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1. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma

Author

Nobre, L, Zapotocky, M, Khan, S, Fukuoka, K, Fonseca, A, McKeown, T, Sumerauer, D, Vicha, A, Grajkowska, WA, Trubicka, J, Li, KKW, Ng, H-K, Massimi, L, Lee, JY, Kim, S-K, Zelcer, S, Vasiljevic, A, Faure-Conter, C, Hauser, P, Lach, B, Van Veelen-Vincent, M-L, French, PJ, Van Meir, EG, Weiss, WA, Gupta, N, Pollack, IF, Hamilton, RL, Rao, AAN, Giannini, C, Rubin, JB, Moore, AS, Chambless, LB, Vibhakar, R, Ra, YS, Massimino, M, McLendon, RE, Wheeler, H, Zollo, M, Ferruci, V, Kumabe, T, Faria, CC, Sterba, J, Jung, S, Lopez-Aguilar, E, Mora, J, Carlotti, CG, Olson, JM, Leary, S, Cain, J, Krskova, L, Zamecnik, J, Hawkins, CE, Tabori, U, Huang, A, Bartels, U, Northcott, PA, Taylor, MD, Yip, S, Hansford, JR, Bouffet, E, Ramaswamy, V, Nobre, L, Zapotocky, M, Khan, S, Fukuoka, K, Fonseca, A, McKeown, T, Sumerauer, D, Vicha, A, Grajkowska, WA, Trubicka, J, Li, KKW, Ng, H-K, Massimi, L, Lee, JY, Kim, S-K, Zelcer, S, Vasiljevic, A, Faure-Conter, C, Hauser, P, Lach, B, Van Veelen-Vincent, M-L, French, PJ, Van Meir, EG, Weiss, WA, Gupta, N, Pollack, IF, Hamilton, RL, Rao, AAN, Giannini, C, Rubin, JB, Moore, AS, Chambless, LB, Vibhakar, R, Ra, YS, Massimino, M, McLendon, RE, Wheeler, H, Zollo, M, Ferruci, V, Kumabe, T, Faria, CC, Sterba, J, Jung, S, Lopez-Aguilar, E, Mora, J, Carlotti, CG, Olson, JM, Leary, S, Cain, J, Krskova, L, Zamecnik, J, Hawkins, CE, Tabori, U, Huang, A, Bartels, U, Northcott, PA, Taylor, MD, Yip, S, Hansford, JR, Bouffet, E, and Ramaswamy, V

Abstract

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.

Published
2020

2. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis

Author

Thompson, EM, Hielscher, T, Bouffet, E, Remke, M, Luu, B, Gururangan, S, McLendon, RE, Bigner, DD, Lipp, ES, Perreault, S, Cho, YJ, Grant, G, Kim, SK, Lee, JY, Rao, AAN, Giannini, C, Li, KKW, Ng, HK, Yao, Y, Kumabe, T, Tominaga, T, Grajkowska, WA, Perek-Polnik, M, Low, DCY, Seow, WT, Chang, KTE, Mora, J, Pollack, IF, Hamilton, RL, Leary, S, Moore, AS, Ingram, WJ, Hallahan, AR, Jouvet, A, Fèvre-Montange, M, Vasiljevic, A, Faure-Conter, C, Shofuda, T, Kagawa, N, Hashimoto, N, Jabado, N, Weil, AG, Gayden, T, Wataya, T, Shalaby, T, Grotzer, M, Zitterbart, K, Sterba, J, Kren, L, Hortobágyi, T, Klekner, A, László, B, Pócza, T, Hauser, P, Schüller, U, Jung, S, Jang, WY, French, PJ, Kros, JM, van Veelen, MLC, Massimi, L, Leonard, JR, Rubin, JB, Vibhakar, R, Chambless, LB, Cooper, MK, Thompson, RC, Faria, CC, Carvalho, A, Nunes, S, Pimentel, J, Fan, X, Muraszko, KM, López-Aguilar, E, Lyden, D, Garzia, L, Shih, DJH, Kijima, N, Schneider, C, Adamski, J, Northcott, PA, Kool, M, Jones, DTW, Chan, JA, Nikolic, A, Garre, ML, Van Meir, EG, Osuka, S, Olson, JJ, Jahangiri, A, and Castro, BA

Subjects
Adult, Male, Canada, Brain Neoplasms, Infant, Prognosis, Magnetic Resonance Imaging, Combined Modality Therapy, Disease-Free Survival, Child, Preschool, Disease Progression, Humans, Female, Child, Medulloblastoma, Retrospective Studies
Abstract

© 2016 Elsevier Ltd Background Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. Methods We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. Findings We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07–1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87–1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71–1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75–1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67–1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22–3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00–4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93–2·99, p=0·084). Interpretation The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection. Funding Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.

