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1. A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle

Author

Goode, B, Mondal, G, Hyun, M, Ruiz, DG, Lin, YH, Van Ziffle, J, Joseph, NM, Onodera, C, Talevich, E, Grenert, JP, Hewedi, IH, Snuderl, M, Brat, DJ, Kleinschmidt-Demasters, BK, Rodriguez, FJ, Louis, DN, Yong, WH, Lopes, MB, Rosenblum, MK, Butowski, N, Tihan, T, Bollen, AW, Phillips, JJ, Wiita, AP, Yeh, I, Jacobson, MP, Bastian, BC, Perry, A, and Solomon, DA

Subjects
Neurosciences, Brain Cancer, Genetics, Rare Diseases, Human Genome, Brain Disorders, Clinical Research, Cancer, 2.1 Biological and endogenous factors
Abstract

Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Despite being histologically low-grade, chordoid gliomas are often associated with poor outcome, as their stereotypic location in the third ventricle makes resection challenging and efficacious adjuvant therapies have not been developed. Here we performed genomic profiling on 13 chordoid gliomas and identified a recurrent D463H missense mutation in PRKCA in all tumors, which localizes in the kinase domain of the encoded protein kinase C alpha (PKCα). Expression of mutant PRKCA in immortalized human astrocytes led to increased phospho-ERK and anchorage-independent growth that could be blocked by MEK inhibition. These studies define PRKCA as a recurrently mutated oncogene in human cancer and identify a potential therapeutic vulnerability in this uncommon brain tumor.

Published
2018

3. 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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5. P15.01.A Metabolic-imaging of human glioblastoma explants: a new precision-medicine model to predict treatment response early

Author

Morelli, M, primary, Lessi, F, additional, Di Stefano, A, additional, Santonocito, O, additional, Gambacciani, C, additional, Pieri, F, additional, Aquila, F, additional, Ferri, G, additional, Snuderl, M, additional, Mulholland, P, additional, Ottaviani, D, additional, Aretini, P, additional, Pasqualetti, F, additional, Franceschi, S, additional, and Mazzanti, C, additional

Published
2022
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7. ETMR-06. Molecular and clinical characteristics of CNS tumors withBCOR(L1) fusion/internal tandem duplication

Author

Gojo, J, Schmitt-Hoffner, F, Mauermann, M, von Hoff, K, Sill, M, Korshunov, A, Stichel, D, Capper, D, Tauziede-Espariat, A, Varlet, P, Aldape, K, Abdullaev, Z, Donson, A, Pahnke, J, Schüller, U, Tran, I, Galbraith, K, Snuderl, M, Alexandrescu, S, Brandner, S, Łastowska, M, Miele, E, Lugt, JV, Meijer, L, Bunt, J, Kramm, C, Hansford, JR, Krskova, L, Zapotocky, M, Nobusawa, S, Solomon, D, Haberler, C, Jones, B, Sturm, D, Sahm, F, Jäger, N, Pfister, SM, Kool, M, Gojo, J, Schmitt-Hoffner, F, Mauermann, M, von Hoff, K, Sill, M, Korshunov, A, Stichel, D, Capper, D, Tauziede-Espariat, A, Varlet, P, Aldape, K, Abdullaev, Z, Donson, A, Pahnke, J, Schüller, U, Tran, I, Galbraith, K, Snuderl, M, Alexandrescu, S, Brandner, S, Łastowska, M, Miele, E, Lugt, JV, Meijer, L, Bunt, J, Kramm, C, Hansford, JR, Krskova, L, Zapotocky, M, Nobusawa, S, Solomon, D, Haberler, C, Jones, B, Sturm, D, Sahm, F, Jäger, N, Pfister, SM, and Kool, M

Abstract

Central nervous system (CNS) tumor with BCOR internal tandem duplication (BCOR-ITD) have recently been introduced in the 5th edition of the WHO classification of CNS tumors, however, their molecular makeup and clinical characteristics remain widely enigmatic. This is further complicated by the recent discovery of tumors characterized by gene fusions involving BCOR or its homologue BCORL1. We identified a cohort of 206 BCOR altered CNS tumors via DNA methylation profiling and conducted in-depth molecular and clinical characterization in an international effort. By performing t-SNE clustering analysis we found that BCOR-fusion tumors form a distinct cluster (n=61), adjacent to BCOR-ITD cases (n=145). The identified fusion partners of BCOR(L1) included EP300 (n=20), CREBBP (n=5), and NUTM2HP (n=1). Notably, three cases within the BCOR-ITD cluster harbored a c-terminal intragenic deletion within BCOR. With respect to clinical characteristics gender ratio was balanced in BCOR-fusion cases (m/f, 1.1), whereas predominance of male patients was observed in the BCOR-ITD group (m/f, 1.5). Moreover, age at diagnosis of BCOR-fusion patients was higher as compared to BCOR-ITD cases (15 vs 4.5 years). Interestingly, BCOR-fusion tumors were exclusively found in the supratentorial region being originally diagnosed as ependymomas or gliomas whereas BCOR-ITD emerged across the entire CNS with diverse original diagnoses. 8% of BCOR-ITD and none of BCOR-fusion cases were disseminated at diagnosis. In line with this observation, 40% of first relapses within the BCOR-ITD group were metastatic which was less frequent in BCOR-fusion tumors. Survival estimates demonstrated no differences, generally showing short median PFS (BCOR-fusion, 2 years, n=15; BCOR-ITD, 1.8 years, n=55) and intermediate OS rates (BCOR-fusion, 6.8 years, n=18; BCOR-ITD 6.3 years, n=60). Further molecular and clinical characterization is ongoing potentially revealing first therapeutic leads for these highly a

