarkers, Tumor, Chordoma, Cluster Analysis, Humans, Child, Rhabdoid Tumor, Molecular entity, DNA Copy Number Variation, Cluster Analysi, business.industry, Brain Neoplasms, Poorly differentiated, SMARCB1 Protein, Teratoma, Infant, DNA Methylation, medicine.disease, Prognosis, Smarcb1 ini1, Survival Analysis, 030220 oncology & carcinogenesis, Child, Preschool, Cancer research, Female, Neurology (clinical), Survival Analysi, Differential diagnosis, business, 030217 neurology & neurosurgery, Human
Abstract

Lettera no abstract

Published
2016

48. Meningiomas: Sex-Specific Differences and Prognostic Implications of a Chromosome X Loss.

Author

Berghaus N, Hielscher T, Savran D, Schrimpf D, Maas SLN, Preusser M, Weller M, Acker T, Herold-Mende C, Wick W, von Deimling A, and Sahm F

Abstract

Background: Meningiomas are the most common primary intracranial tumours in adults. Several studies proposed new stratification systems with a more accurate risk prediction than the WHO grading, e.g. based on methylation and copy number variations (CNVs). Yet, common shortcomings in these analyses are either a lack of stratification by sex of patients or excluding the gonososmes from CNV assessment., Methods: Within this study, DNA methylation array data from 7,424 meningioma samples as well as targeted sequencing, clinical annotations and morphology subtyping of 796 samples were examined for differences between females and males regarding mutations, methylation classes, copy number variations and histology., Results: Meningiomas from females accounted for about 53 % of the malignant tumours and present a loss of one X chromosome in 57 % of these malignant cases. In the group of benign tumours, females comprised about 75 % of the patients. Therein, a loss of one X chromosome was detected in only about 10 % of the cases but was associated with a significantly worse progression free survival., Conclusion: Although genomic instability is a common feature of malignant meningiomas, particularly loss of the X chromosome in tumours of female patients in otherwise histologically and molecularly low-risk tumours confers higher risk. Hence, the gonosomal copy number status can be leveraged for increased diagnostic accuracy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Published
2024
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49. Identification of a putative molecular subtype of adult-type diffuse astrocytoma with recurrent MAPK pathway alterations.

Author

Sievers P, Bielle F, Göbel K, Schrimpf D, Nichelli L, Mathon B, Appay R, Boldt HB, Dohmen H, Selignow C, Acker T, Vicha A, Martinetto H, Schweizer L, Schüller U, Brandner S, Wesseling P, Schmid S, Capper D, Abdullaev Z, Aldape K, Korshunov A, Krieg SM, Wick W, Pfister SM, von Deimling A, Reuss DE, Jones DTW, and Sahm F

Subjects
Humans, Adult, Male, Female, Middle Aged, Mutation genetics, Astrocytoma genetics, Astrocytoma pathology, Brain Neoplasms genetics, Brain Neoplasms pathology, MAP Kinase Signaling System physiology, MAP Kinase Signaling System genetics
Published
2024
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50. Clinically unfavorable transcriptome subtypes of non-WNT/non-SHH medulloblastomas are associated with a predominance in proliferating and progenitor-like cell subpopulations.

Author

Okonechnikov K, Schrimpf D, Koster J, Sievers P, Milde T, Sahm F, Jones DTW, von Deimling A, Pfister SM, Kool M, and Korshunov A

Subjects
Humans, Cell Proliferation genetics, Male, Child, Female, Child, Preschool, Adolescent, Prognosis, Medulloblastoma genetics, Medulloblastoma pathology, Medulloblastoma metabolism, Transcriptome, Cerebellar Neoplasms genetics, Cerebellar Neoplasms pathology, Cerebellar Neoplasms metabolism
Abstract

The non-WNT/non-SHH (Grp3/Grp4) medulloblastomas (MBs) include eight second-generation subgroups (SGS; I-VIII) each with distinct molecular and clinical characteristics. Recently, we also identified two prognostically relevant transcriptome subtypes within each SGS MB, which are associated with unique gene expression signatures and signaling pathways. These prognostic subsets may be in connection to the intra-tumoral cell landscape that underlies SGS MB clinical-molecular diversity. Here, we performed a deconvolution analysis of the Grp3/Grp4 MB bulk RNA profiles using the previously identified single-cell RNA-seq reference dataset and focusing on variability in the cellular composition of SGS MB. RNA deconvolution analysis of the Grp3/Grp4 MB disclosed the subgroup-specific neoplastic cell subpopulations. Neuronally differentiated axodendritic GP3-C1 and glutamatergic GP4-C1 subpopulations were distributed within Grp3- and Grp4-associated SGS MB, respectively. Progenitor GP3-B2 subpopulation was prominent in aggressive SGS II MB, whereas photoreceptor/visual perception GP3/4-C2 cell content was typical for SGS III/IV MB. The current study also revealed significant variability in the proportions of cell subpopulations between clinically relevant SGS MB transcriptome subtypes, where unfavorable cohorts were enriched with cell cycle and progenitor-like cell subpopulations and, vice versa, favorable subtypes were composed of neuronally differentiated cell fractions predominantly. A higher than median proportion of proliferating and progenitor cell subpopulations conferred the shortest survival of the Grp3 and Grp 4 MB, and similar survival associations were identified for all SGS MB except SGS IV MB. In summary, the recently identified clinically relevant Grp3/Grp4 MB transcriptome subtypes are composed of different cell populations. Future studies should aim to validate the prognostic and therapeutic role of the identified Grp3/Grp4 MB inter-tumoral cellular heterogeneity. The application of the single-cell techniques on each SGS MB separately could help to clarify the clinical significance of subgroup-specific variability in tumor cell content and its relation with prognostic transcriptome signatures identified before., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2024
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