Published
2016
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3. Cytogenetic prognostication within medulloblastoma subgroups

Author

Shih, DJH, Northcott, PA, Remke, M, Korshunov, A, Ramaswamy, V, Kool, M, Luu, B, Yao, Y, Wang, X, Dubuc, AM, Garzia, L, Peacock, J, Mack, SC, Wu, X, Rolider, A, Morrissy, AS, Cavalli, FMG, Jones, DTW, Zitterbart, K, Faria, CC, Schüller, U, Kren, L, Kumabe, T, Tominaga, T, Ra, YS, Garami, M, Hauser, P, Chan, JA, Robinson, S, Bognár, L, Klekner, A, Saad, AG, Liau, LM, Albrecht, S, Fontebasso, A, Cinalli, G, De Antonellis, P, Zollo, M, Cooper, MK, Thompson, RC, Bailey, S, Lindsey, JC, Di Rocco, C, Massimi, L, Michiels, EMC, Scherer, SW, Phillips, JJ, Gupta, N, Fan, X, Muraszko, KM, Vibhakar, R, Eberhart, CG, Fouladi, M, Lach, B, Jung, S, Wechsler-Reya, RJ, Fèvre-Montange, M, Jouvet, A, Jabado, N, Pollack, IF, Weiss, WA, Lee, JY, Cho, BK, Kim, SK, Wang, KC, Leonard, JR, Rubin, JB, De Torres, C, Lavarino, C, Mora, J, Cho, YJ, Tabori, U, Olson, JM, Gajjar, A, Packer, RJ, Rutkowski, S, Pomeroy, SL, French, PJ, Kloosterhof, NK, Kros, JM, Van Meir, EG, Clifford, SC, Bourdeaut, F, Delattre, O, Doz, FF, Hawkins, CE, Malkin, D, and Grajkowska, WA

Subjects
Male, Adolescent, Kruppel-Like Transcription Factors, Zinc Finger Protein Gli2, Risk Assessment, Proto-Oncogene Proteins c-myc, Cytogenetics, Young Adult, Risk Factors, Predictive Value of Tests, Biomarkers, Tumor, Humans, Hedgehog Proteins, Oncology & Carcinogenesis, Child, In Situ Hybridization, Fluorescence, Proportional Hazards Models, Chromosomes, Human, Pair 14, Oncology And Carcinogenesis, Chromosomes, Human, Pair 11, Gene Expression Profiling, Nuclear Proteins, Reproducibility of Results, Infant, Prognosis, Gene Expression Regulation, Neoplastic, Wnt Proteins, Tissue Array Analysis, Child, Preschool, Female, Medulloblastoma
Abstract

Purpose: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials. © 2014 by American Society of Clinical Oncology.

Published
2014
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4. Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Author

Northcott, PA, Shih, DJH, Peacock, J, Garzia, L, Sorana Morrissy, A, Zichner, T, Stútz, AM, Korshunov, A, Reimand, J, Schumacher, SE, Beroukhim, R, Ellison, DW, Marshall, CR, Lionel, AC, MacK, S, Dubuc, A, Yao, Y, Ramaswamy, V, Luu, B, Rolider, A, Cavalli, FMG, Wang, X, Remke, M, Wu, X, Chiu, RYB, Chu, A, Chuah, E, Corbett, RD, Hoad, GR, Jackman, SD, Li, Y, Lo, A, Mungall, KL, Ming Nip, K, Qian, JQ, Raymond, AGJ, Thiessen, N, Varhol, RJ, Birol, I, Moore, RA, Mungall, AJ, Holt, R, Kawauchi, D, Roussel, MF, Kool, M, Jones, DTW, Witt, H, Fernandez-L, A, Kenney, AM, Wechsler-Reya, RJ, Dirks, P, Aviv, T, Grajkowska, WA, Perek-Polnik, M, Haberler, CC, Delattre, O, Reynaud, SS, Doz, FF, Pernet-Fattet, SS, Cho, BK, Kim, SK, Wang, KC, Scheurlen, W, Eberhart, CG, Fèvre-Montange, M, Jouvet, A, Pollack, IF, Fan, X, Muraszko, KM, Yancey Gillespie, G, Di Rocco, C, Massimi, L, Michiels, EMC, Kloosterhof, NK, French, PJ, Kros, JM, Olson, JM, Ellenbogen, RG, Zitterbart, K, Kren, L, Thompson, RC, and Cooper, MK

Subjects
Oncogene Proteins, Fusion, DNA Copy Number Variations, Genome, Human, General Science & Technology, NF-kappa B, Genes, myc, Proteins, Nerve Tissue Proteins, Genomics, Translocation, Genetic, Transforming Growth Factor beta, Gene Duplication, Genomic Structural Variation, MD Multidisciplinary, Humans, Hedgehog Proteins, RNA, Long Noncoding, Cerebellar Neoplasms, Carrier Proteins, Child, Medulloblastoma, Signal Transduction
Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy. © 2012 Macmillan Publishers Limited. All rights reserved.