Published
2022

8. 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

12. PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum

Author

Alhalabi, K.T. Stichel, D. Sievers, P. Peterziel, H. Sommerkamp, A.C. Sturm, D. Wittmann, A. Sill, M. Jäger, N. Beck, P. Pajtler, K.W. Snuderl, M. Jour, G. Delorenzo, M. Martin, A.M. Levy, A. Dalvi, N. Hansford, J.R. Gottardo, N.G. Uro-Coste, E. Maurage, C.-A. Godfraind, C. Vandenbos, F. Pietsch, T. Kramm, C. Filippidou, M. Kattamis, A. Jones, C. Øra, I. Mikkelsen, T.S. Zapotocky, M. Sumerauer, D. Scheie, D. McCabe, M. Wesseling, P. Tops, B.B.J. Kranendonk, M.E.G. Karajannis, M.A. Bouvier, N. Papaemmanuil, E. Dohmen, H. Acker, T. von Hoff, K. Schmid, S. Miele, E. Filipski, K. Kitanovski, L. Krskova, L. Gojo, J. Haberler, C. Alvaro, F. Ecker, J. Selt, F. Milde, T. Witt, O. Oehme, I. Kool, M. von Deimling, A. Korshunov, A. Pfister, S.M. Sahm, F. Jones, D.T.W.

Abstract

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens. © 2021, The Author(s).

Published
2021

13. 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

14. PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum

Author

Alhalabi, KT, Stichel, D, Sievers, P, Peterziel, H, Sommerkamp, AC, Sturm, D, Wittmann, A, Sill, M, Jaeger, N, Beck, P, Pajtler, KW, Snuderl, M, Jour, G, Delorenzo, M, Martin, AM, Levy, A, Dalvi, N, Hansford, JR, Gottardo, NG, Uro-Coste, E, Maurage, C-A, Godfraind, C, Vandenbos, F, Pietsch, T, Kramm, C, Filippidou, M, Kattamis, A, Jones, C, Ora, I, Mikkelsen, TS, Zapotocky, M, Sumerauer, D, Scheie, D, McCabe, M, Wesseling, P, Tops, BBJ, Kranendonk, MEG, Karajannis, MA, Bouvier, N, Papaemmanuil, E, Dohmen, H, Acker, T, von Hoff, K, Schmid, S, Miele, E, Filipski, K, Kitanovski, L, Krskova, L, Gojo, J, Haberler, C, Alvaro, F, Ecker, J, Selt, F, Milde, T, Witt, O, Oehme, I, Kool, M, von Deimling, A, Korshunov, A, Pfister, SM, Sahm, F, Jones, DTW, Alhalabi, KT, Stichel, D, Sievers, P, Peterziel, H, Sommerkamp, AC, Sturm, D, Wittmann, A, Sill, M, Jaeger, N, Beck, P, Pajtler, KW, Snuderl, M, Jour, G, Delorenzo, M, Martin, AM, Levy, A, Dalvi, N, Hansford, JR, Gottardo, NG, Uro-Coste, E, Maurage, C-A, Godfraind, C, Vandenbos, F, Pietsch, T, Kramm, C, Filippidou, M, Kattamis, A, Jones, C, Ora, I, Mikkelsen, TS, Zapotocky, M, Sumerauer, D, Scheie, D, McCabe, M, Wesseling, P, Tops, BBJ, Kranendonk, MEG, Karajannis, MA, Bouvier, N, Papaemmanuil, E, Dohmen, H, Acker, T, von Hoff, K, Schmid, S, Miele, E, Filipski, K, Kitanovski, L, Krskova, L, Gojo, J, Haberler, C, Alvaro, F, Ecker, J, Selt, F, Milde, T, Witt, O, Oehme, I, Kool, M, von Deimling, A, Korshunov, A, Pfister, SM, Sahm, F, and Jones, DTW

Abstract

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

Published
2021

15. 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

17. Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC) - a molecularly defined glioneuronal CNS tumour class displaying recurrent monosomy 14

Author

Deng, M. Y., Sill, M., Sturm, D., Stichel, D., Witt, H., Ecker, J., Wittmann, A., Schittenhelm, J., Ebinger, M., Schuhmann, M. U., Figarella-Branger, D., Aronica, E., Staszewski, O., Preusser, M., Haberler, C., Lauten, M., Schueller, U., Hartmann, C., Snuderl, M., Dunham, C., Jabado, N., Wesseling, P., Deckert, M., Keyvani, K., Gottardo, N., Giangaspero, F., von Hoff, K., Ellison, D. W., Pietsch, T., Herold-Mende, C., Milde, T., Witt, O., Kool, M., Korshunov, A., Wick, W., von Deimling, A., Pfister, S. M., Jones, D. T. W., Sahm, F., Deng, M. Y., Sill, M., Sturm, D., Stichel, D., Witt, H., Ecker, J., Wittmann, A., Schittenhelm, J., Ebinger, M., Schuhmann, M. U., Figarella-Branger, D., Aronica, E., Staszewski, O., Preusser, M., Haberler, C., Lauten, M., Schueller, U., Hartmann, C., Snuderl, M., Dunham, C., Jabado, N., Wesseling, P., Deckert, M., Keyvani, K., Gottardo, N., Giangaspero, F., von Hoff, K., Ellison, D. W., Pietsch, T., Herold-Mende, C., Milde, T., Witt, O., Kool, M., Korshunov, A., Wick, W., von Deimling, A., Pfister, S. M., Jones, D. T. W., and Sahm, F.

Abstract

Aims DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. Patients and methods DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. Results Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. Conclusions DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.

Published
2020

18. Abstract B71: Molecular heterogeneity and novel oncogenic fusions in RELA- and YAP1-negative supratentorial ependymoma

Author

Ghasemi, D.R., primary, Okonechnikov, K., additional, Korshunov, A., additional, Sill, M., additional, Zheng, T., additional, Huebner, J.M., additional, Maass, K.K., additional, Benzel, J., additional, Snuderl, M., additional, Gojo, J., additional, Schüller, U., additional, Gerber, N.U., additional, Stoler, I., additional, Hernáiz-Driever, P., additional, Milde, T., additional, Sturm, D., additional, Chapman, R., additional, Grundy, R.G., additional, von Deimling, A., additional, Kawauchi, D., additional, Jones, D.T.W., additional, Kool, M., additional, Pfister, S.M., additional, Sahm, F., additional, and Pajtler, K.W., additional

Published
2020
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19. Diffuse glioneuronal tumour with oligodendroglioma‐like features and nuclear clusters (DGONC) – a molecularly defined glioneuronal CNS tumour class displaying recurrent monosomy 14

Author

Deng, M. Y., primary, Sill, M., additional, Sturm, D., additional, Stichel, D., additional, Witt, H., additional, Ecker, J., additional, Wittmann, A., additional, Schittenhelm, J., additional, Ebinger, M., additional, Schuhmann, M. U., additional, Figarella‐Branger, D., additional, Aronica, E., additional, Staszewski, O., additional, Preusser, M., additional, Haberler, C., additional, Lauten, M., additional, Schüller, U., additional, Hartmann, C., additional, Snuderl, M., additional, Dunham, C., additional, Jabado, N., additional, Wesseling, P., additional, Deckert, M., additional, Keyvani, K., additional, Gottardo, N., additional, Giangaspero, F., additional, Hoff, K., additional, Ellison, D. W., additional, Pietsch, T., additional, Herold-Mende, C., additional, Milde, T., additional, Witt, O., additional, Kool, M., additional, Korshunov, A., additional, Wick, W., additional, Deimling, A., additional, Pfister, S. M., additional, Jones, D. T. W., additional, and Sahm, F., additional

Published
2020
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20. High-grade endometrial stromal sarcoma with ZC3H7B-BCOR fusion.

Author

Aldera, A. P., Chiang, S., Snuderl, M., Jour, G., James, R. W., and Botha, M. H.

Subjects
BOWEL obstructions, SEQUENCE analysis, IMMUNOHISTOCHEMISTRY, CANCER relapse, METASTASIS, MOLECULAR pathology, ENDOMETRIAL tumors, GENES, SARCOMA, RARE diseases
Abstract

High-grade endometrial stromal sarcoma (HG ESS) is a rare malignant mesenchymal tumour of the uterus which is prone to locoregional recurrence and has a poor prognosis. Recently, distinct molecular genetic subtypes have been described, most notably those harbouring YWHAE-NUTM2A/B fusion, ZC3H7B-BCOR fusion and BCOR internal tandem duplications. We present a case of a 50-year-old woman who initially presented with bowel obstruction and metastatic disease. Her clinical course was characterised by advanced stage and multiple recurrences. Histologically, the tumour showed typical ovoid to spindled cytomorphology with myxoid stroma, relatively uniform nuclear features, and brisk mitotic activity. Immunohistochemistry was negative for CD10, SMA and desmin, but showed strong and diffuse positive labelling with cyclin D1. Next-generation RNA sequencing showed a ZC3H7BBCOR fusion. Awareness of this recently described molecular subcategory of HG ESS and its typical histological features is crucial in separating it from its pathological mimics and in establishing the correct diagnosis. [ABSTRACT FROM AUTHOR]

Published
2022
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21. 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

24. Coevolution of Solid Stress and Interstitial Fluid Pressure in Tumors During Progression: Implications for Vascular Collapse

Author

Stylianopoulos, T., Martin, J. D., Snuderl, M., Mpekris, F., Jain, S. R., Jain, R. K., and Stylianopoulos, T. [0000-0002-3093-1696]

Subjects
Male, Cancer Research, Pathology, Hydrostatic pressure, Vascular permeability, Mice, SCID, animal cell, Mice, Models, Neoplasms, Extracellular fluid, cancer cell, Tumor, article, Tumor Burden, tumor growth, collapse, Lymphatic system, priority journal, Oncology, coevolution, Disease Progression, growth rate, Perfusion, Algorithms, medicine.medical_specialty, Physiological, Biology, Stress, SCID, Models, Biological, Article, animal tissue, Cell Line, tissue pressure, in vivo study, vascular fragility, blood vessel permeability, male, Stress, Physiological, In vivo, Cell Line, Tumor, Hydrostatic Pressure, medicine, Humans, Animals, controlled study, human, mouse, Cell Proliferation, nonhuman, hypoxia, human cell, animal model, Extracellular Fluid, Biological, human tissue, cell proliferation, tumor volume, Tumor progression, Cancer cell, mathematical model, Neoplasm Transplantation
Abstract

The stress harbored by the solid phase of tumors is known as solid stress. Solid stress can be either applied externally by the surrounding normal tissue or induced by the tumor itself due to its growth. Fluid pressure is the isotropic stress exerted by the fluid phase. We recently showed that growth-induced solid stress is on the order of 1.3 to 13.0 kPa (10–100 mmHg) – high enough to cause compression of fragile blood vessels, resulting in poor perfusion and hypoxia. However, the evolution of growth-induced stress with tumor progression and its effect on cancer cell proliferation in vivo is not understood. To this end, we developed a mathematical model for tumor growth that takes into account all three types of stresses: growth-induced stress, externally applied stress, and fluid pressure. First, we conducted in vivo experiments and found that growth-induced stress is related to tumor volume through a biexponential relationship. Then, we incorporated this information into our mathematical model and showed that due to the evolution of growth-induced stress, total solid stress levels are higher in the tumor interior and lower in the periphery. Elevated compressive solid stress in the interior of the tumor is sufficient to cause the collapse of blood vessels and results in a lower growth rate of cancer cells compared with the periphery, independently from that caused by the lack of nutrients due to vessel collapse. Furthermore, solid stress in the periphery of the tumor causes blood vessels in the surrounding normal tissue to deform to elliptical shapes. We present histologic sections of human cancers that show such vessel deformations. Finally, we found that fluid pressure increases with tumor growth due to increased vascular permeability and lymphatic impairment, and is governed by the microvascular pressure. Crucially, fluid pressure does not cause vessel compression of tumor vessels. Cancer Res; 73(13); 3833–41. ©2013 AACR.