Published
2012
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5. WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

Author

Zhukova, N, Ramaswamy, V, Remke, M, Martin, DC, Castelo-Branco, P, Zhang, CH, Fraser, M, Tse, K, Poon, R, Shih, DJH, Baskin, B, Ray, PN, Bouffet, E, Dirks, P, von Bueren, AO, Pfaff, E, Korshunov, A, Jones, DTW, Northcott, PA, Kool, M, Pugh, TJ, Pomeroy, SL, Cho, YJ, Pietsch, T, Gessi, M, Rutkowski, S, Bognár, L, Cho, BK, Eberhart, CG, Conter, CF, Fouladi, M, French, PJ, Grajkowska, WA, Gupta, N, Hauser, P, Jabado, N, Vasiljevic, A, Jung, S, Kim, SK, Klekner, A, Kumabe, T, Lach, B, Leonard, JR, Liau, LM, Massimi, L, Pollack, IF, Ra, YS, Rubin, JB, Van Meir, EG, Wang, KC, Weiss, WA, Zitterbart, K, Bristow, RG, Alman, B, Hawkins, CE, Malkin, D, Clifford, SC, Pfister, SM, Taylor, MD, Tabori, U, Zhukova, N, Ramaswamy, V, Remke, M, Martin, DC, Castelo-Branco, P, Zhang, CH, Fraser, M, Tse, K, Poon, R, Shih, DJH, Baskin, B, Ray, PN, Bouffet, E, Dirks, P, von Bueren, AO, Pfaff, E, Korshunov, A, Jones, DTW, Northcott, PA, Kool, M, Pugh, TJ, Pomeroy, SL, Cho, YJ, Pietsch, T, Gessi, M, Rutkowski, S, Bognár, L, Cho, BK, Eberhart, CG, Conter, CF, Fouladi, M, French, PJ, Grajkowska, WA, Gupta, N, Hauser, P, Jabado, N, Vasiljevic, A, Jung, S, Kim, SK, Klekner, A, Kumabe, T, Lach, B, Leonard, JR, Liau, LM, Massimi, L, Pollack, IF, Ra, YS, Rubin, JB, Van Meir, EG, Wang, KC, Weiss, WA, Zitterbart, K, Bristow, RG, Alman, B, Hawkins, CE, Malkin, D, Clifford, SC, Pfister, SM, Taylor, MD, and Tabori, U

Abstract

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% ± 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% ± 2% vs. 57.4% ± 1.8% (p < 0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% ± 1.5% in lithium treated cells vs. 56.6 ± 3% (p < 0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% ± 8% for lithium treated cells vs. 27% ± 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.

Published
2014

6. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Author

Remke, M, Ramaswamy, V, Peacock, J, Shih, DJH, Koelsche, C, Northcott, PA, Hill, N, Cavalli, FMG, Kool, Mirjam, Wang, X, Mack, SC, Barszczyk, M, Morrissy, AS, Wu, XC, Agnihotri, S, Luu, B, Jones, DTW, Garzia, L, Dubuc, AM, Zhukova, N, Vanner, R, Kros, J.M., French, Pim, van Meir, EG, Vibhakar, R, Zitterbart, K, Chan, JA, Bognar, L, Klekner, A, Lach, B, Jung, S, Saad, AG, Albrecht, S, Liau, LM, Zollo, M, Cooper, MK, Thompson, RC, Delattre, OO, Bourdeaut, F, Doz, FF, Garami, M, Hauser, P, Carlotti, CG, Van Meter, TE, Massimi, L, Fults, D, Pomeroy, SL, Kumabe, T, Ra, YS, Leonard, JR, Elbabaa, SK, Mora, J, Rubin, JB, Cho, YJ, McLendon, RE, Bigner, DD, Eberhart, CG, Fouladi, M, Wechsler-Reya, RJ, Faria, CC, Croul, SE, Huang, A, Bouffet, E, Hawkins, CE, Dirks, PB, Weiss, WA, Schuller, U, Pollack, IF, Rutkowski, S, Meyronet, D, Jouvet, A, Fevre-Montange, M, Jabado, N, Perek-Polnik, M, Grajkowska, WA, Kim, SK, Rutka, JT, Malkin, D, Tabori, U, Pfister, SM, Korshunov, A, von Deimling, A, Taylor, MD, Remke, M, Ramaswamy, V, Peacock, J, Shih, DJH, Koelsche, C, Northcott, PA, Hill, N, Cavalli, FMG, Kool, Mirjam, Wang, X, Mack, SC, Barszczyk, M, Morrissy, AS, Wu, XC, Agnihotri, S, Luu, B, Jones, DTW, Garzia, L, Dubuc, AM, Zhukova, N, Vanner, R, Kros, J.M., French, Pim, van Meir, EG, Vibhakar, R, Zitterbart, K, Chan, JA, Bognar, L, Klekner, A, Lach, B, Jung, S, Saad, AG, Albrecht, S, Liau, LM, Zollo, M, Cooper, MK, Thompson, RC, Delattre, OO, Bourdeaut, F, Doz, FF, Garami, M, Hauser, P, Carlotti, CG, Van Meter, TE, Massimi, L, Fults, D, Pomeroy, SL, Kumabe, T, Ra, YS, Leonard, JR, Elbabaa, SK, Mora, J, Rubin, JB, Cho, YJ, McLendon, RE, Bigner, DD, Eberhart, CG, Fouladi, M, Wechsler-Reya, RJ, Faria, CC, Croul, SE, Huang, A, Bouffet, E, Hawkins, CE, Dirks, PB, Weiss, WA, Schuller, U, Pollack, IF, Rutkowski, S, Meyronet, D, Jouvet, A, Fevre-Montange, M, Jabado, N, Perek-Polnik, M, Grajkowska, WA, Kim, SK, Rutka, JT, Malkin, D, Tabori, U, Pfister, SM, Korshunov, A, von Deimling, A, and Taylor, MD