Published
2013

25. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway

Author

Huse, JT, Snuderl, M, Jones, DTW, Brathwaite, CD, Altman, N, Lavi, E, Saffery, R, Sexton-Oates, A, Blumcke, I, Capper, D, Karajannis, MA, Benayed, R, Chavez, L, Thomas, C, Serrano, J, Borsu, L, Ladanyi, M, Rosenblum, MK, Huse, JT, Snuderl, M, Jones, DTW, Brathwaite, CD, Altman, N, Lavi, E, Saffery, R, Sexton-Oates, A, Blumcke, I, Capper, D, Karajannis, MA, Benayed, R, Chavez, L, Thomas, C, Serrano, J, Borsu, L, Ladanyi, M, and Rosenblum, MK

Abstract

Epileptogenic tumors affecting children and young adults are a morphologically diverse collection of neuroepithelial neoplasms that, as a group, exhibit varying levels of glial and/or neuronal differentiation. Recent advances in molecular profiling technology, including comprehensive DNA sequencing and methylation analysis, have enabled the application of more precise and biologically relevant classification schemes to these tumors. In this report, we describe a morphologically and molecularly distinct epileptogenic neoplasm, the polymorphous low-grade neuroepithelial tumor of the young (PLNTY), which likely accounts for a sizable portion of oligodendroglioma-like tumors affecting the pediatric population. Characteristic microscopic findings most notably include infiltrative growth, the invariable presence of oligodendroglioma-like cellular components, and intense immunolabeling for cluster of differentiation 34 (CD34). Moreover, integrative molecular profiling reveals a distinct DNA methylation signature for PLNTYs, along with frequent genetic abnormalities involving either B-Raf proto-oncogene (BRAF) or fibroblast growth factor receptors 2 and 3 (FGFR2, FGFR3). These findings suggest that PLNTY represents a distinct biological entity within the larger spectrum of pediatric, low-grade neuroepithelial tumors.

Published
2017

26. A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer

Author

Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Chemistry, Griffith, Linda G, Bawendi, Moungi G, Whitley, M. J., Cardona, D. M., Lazarides, A. L., Spasojevic, I., Ferrer, J. M., Lee, C.-L., Snuderl, M., Blazer, D. G., Hwang, E. S., Greenup, R. A., Mosca, P. J., Mito, J. K., Cuneo, K. C., Larrier, N. A., OReilly, E. K., Riedel, R. F., Eward, W. C., Strasfeld, D. B., Fukumura, D., Lee, W. D., Kirsch, D. G., Brigman, B. E., Cahill, Joan, Jain, Rakesh J., Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Chemistry, Griffith, Linda G, Bawendi, Moungi G, Whitley, M. J., Cardona, D. M., Lazarides, A. L., Spasojevic, I., Ferrer, J. M., Lee, C.-L., Snuderl, M., Blazer, D. G., Hwang, E. S., Greenup, R. A., Mosca, P. J., Mito, J. K., Cuneo, K. C., Larrier, N. A., OReilly, E. K., Riedel, R. F., Eward, W. C., Strasfeld, D. B., Fukumura, D., Lee, W. D., Kirsch, D. G., Brigman, B. E., Cahill, Joan, and Jain, Rakesh J.

Abstract

Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.

Published
2017

28. 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

29. GPR133 (ADGRD1), an adhesion G-protein-coupled receptor, is necessary for glioblastoma growth

Author

Bayin, N S, primary, Frenster, J D, additional, Kane, J R, additional, Rubenstein, J, additional, Modrek, A S, additional, Baitalmal, R, additional, Dolgalev, I, additional, Rudzenski, K, additional, Scarabottolo, L, additional, Crespi, D, additional, Redaelli, L, additional, Snuderl, M, additional, Golfinos, J G, additional, Doyle, W, additional, Pacione, D, additional, Parker, E C, additional, Chi, A S, additional, Heguy, A, additional, MacNeil, D J, additional, Shohdy, N, additional, Zagzag, D, additional, and Placantonakis, D G, additional

Published
2016
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33. SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance.

Author

Kim, D., Fiske, B.P., Birsoy, K., Freinkman, E., Kami, K., Possemato, R.L., Chudnovsky, Y., Pacold, M.E., Chen, W.W., Cantor, J.R., Shelton, L.M., Gui, D.Y., Kwon, M., Ramkissoon, S.H., Ligon, K.L., Kang, S.W., Snuderl, M., der Heiden, M.G. Van, Sabatini, D.M., Kim, D., Fiske, B.P., Birsoy, K., Freinkman, E., Kami, K., Possemato, R.L., Chudnovsky, Y., Pacold, M.E., Chen, W.W., Cantor, J.R., Shelton, L.M., Gui, D.Y., Kwon, M., Ramkissoon, S.H., Ligon, K.L., Kang, S.W., Snuderl, M., der Heiden, M.G. Van, and Sabatini, D.M.

Abstract

Item does not contain fulltext, Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment. Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.