Abstract

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in < 5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.

Published
2013

7. Intertumoral Heterogeneity within Medulloblastoma Subgroups

Author

Luca Massimi, Caterina Giannini, Betty Luu, Cynthia Hawkins, Byung Kyu Cho, James T. Rutka, G. Yancey Gillespie, Timothy E. Van Meter, Almos Klekner, Young Shin Ra, Carolina Nor, Anna Goldenberg, Rajeev Vibhakar, Hideo Nakamura, Gaetano Finocchiaro, Massimo Zollo, John Peacock, Marta Perek-Polnik, Keren Isaev, Alvaro Lassaletta, Amulya A. Nageswara Rao, Florence M.G. Cavalli, Maura Massimino, Livia Garzia, Jüri Reimand, Charles G. Eberhart, Maryam Fouladi, Enrique López-Aguilar, Annie Huang, Cécile Faure-Conter, Gary D. Bader, Jaume Mora, Ho Keung Ng, James M. Olson, Jennifer A. Chan, Erwin G. Van Meir, Daniela Pretti da Cunha Tirapelli, Hamza Farooq, Fernando Chico Ponce de León, Linda M. Liau, Kay Ka Wai Li, Shenandoah Robinson, Anne Jouvet, Tomoko Shofuda, José Pimentel, Reid C. Thompson, Yuan Yao Thompson, Ian F. Pollack, Nada Jabado, Boleslaw Lach, Pim J. French, Joshua B. Rubin, Eric Bouffet, Alexandre Vasiljevic, Ali G. Saad, Michael K. Cooper, Satoru Osuka, Peter B. Dirks, Jaroslav Sterba, Johan M. Kros, Claudia C. Faria, Kyu-Chang Wang, Seung-Ki Kim, Shin Jung, Craig Daniels, A. Sorana Morrissy, Ladislav Rampášek, Andrew R. Hallahan, Sarah Leary, Wiesława Grajkowska, Uri Tabori, Marc Remke, Samer K. Elbabaa, Michael D. Taylor, Andrew S. Moore, Toshihiro Kumabe, Mario Perezpeña-Diazconti, Vijay Ramaswamy, Ronald L. Hamilton, Claudia M. Kuzan-Fischer, Marie Lise C. van Veelen, Helen Wheeler, Michal Zapotocky, Ji Yeoun Lee, David Shih, Jeffrey R. Leonard, Karel Zitterbart, Carlos Gilberto Carlotti, Steffen Albrecht, Jonathon Torchia, Peter Hauser, Ute Bartels, William A. Weiss, Sameer Agnihotri, Lola B. Chambless, Neurosurgery, Pathology, Neurology, Cavalli, Fmg, Remke, M, Rampasek, L, Peacock, J, Shih, Djh, Luu, B, Garzia, L, Torchia, J, Nor, C, Morrissy, A, Agnihotri, S, Thompson, Yy, Kuzan-Fischer, Cm, Farooq, H, Isaev, K, Daniels, C, Cho, Bk, Kim, Sk, Wang, Kc, Lee, Jy, Grajkowska, Wa, Perek-Polnik, M, Vasiljevic, A, Faure-Conter, C, Jouvet, A, Giannini, C, Nageswara Rao, Aa, Li, Kkw, Ng, Hk, Eberhart, Cg, Pollack, If, Hamilton, Rl, Gillespie, Gy, Olson, Jm, Leary, S, Weiss, Wa, Lach, B, Chambless, Lb, Thompson, Rc, Cooper, Mk, Vibhakar, R, Hauser, P, van Veelen, Mc, Kros, Jm, French, Pj, Ra, Y, Kumabe, T, López-Aguilar, E, Zitterbart, K, Sterba, J, Finocchiaro, G, Massimino, M, Van Meir, Eg, Osuka, S, Shofuda, T, Klekner, A, Zollo, M, Leonard, Jr, Rubin, Jb, Jabado, N, Albrecht, S, Mora, J, Van Meter, Te, Jung, S, Moore, A, Hallahan, Ar, Chan, Ja, Tirapelli, Dpc, Carlotti, Cg, Fouladi, M, Pimentel, J, Faria, Cc, Saad, Ag, Massimi, L, Liau, Lm, Wheeler, H, Nakamura, H, Elbabaa, Sk, Perezpeña-Diazconti, M, Chico Ponce de León, F, Robinson, S, Zapotocky, M, Lassaletta, A, Huang, Weiping, Hawkins, Ce, Tabori, U, Bouffet, E, Bartels, U, Dirks, Pb, Rutka, Jt, Bader, Gd, Reimand, J, Goldenberg, A, Ramaswamy, V, Taylor, Md, Cavalli F.M.G., Remke M., Rampasek L., Peacock J., Shih D.J.H., Luu B., Garzia L., Torchia J., Nor C., Morrissy A.S., Agnihotri S., Thompson Y.Y., Kuzan-Fischer C.M., Farooq H., Isaev K., Daniels C., Cho B.-K., Kim S.-K., Wang K.-C., Lee J.Y., Grajkowska W.A., Perek-Polnik M., Vasiljevic A., Faure-Conter C., Jouvet A., Giannini C., Nageswara Rao A.A., Li K.K.W., Ng H.-K., Eberhart C.G., Pollack I.F., Hamilton R.L., Gillespie G.Y., Olson J.M., Leary S., Weiss W.A., Lach B., Chambless L.B., Thompson R.C., Cooper M.K., Vibhakar R., Hauser P., van Veelen M.-L.C., Kros J.M., French P.J., Ra Y.S., Kumabe T., Lopez-Aguilar E., Zitterbart K., Sterba J., Finocchiaro G., Massimino M., Van Meir E.G., Osuka S., Shofuda T., Klekner A., Zollo M., Leonard J.R., Rubin J.B., Jabado N., Albrecht S., Mora J., Van Meter T.E., Jung S., Moore A.S., Hallahan A.R., Chan J.A., Tirapelli D.P.C., Carlotti C.G., Fouladi M., Pimentel J., Faria C.C., Saad A.G., Massimi L., Liau L.M., Wheeler H., Nakamura H., Elbabaa S.K., Perezpena-Diazconti M., Chico Ponce de Leon F., Robinson S., Zapotocky M., Lassaletta A., Huang A., Hawkins C.E., Tabori U., Bouffet E., Bartels U., Dirks P.B., Rutka J.T., Bader G.D., Reimand J., Goldenberg A., Ramaswamy V., and Taylor M.D.