Published
2015

34. MB-17 * NOVEL CANDIDATE ONCOGENIC DRIVERS IN PINEOBLASTOMA

Author

Snuderl, M., primary, Kannan, K., additional, Aminova, O., additional, Dolgalev, I., additional, Heguy, A., additional, Faustin, A., additional, Zagzag, D., additional, Gardner, S., additional, Allen, J., additional, Wisoff, J., additional, Capper, D., additional, Hovestadt, V., additional, Ahsan, S., additional, Eberhart, C., additional, Pfister, S., additional, Jones, D., additional, and Karajannis, M., additional

Published
2015
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35. INCREASED PERFUSION DUE TO VASCULAR NORMALIZATION IMPROVES OXYGENATION AND SURVIVAL IN GLIOBLASTOMA PATIENTS TREATED WITH CEDIRANIB WITH OR WITHOUT CHEMORADIATION

Author

Batchelor, T. T., primary, Gerstner, E. R., additional, Emblem, K. E., additional, Duda, D. G., additional, Kalpathy-Cramer, J., additional, Snuderl, M., additional, Ancukiewicz, M., additional, Polaskova, P., additional, Pinho, M. C., additional, Jennings, D., additional, Plotkin, S. R., additional, Chi, A. S., additional, Eichler, A. F., additional, Dietrich, J., additional, Hochberg, F. H., additional, Lu-Emerson, C., additional, Iafrate, A. J., additional, Ivy, S. P., additional, Rosen, B., additional, Loeffler, J. S., additional, Wen, P. Y., additional, Sorensen, A. G., additional, and Jain, R. K., additional

Published
2014
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36. Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma

Author

Lu-Emerson, C., primary, Snuderl, M., additional, Kirkpatrick, N. D., additional, Goveia, J., additional, Davidson, C., additional, Huang, Y., additional, Riedemann, L., additional, Taylor, J., additional, Ivy, P., additional, Duda, D. G., additional, Ancukiewicz, M., additional, Plotkin, S. R., additional, Chi, A. S., additional, Gerstner, E. R., additional, Eichler, A. F., additional, Dietrich, J., additional, Stemmer-Rachamimov, A. O., additional, Batchelor, T. T., additional, and Jain, R. K., additional

Published
2013
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37. Abstract P3-12-03: Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases.

Author

Kodack, DP, primary, Chung, E, additional, Yamashita, H, additional, Incio, J, additional, Peters, A, additional, Song, Y, additional, Ager, E, additional, Huang, Y, additional, Farrar, C, additional, Lussiez, A, additional, Goel, S, additional, Snuderl, M, additional, Kamoun, W, additional, Hiddingh, L, additional, Tannous, BA, additional, Fukumura, D, additional, Engelman, JA, additional, and Jain, RK, additional

Published
2012
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38. CLIN-PATHOLOGY

Author

Alexandru, D., primary, Satyadev, R., additional, So, W., additional, Lee, S. H., additional, Lee, Y. S., additional, Hong, Y.-K., additional, Kang, C. S., additional, Rodgers, S. D., additional, Marascalchi, B. J., additional, Strom, R. G., additional, Riina, H., additional, Samadani, U., additional, Frempong-Boadu, A., additional, Babu, R., additional, Sen, C., additional, Zagzag, D., additional, Anderson, M. D., additional, Abel, T. W., additional, Moots, P. L., additional, Odia, Y., additional, Orr, B. A., additional, Eberhart, C. G., additional, Rodriguez, F., additional, Sweis, R. T., additional, Lavingia, J., additional, Connelly, J., additional, Cochran, E., additional, van den Bent, M., additional, Hartmann, C., additional, Preusser, M., additional, Strobel, T., additional, Dubbink, H. J., additional, Kros, J. M., additional, von Deimling, A., additional, Boisselier, B., additional, Sanson, M., additional, Halling, K. C., additional, Diefes, K. L., additional, Aldape, K., additional, Giannini, C., additional, Rodriguez, F. J., additional, Ligon, A. H., additional, Horkayne-Szakaly, I., additional, Rushing, E. J., additional, Ligon, K. L., additional, Vena, N., additional, Garcia, D. I., additional, Douglas Cameron, J., additional, Raghunathan, A., additional, Wani, K., additional, Armstrong, T. S., additional, Vera-Bolanos, E., additional, Fouladi, M., additional, Gajjar, A., additional, Goldman, S., additional, Lehman, N. L., additional, Metellus, P., additional, Mikkelsen, T., additional, Necesito-Reyes, M. J. T., additional, Omuro, A., additional, Packer, R. J., additional, Partap, S., additional, Pollack, I. F., additional, Prados, M. D., additional, Ian Robbins, H., additional, Soffietti, R., additional, Wu, J., additional, Gilbert, M. R., additional, Aldape, K. D., additional, Prosniak, M., additional, Harshyne, L. A., additional, Andrews, D. W., additional, Craig Hooper, D., additional, Kagawa, N., additional, Hosen, N., additional, Kijima, N., additional, Hirayama, R., additional, Chiba, Y., additional, Yamamoto, F., additional, Kinoshita, M., additional, Hashimoto, N., additional, Fujimoto, Y., additional, Yoshimine, T., additional, Hu, J., additional, Nuno, M., additional, Patil, C., additional, Rudnick, J., additional, Phuphanich, S., additional, Bannykh, S., additional, Chu, R., additional, Yu, J., additional, Black, K., additional, Choi, J., additional, Kim, D., additional, Shim, K. W., additional, Kim, S. H., additional, Kanno, H., additional, Nishihara, H., additional, Tanaka, S., additional, Yanagi, T., additional, Buczkowicz, P., additional, Khuong-Quang, D.-A., additional, Rakopoulos, P., additional, Bouffet, E., additional, Morrison, A., additional, Bartels, U., additional, Pfister, S. M., additional, Jabado, N., additional, Hawkins, C., additional, Weinberg, B. D., additional, Newell, K. L., additional, Kumar, P., additional, Wang, F., additional, Venneti, S., additional, Madden, M., additional, Coyne, T., additional, Phillips, J., additional, Gorovets, D., additional, Huse, J., additional, Kofler, J., additional, Lu, C., additional, Tihan, T., additional, Sullivan, L., additional, Santi, M., additional, Judkins, A., additional, Thompson, C., additional, Perry, A., additional, Iorgulescu, J. B., additional, Laufer, I., additional, Hameed, M., additional, Lis, E., additional, Boland, P., additional, Komotar, R., additional, Bilsky, M., additional, Amato-Watkins, A. C., additional, Neal, J., additional, Rees, A. D., additional, Davies, J. S., additional, Hayhurst, C., additional, Lu-Emerson, C., additional, Snuderl, M., additional, Davidson, C., additional, Kirkpatrick, N. D., additional, Huang, Y., additional, Duda, D. G., additional, Ancukiewicz, M., additional, Stemmer-Rachamimov, A., additional, Batchelor, T. T., additional, Jain, R. K., additional, Ellezam, B., additional, Theeler, B. J., additional, Sadighi, Z. S., additional, Mehta, V., additional, Tran, M.-D. T., additional, Adesina, A. M., additional, Puduvalli, V. K., additional, and Bruner, J. M., additional

Published
2012
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39. SURGICAL THERAPIES

Author

Chambless, L. B., primary, Parker, S. L., additional, Hassam-Malani, L., additional, McGirt, M. J., additional, Thompson, R. C., additional, Zhou, T., additional, Meng, X., additional, Xu, B., additional, Wei, S., additional, Chen, X., additional, De Witt Hamer, P. C., additional, Robles, S. G., additional, Zwinderman, A. H., additional, Duffau, H., additional, Berger, M. S., additional, Gonzalez, J. D. S. R., additional, Alberto, O. V., additional, Patricia, H. M., additional, Chaichana, K., additional, Pendleton, C., additional, Chambless, L., additional, Nathan, J., additional, Camara-Quintana, J., additional, Li, G., additional, Harsh, G., additional, Thompson, R., additional, Lim, M., additional, Quinones-Hinojosa, A., additional, Oppenlander, M. E., additional, Wolf, A., additional, Porter, R., additional, Nakaji, P., additional, Smith, K. A., additional, Spetzler, R. F., additional, Sanai, N., additional, Kim, J. H., additional, Clark, A. J., additional, Jahangiri, A., additional, Sughrue, M. E., additional, McDermott, M. W., additional, Aghi, M. K., additional, Chen, C., additional, Kasper, E., additional, Warnke, P., additional, Park, C.-K., additional, Lee, S.-H., additional, Song, S. W., additional, Kim, J. W., additional, Kim, T. M., additional, Yamaguchi, F., additional, Omura, T., additional, Ten, H., additional, Ishii, Y., additional, Kojima, T., additional, Takahashi, H., additional, Teramoto, A., additional, Pereira, E. A., additional, Livermore, J., additional, Ansorge, O., additional, Bojanic, S., additional, Tong, H., additional, Yu, X., additional, Zhou, D., additional, Hou, Y., additional, Zhou, Z., additional, Zhang, J., additional, Fabiano, A. J., additional, Rigual, N., additional, Munich, S., additional, Fenstermaker, R. A., additional, Wang, F., additional, Zhao, Y., additional, Xu, B.-n., additional, Kim, E. H., additional, Oh, M. C., additional, Lee, E. J., additional, Kim, S. H., additional, Kim, Y.-H., additional, Kim, C.-Y., additional, Kim, Y. H., additional, Han, J. H., additional, Kim, S.-K., additional, Paek, S. H., additional, Wang, K.-C., additional, Kim, D. G., additional, Jung, H.-W., additional, Krex, D., additional, Lindner, C., additional, Juratli, T., additional, Raue, C., additional, Schackert, G., additional, Valdes, P. A., additional, Kim, A., additional, Leblond, F., additional, Conde, O. M., additional, Harris, B. T., additional, Paulsen, K. D., additional, Wilson, B. C., additional, Roberts, D. W., additional, Occhiogrosso, G., additional, Cascardi, P., additional, Blagia, M., additional, De Tommasi, A., additional, Gelinas-Phaneuf, N., additional, Choudhury, N., additional, Al-Habib, A., additional, Cabral, A., additional, Nadeau, E., additional, Vincent, M., additional, Pazos, V., additional, Debergue, P., additional, DiRaddo, R., additional, Del Maestro, R. F., additional, Guha-Thakurta, N., additional, Prabhu, S. S., additional, Schulder, M., additional, Zavarella, S., additional, Nardi, D., additional, Schaffer, S., additional, Ruge, M. I., additional, Grau, S., additional, Fuetsch, M., additional, Kickingereder, P., additional, Hamisch, C., additional, Treuer, H., additional, Voges, J., additional, Sturm, V., additional, Choy, W., additional, Yew, A., additional, Spasic, M., additional, Nagasawa, D., additional, Kim, W., additional, Yang, I., additional, Quigley, M. R., additional, Hobbs, J., additional, Bhatia, S., additional, Cohen, Z. R., additional, Shimon, I., additional, Hadani, M., additional, Carapella, C. M., additional, Oppido, P. A., additional, Vidiri, A., additional, Telera, S., additional, Pompili, A., additional, Villani, V., additional, Fabi, A., additional, Pace, A., additional, Cahill, D., additional, Wang, M., additional, Won, M., additional, Aldape, K., additional, Maywald, R., additional, Hegi, M., additional, Mehta, M., additional, Gilbert, M., additional, Sulman, E., additional, Vogelbaum, M., additional, Narayana, A., additional, Kunnakkat, S. D., additional, Parker, E., additional, Gruber, D., additional, Gruber, M., additional, Knopp, E., additional, Zagzag, D., additional, Golfinos, J., additional, Dziurzynski, K., additional, Blas-Boria, D., additional, Suki, D., additional, Prabhu, S., additional, Puduvalli, V., additional, Levine, N., additional, Bloch, O., additional, Han, S. J., additional, Kaur, G., additional, Parsa, A. T., additional, Fukui, O., additional, Chew, B., additional, DePowell, J. J., additional, Sanders-Taylor, C., additional, Guarnaschelli, J., additional, McPherson, C., additional, Sheth, S. A., additional, Snuderl, M., additional, Kwon, C.-S., additional, Wirth, D., additional, Yaroslavsky, A., additional, Curry, W. T., additional, Vogelbaum, M. A., additional, Hadjipanayis, C. G., additional, Mehta, M. P., additional, Gilbert, M. R., additional, Megyesi, J. F., additional, Macdonald, D., additional, Wang, B., additional, Pierre, G. H.-S., additional, Hoover, J. M., additional, Goerss, S. J., additional, Kaufmann, T. J., additional, Meyer, F. B., additional, Parney, I. F., additional, Guthikonda, B., additional, Thakur, J., additional, Khan, I., additional, Ahmed, O., additional, Shorter, C., additional, Wilson, J., additional, Welsh, J., additional, Cuellar, H., additional, and Jeroudi, M., additional