Subjects
0301 basic medicine, Cancer Research, medulloblastoma, CURRENT CONSENSUS, copy number, Bioinformatics, subgroups, Cohort Studies, Individual data, Cluster Analysis, R PACKAGE, Precision Medicine, GENECHIP DATA, Sonic hedgehog, ADULT MEDULLOBLASTOMA, DNA Copy Number Variation, Cancer, Pediatric, Genomics, methylation, CANCER, 3. Good health, Oncology, DNA methylation, Human, Pediatric Research Initiative, DNA Copy Number Variations, Pediatric Cancer, Oncology and Carcinogenesis, Computational biology, Biology, Article, CLASSIFICATION, Homogeneous clusters, 03 medical and health sciences, Rare Diseases, Genetics, medicine, Humans, Oncology & Carcinogenesis, Cerebellar Neoplasms, RECURRENCE, neoplasms, Medulloblastoma, Cluster Analysi, gene expression, MUTATIONS, subgroup, Gene Expression Profiling, Human Genome, Neurosciences, integrative clustering, DNA Methylation, medicine.disease, Precision medicine, MEDULOBLASTOMA, Brain Disorders, nervous system diseases, Brain Cancer, Gene expression profiling, stomatognathic diseases, 030104 developmental biology, Genomic, biology.protein, MOLECULAR SUBGROUPS, GENOMIC DATA, Cohort Studie
Abstract

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Published
2017

8. Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: A retrospective multicohort analysis