Published
2011
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41. Glioblastoma Recurrence after Cediranib Therapy in Patients: Lack of 'Rebound' Revascularization as Mode of Escape

Author

di Tomaso, E., Snuderl, M., Kamoun, W. S., Duda, Dan Gabriel, Auluck, P. K., Fazlollahi, L., Andronesi, Ovidiu C, Frosch, Matthew P., Wen, Patrick Yung Chih, Plotkin, Scott Randall, Hedley-Whyte, E. Tessa, Sorensen, A, Batchelor, Tracy Todd, and Jain, Radhika

Abstract

Recurrent glioblastomas (rGBM) invariably relapse after initial response to anti-VEGF therapy. There are two prevailing hypotheses on how these tumors escape antiangiogenic therapy: switch to VEGF-independent angiogenic pathways and vessel co-option. However, direct evidence in rGBM patients is lacking. Thus, we compared molecular, cellular and vascular parameters in autopsy tissues from five rGBM patients who had been treated with the pan-VEGF receptor tyrosine kinase inhibitor cediranib versus seven patients who received no therapy or chemoradiation but no antiangiogenic agents. After cediranib treatment, endothelial proliferation and glomeruloid vessels were decreased, and vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere. In addition, tumor endothelial cells expressed molecular markers specific to the blood-brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy. Surprisingly, in cediranib-treated GBM cellular density in the central area of the tumor was lower than in control cases and gradually decreased towards the infiltrating edge, indicative of a change in growth pattern of rGBMs after cediranib treatment, unlike that after chemo-radiation. Finally, cediranib treated GBMs showed high levels of PDGF-C and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy. In summary, we show that rGBMs switch their growth pattern after anti-VEGF therapy – characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis and blood vessels with normal molecular expression and morphology without a second wave of angiogenesis.

Published
2011
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44. NTRK2 Fusion Driven Pediatric Glioblastoma: Identification of key molecular drivers by personalized oncology

Author

Levine, Shen, Y, Mungall, K, Serrano, J, Snuderl, M, Pleasance, E, Jones, SJM, Laskin, J, Marra, MA, Rassekh, R, Deyell, R, Yip, S, Cheng, S, and Dunham, C

Abstract

We describe the case of an 11-month-old girl with a rare cerebellar glioblastoma driven by a NACC2-NTRK2(Nucleus Accumbens Associated Protein 2-Neurotrophic Receptor Tyrosine Kinase 2) fusion. Initial workup of our case demonstrated homozygous CDKN2Adeletion, but immunohistochemistry for other driver mutations, including IDH1 R132H, BRAF V600E, and H3F3A K27M were negative, and ATRX was retained. Tissue was subsequently submitted for personalized oncogenomic analysis, including whole genome and whole transcriptome sequencing, which demonstrated an activating NTRK2fusion, as well as high PD-L1 expression, which was subsequently confirmed by immunohistochemistry. Furthermore, H3and IDHdemonstrated wildtype status. These findings suggested the possibility of treatment with either NTRK- or immune checkpoint- inhibitors through active clinical trials. Ultimately, the family pursued standard treatment that involved Head Start III chemotherapy and proton radiotherapy. Notably, at most recent follow upapproximately two years from initial diagnosis, the patient is in disease remission and thriving, suggesting favorable biology despite histologic malignancy. This case illustrates the value of personalized oncogenomics, as the molecular profiling revealed two actionable changes that would not have been apparent through routine diagnostics. NTRKfusions are known oncogenic drivers in a range of cancer types, but this is the first report of a NACC2-NTRK2fusion in a glioblastoma.LEARNING OBJECTIVESThis presentation will enable the learner to:1.Explore the current molecular landscape of pediatric high grade gliomas2.Recognize the value of personalized oncogenomic analysis, particularly in rare and/or aggressive tumors3.Discuss the current status of NTRK inhibitor clinical trials

Published
2019
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49. Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Author

Didier Frappaz, Shiyang Wang, Matija Snuderl, Catriona Ling, Rahul Krishnatry, Romain Perbet, Elizabeth Finch, David Sumerauer, Alexandre Vasiljevic, Nataliya Zhukova, Annie Huang, A. T. Chan, Matthew Mistry, Zhi Feng Shi, Cecile Faure Conter, Adam Fleming, Jean Mulcahy-Levy, Nicholas K. Foreman, Matthias A. Karajannis, Ibrahim Qaddoumi, Vijay Ramaswamy, Amulya A. Nageswara Rao, Julie H. Harreld, Anne Sophie Carret, Roger J. Packer, Samantha Mascelli, Cheng-Ying Ho, Theodore Nicolaides, Eric Bouffet, Shayna Zelcer, David W. Ellison, Mark W. Kieran, Keith L. Ligon, Sarah Leary, Ute Bartels, Tara McKeown, Sabine Mueller, Maria Luisa Garrè, Scott Ryall, Bev Wilson, Peter B. Dirks, Michael D. Taylor, Peter Hauser, James T. Rutka, Lenka Krskova, Michal Zapotocky, Courtney A. Crane, Ho Keung Ng, Ofelia Cruz, Carmen de Torres, Ying Mao, Uri Tabori, Alvaro Lassaletta, Marion Honnorat, Anthony Arnoldo, Paolo Nozza, David D. Eisenstat, Valerie Larouche, Alessandro Raso, Shiyi Chen, Nada Jabado, Karen Silva, Ruth G. Tatevossian, Cynthia Hawkins, Ana Guerreiro Stucklin, Jim Loukides, Caterina Giannini, James Dalton, Lassaletta A., Zapotocky M., Mistry M., Ramaswamy V., Honnorat M., Krishnatry R., Stucklin A.G., Zhukova N., Arnoldo A., Ryall S., Ling C., McKeown T., Loukides J., Cruz O., De Torres C., Ho C.-Y., Packer R.J., Tatevossian R., Qaddoumi I., Harreld J.H., Dalton J.D., Mulcahy-Levy J., Foreman N., Karajannis M.A., Wang S., Snuderl M., Rao A.N., Giannini C., Kieran M., Ligon K.L., Garre M.L., Nozza P., Mascelli S., Raso A., Mueller S., Nicolaides T., Silva K., Perbet R., Vasiljevic A., Conter C.F., Frappaz D., Leary S., Crane C., Chan A., Ng H.-K., Shi Z.-F., Mao Y., Finch E., Eisenstat D., Wilson B., Carret A.S., Hauser P., Sumerauer D., Krskova L., Larouche V., Fleming A., Zelcer S., Jabado N., Rutka J.T., Dirks P., Taylor M.D., Chen S., Bartels U., Huang A., Ellison D.W., Bouffet E., Hawkins C., and Tabori U.

Subjects
Oncology, Male, Cancer Research, Pathology, medicine.medical_treatment, Pediatrics, Cohort Studies, 0302 clinical medicine, CDKN2A, Brain Stem Neoplasms, Child, Brain Neoplasms, Glioma, Prognosis, 030220 oncology & carcinogenesis, Child, Preschool, Cohort, Female, Human, Cohort study, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Adolescent, Prognosi, Brain Neoplasm, 03 medical and health sciences, Internal medicine, Original Reports, medicine, Adjuvant therapy, Humans, Diencephalon, Preschool, neoplasms, Brain Stem Neoplasm, Chemotherapy, business.industry, Infant, medicine.disease, digestive system diseases, BRAF V600E, Mutation, Cohort Studie, Neoplasm Grading, business, human activities, 030217 neurology & neurosurgery, Progressive disease
Abstract

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

Published
2017

50. Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases.

Author

Kodack, D. P., Chung, E., Yamashita, H., Incio, J., Peters, A., Song, Y., Ager, E., Huang, Y., Farrar, C, Lussiez, A., Goel, S., Snuderl, M., Kamoun, W., Hiddingh, L., Tannous, B. A., Fukumura, D., Engelman, J. A., and Jain, R. K.

Subjects
*BRAIN metastasis, *HER2 gene, *BREAST cancer, *TUMORS, *CANCER
Abstract

Brain metastases remain a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Unlike HER2-amplified breast tumors growing in extra-cranial locations, brain metastases do not respond well to HER2 inhibitors and are often the reason for treatment failure. One of the major challenges in studying brain metastases is the lack of preclinical models. We developed a HER2-amplified mouse model of brain metastasis using an orthotopic xenograft of BT474 cells in mice. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib failed to contain brain metastatic tumor growth. Based on previous findings from our laboratory suggesting a role of vascular endothelial growth factor (VEGF) in the resistance of HER2-overexpressing breast cancer brain metastases to trastuzumab, we combined HER2 inhibitors with the anti-VEGFR2 antibody DC101. The combination of either trastuzumab and DC101 or lapatinib and DC101 significantly slowed metastatic tumor growth in the brain, and resulted in a striking improvement in overall survival. The benefit is due largely to an anti-angiogenic effect. The combination of anti-HER2 and anti-VEGFR2 therapy reduced both the total and functional microvascular density in the brain metastatic tumors. Moreover, tumor tissues under combination therapy showed a marked increase in necrosis. Preclinical and clinical evidence suggest that the combination of trastuzumab and lapatinib is superior to either agent alone -- though this has never been tested in the brain metastatic setting. We consistently observed increased phosphorylation of HER2 in breast tumor cells growing in the brain compared with the mammary fat pad. In addition, while short-term lapatinib treatment significantly reduced HER2 activation in the brain, it could do so only to the level of that observed in the untreated mammary fat pad - and this effect disappeared over time. We hypothesized that more pronounced HER2 inhibition would be beneficial to these brain metastases with increased HER2 activation. We show here a significant growth delay with the combination of the two HER2 inhibitors compared with monotherapy. Moreover, we found a dramatic brain metastatic tumor growth delay in mice treated with both HER2 inhibitors, trastuzumab and lapatinib, and DC101. The triple combination prolonged overall survival 5 times longer than control-treated mice. Brain metastasis from breast cancer is considered the "final frontier" of breast cancer research and treatment. Our findings support the clinical development of a three-drug regimen of trastuzumab, lapatinib and a VEGF pathway inhibitor for the treatment of HER2-amplified breast cancer brain metastases. While the anti-VEGF antibody bevacizumab in combination with trastuzumab and chemotherapy has shown some promise in HER2-positive metastatic breast cancer patient, there are no data on its efficacy in the context of brain metastases. A clinical trial is now recruiting patients to evaluate the efficacy of bevacizumab in breast cancer patients with active brain metastases, including its combination with trastuzumab in patients with HER2-positive disease. This trial may provide clinical evidence for the approach presented here. [ABSTRACT FROM AUTHOR]

Published
2012
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