Author

Uri Tabori, Marta M. Alonso, Frank S. Lieberman, James T. Rutka, Xing Fan, Kevin Petrecca, Michael A. Grotzer, Lyndsey Emery, Jennifer A. Chan, Luca Massimi, Elizabeth Vera-Bolanos, Antonio Omuro, Richard Everson, Stewart Goldman, Sarah Leary, Alvaro Lassaletta, Sofia Nunes, Ralph P. Ermoian, Betty Luu, Cynthia Hawkins, Amulya A. Nageswara Rao, Jeffrey R. Leonard, Maura Massimino, Teresa Tuñón, Massimo Zollo, James M. Olson, Almos Klekner, Andrey Korshunov, Ute Bartels, Tong Lin, Roger J. Packer, Matthias A. Karajannis, David W. Ellison, Christopher Dunham, David D. Eisenstat, Jaume Mora, Martin Mynarek, Erwin G. Van Meir, Roger E. McLendon, Karel Zitterbart, Corrine Gardner, Giuseppe Cinalli, Amar Gajjar, Kenneth Aldape, Karin M. Muraszko, Vijay Ramaswamy, Thomas Hielscher, Ronald L. Hamilton, Lola B. Chambless, Michael D. Prados, David T.W. Jones, Harshad Ladha, Horacio Soto, Wiesława Grajkowska, Jason E. Cain, Felice Giangaspero, Marcel Kool, Eric S. Lipp, William H. Yong, Andrew J. Grossbach, Tibor Hortobágyi, Tarek Shalaby, Helen Wheeler, Peter Hauser, Marie Lise C. van Veelen, Kristian W. Pajtler, Dorcas Fulton, Mariarita Santi, László Bognár, Jaroslav Sterba, Jing Wu, Ji Yeoun Lee, Carlos Gilberto Carlotti, Katja von Hoff, Stefan Rutkowski, Michael D. Taylor, Daniela Pretti da Cunha Tirapelli, Phillipe Metellus, Stephen C. Mack, Thomas E. Merchant, Samer K. Elbabaa, Marc Remke, Girish Dhall, Riccardo Soffietti, Eric Bouffet, Miguel A. Guzman, Khalida Wani, Charles G. Eberhart, Terri S. Armstrong, Tom Mikkelsen, Francesca R. Buttarelli, Nada Jabado, Paul G. Fisher, Juliette Hukin, Maryam Fouladi, Sama Ahsan, Sueli Mieko Oba-Shinjo, Linda M. Liau, Satoru Osuka, Sridharan Gururangan, Peter B. Dirks, Eugene Hwang, Howard Colman, H. Ian Robins, Caterina Giannini, Suely Kazue Nagahashi Marie, Frank van Landeghem, Mark R. Gilbert, Ulrich Schüller, Florence M.G. Cavalli, David Zagzag, Ian F. Pollack, Claudia C. Faria, Stefan M. Pfister, Shin Jung, Ramaswamy, V, Hielscher, T, Mack, Sc, Lassaletta, A, Lin, T, Pajtler, Kw, Jones, Dt, Luu, B, Cavalli, Fm, Aldape, K, Remke, M, Mynarek, M, Rutkowski, S, Gururangan, S, Mclendon, Re, Lipp, E, Dunham, C, Hukin, J, Eisenstat, Dd, Fulton, D, van Landeghem, Fk, Santi, M, van Veelen, Ml, Van Meir, Eg, Osuka, S, Fan, X, Muraszko, Km, Tirapelli, Dp, Oba Shinjo, Sm, Marie, Sk, Carlotti, Cg, Lee, Jy, Rao, Aa, Giannini, C, Faria, Cc, Nunes, S, Mora, J, Hamilton, Rl, Hauser, P, Jabado, N, Petrecca, K, Jung, S, Massimi, L, Zollo, Massimo, Cinalli, G, Bognár, L, Klekner, A, Hortobágyi, T, Leary, S, Ermoian, Rp, Olson, Jm, Leonard, Jr, Gardner, C, Grajkowska, Wa, Chambless, Lb, Cain, J, Eberhart, Cg, Ahsan, S, Massimino, M, Giangaspero, F, Buttarelli, Fr, Packer, Rj, Emery, L, Yong, Wh, Soto, H, Liau, Lm, Everson, R, Grossbach, A, Shalaby, T, Grotzer, M, Karajannis, Ma, Zagzag, D, Wheeler, H, von Hoff, K, Alonso, Mm, Tuñon, T, Schüller, U, Zitterbart, K, Sterba, J, Chan, Ja, Guzman, M, Elbabaa, Sk, Colman, H, Dhall, G, Fisher, Pg, Fouladi, M, Gajjar, A, Goldman, S, Hwang, E, Kool, M, Ladha, H, Vera Bolanos, E, Wani, K, Lieberman, F, Mikkelsen, T, Omuro, Am, Pollack, If, Prados, M, Robins, Hi, Soffietti, R, Wu, J, Metellus, P, Tabori, U, Bartels, U, Bouffet, E, Hawkins, Ce, Rutka, Jt, Dirks, P, Pfister, Sm, Merchant, Te, Gilbert, Mr, Armstrong, T, Korshunov, A, Ellison, Dw, Taylor, M. d., Ramaswamy V., Hielscher T., Mack S.C., Lassaletta A., Lin T., Pajtler K.W., Jones D.T.W., Luu B., Cavalli F.M.G., Aldape K., Remke M., Mynarek M., Rutkowski S., Gururangan S., McLendon R.E., Lipp E.S., Dunham C., Hukin J., Eisenstat D.D., Fulton D., Van Landeghem F.K.H., Santi M., Van Veelen M.-L.C., Van Meir E.G., Osuka S., Fan X., Muraszko K.M., Tirapelli D.P.C., Oba-Shinjo S.M., Marie S.K.N., Carlotti C.G., Lee J.Y., Rao A.A.N., Giannini C., Faria C.C., Nunes S., Mora J., Hamilton R.L., Hauser P., Jabado N., Petrecca K., Jung S., Massimi L., Zollo M., Cinalli G., Bognar L., Klekner A., Hortobagyi T., Leary S., Ermoian R.P., Olson J.M., Leonard J.R., Gardner C., Grajkowska W.A., Chambless L.B., Cain J., Eberhart C.G., Ahsan S., Massimino M., Giangaspero F., Buttarelli F.R., Packer R.J., Emery L., Yong W.H., Soto H., Liau L.M., Everson R., Grossbach A., Shalaby T., Grotzer M., Karajannis M.A., Zagzag D., Wheeler H., Von Hoff K., Alonso M.M., Tunon T., Schuller U., Zitterbart K., Sterba J., Chan J.A., Guzman M., Elbabaa S.K., Colman H., Dhall G., Fisher P.G., Fouladi M., Gajjar A., Goldman S., Hwang E., Kool M., Ladha H., Vera-Bolanos E., Wani K., Lieberman F., Mikkelsen T., Omuro A.M., Pollack I.F., Prados M., Robins H.I., Soffietti R., Wu J., Metellus P., Tabori U., Bartels U., Bouffet E., Hawkins C.E., Rutka J.T., Dirks P., Pfister S.M., Merchant T.E., Gilbert M.R., Armstrong T.S., Korshunov A., Ellison D.W., Taylor M.D., and Neurosurgery

Subjects
Male, Ependymoma, Cancer Research, medicine.medical_treatment, cancer research, oncology, posterior fossa ependymoma, cytoreductive surgery, radiation therapy, Infratentorial Neoplasms, Cohort Studies, 0302 clinical medicine, Retrospective Studie, Medicine, Pediatric ependymoma, Child, 10. No inequality, Infratentorial Neoplasm, biology, Cytoreduction Surgical Procedures, Combined Modality Therapy, 3. Good health, Oncology, Child, Preschool, 030220 oncology & carcinogenesis, Female, Radiology, Human, Adult, medicine.medical_specialty, Adolescent, Fossa, Ependymoma, biomarkers, 03 medical and health sciences, Original Reports, Humans, Retrospective Studies, Chemotherapy, business.industry, Proportional hazards model, Infant, Retrospective cohort study, biology.organism_classification, medicine.disease, Surgery, Radiation therapy, Cohort Studie, business, 030217 neurology & neurosurgery
Abstract

Purpose Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. Methods Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. Results Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. Conclusion The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.

Published
2016

9. Cytogenetic Prognostication Within Medulloblastoma Subgroups

Author

Franck Bourdeaut, Michael K. Cooper, Almos Klekner, Stefan Rutkowski, David Shih, Jeffrey R. Leonard, Simon Bailey, Concezio Di Rocco, Ulrich Schüller, Giuseppe Cinalli, Pim J. French, Cinzia Lavarino, Young Shin Ra, John Peacock, Yuan Yao, A. Sorana Morrissy, William A. Weiss, Nanne K. Kloosterhof, László Bognár, Pasqualino De Antonellis, Teiji Tominaga, Stephen W. Scherer, Paul A. Northcott, David T.W. Jones, Reid C. Thompson, Shenandoah Robinson, Marta Perek-Polnik, Boleslaw Lach, Massimo Zollo, Olivier Delattre, Jennifer A. Chan, Janet C. Lindsey, Xin Wang, Nada Jabado, Karel Zitterbart, David Malkin, Adi Rolider, Roger J. Packer, James M. Olson, Steffen Albrecht, Ji Yeoun Lee, Wiesława Grajkowska, Charles G. Eberhart, Marcel Kool, Vijay Ramaswamy, Seung-Ki Kim, Joanna J. Phillips, Andrey Korshunov, Michael D. Taylor, Florence M.G. Cavalli, Luca Massimi, Xiaochong Wu, Maryam Fouladi, Peter Hauser, Xing Fan, Steven C. Clifford, Leos Kren, Carmen de Torres, Erna M.C. Michiels, Adrian M. Dubuc, Amar Gajjar, Livia Garzia, Eric Bouffet, Ian F. Pollack, Marc Remke, Jaume Mora, Claudia C. Faria, Miklós Garami, Erwin G. Van Meir, Byung Kyu Cho, Karin M. Muraszko, Joshua B. Rubin, Anne Jouvet, Stefan M. Pfister, Nalin Gupta, Johan M. Kros, Shin Jung, Yoon Jae Cho, Rajeev Vibhakar, Linda M. Liau, Stephen C. Mack, Scott L. Pomeroy, Betty Luu, Cynthia Hawkins, Ali G. Saad, Kyu-Chang Wang, Uri Tabori, Michelle Fèvre-Montange, Adam M. Fontebasso, Robert J. Wechsler-Reya, Toshihiro Kumabe, James T. Rutka, François Doz, Shih, Dj, Northcott, Pa, Remke, M, Korshunov, A, Ramaswamy, V, Kool, M, Luu, B, Yao, Y, Wang, X, Dubuc, Am, Garzia, L, Peacock, J, Mack, Sc, Wu, X, Rolider, A, Morrissy, A, Cavalli, Fm, Jones, Dt, Zitterbart, K, Faria, Cc, Schüller, U, Kren, L, Kumabe, T, Tominaga, T, Shin Ra, Y, Garami, M, Hauser, P, Chan, Ja, Robinson, S, Bognár, L, Klekner, A, Saad, Ag, Liau, Lm, Albrecht, S, Fontebasso, A, Cinalli, G, DE ANTONELLIS, Pasqualino, Zollo, Massimo, Cooper, Mk, Thompson, Rc, Bailey, S, Lindsey, Jc, Di Rocco, C, Massimi, L, Michiels, Em, Scherer, Sw, Phillips, Jj, Gupta, N, Fan, X, Muraszko, Km, Vibhakar, R, Eberhart, Cg, Fouladi, M, Lach, B, Jung, S, Wechsler Reya, Rj, Fèvre Montange, M, Jouvet, A, Jabado, N, Pollack, If, Weiss, Wa, Lee, Jy, Cho, Bk, Kim, Sk, Wang, Kc, Leonard, Jr, Rubin, Jb, de Torres, C, Lavarino, C, Mora, J, Cho, Yj, Tabori, U, Olson, Jm, Gajjar, A, Packer, Rj, Rutkowski, S, Pomeroy, Sl, French, Pj, Kloosterhof, Nk, Kros, Jm, Van Meir, Eg, Clifford, Sc, Bourdeaut, F, Delattre, O, Doz, Ff, Hawkins, Ce, Malkin, D, Grajkowska, Wa, Perek Polnik, M, Bouffet, E, Rutka, Jt, Pfister, Sm, Taylor, M. d., Pulmonary Medicine, Pediatrics, Neurology, and Pathology

Subjects
Male, Cancer Research, Pathology, Risk Factors, Young adult, Stage (cooking), Pair 11, Child, In Situ Hybridization, Fluorescence, In Situ Hybridization, Cancer, Pediatric, screening and diagnosis, Tumor, Nuclear Proteins, ORIGINAL REPORTS, Orvostudományok, Prognosis, 3. Good health, Gene Expression Regulation, Neoplastic, Detection, Oncology, Child, Preschool, Predictive value of tests, Female, Patient Safety, Biotechnology, 4.2 Evaluation of markers and technologies, Human, medicine.medical_specialty, Pediatric Research Initiative, Adolescent, Pediatric Cancer, Clinical Sciences, Oncology and Carcinogenesis, Kruppel-Like Transcription Factors, Zinc Finger Protein Gli2, Extent of resection, Klinikai orvostudományok, Risk Assessment, Chromosomes, Fluorescence, Proto-Oncogene Proteins c-myc, Cytogenetics, Young Adult, Rare Diseases, Patient age, Clinical Research, Predictive Value of Tests, Biomarkers, Tumor, medicine, Humans, Hedgehog Proteins, Oncology & Carcinogenesis, Preschool, Proportional Hazards Models, Chromosomes, Human, Pair 14, Medulloblastoma, Neoplastic, business.industry, Proportional hazards model, Chromosomes, Human, Pair 11, Gene Expression Profiling, Pair 14, Reproducibility of Results, Infant, medicine.disease, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, Brain Cancer, Wnt Proteins, Gene Expression Regulation, Tissue Array Analysis, business, Biomarkers
Abstract

Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

Published
2014

10. Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Author

Jenny Q. Qian, Darell D. Bigner, Miklós Garami, Shaun D. Jackman, Wiesława Grajkowska, Nalin Gupta, Johan M. Kros, Poul H. Sorensen, Anna Kenney, Stéphanie Reynaud, Byung Kyu Cho, Ian F. Pollack, Marcel Kool, Steven C. Clifford, Kyu-Chang Wang, Inanc Birol, Tzvi Aviv, Hendrick Witt, Gemma Hoad, Martine F. Roussel, Christine Haberler, Pim J. French, Betty Luu, Cynthia Hawkins, Claudia C. Faria, Richard A. Moore, Karin M. Muraszko, Yuan Yao, Nanne K. Kloosterhof, Rameen Beroukhim, Leos Kren, Erna M.C. Michiels, Jan O. Korbel, Paul A. Northcott, Stefan M. Pfister, Marc Remke, Nina Thiessen, Jennifer A. Chan, Adam M. Fontebasso, Maryam Fouladi, Shin Jung, Richard G. Ellenbogen, Richard Corbett, László Bognár, Yoon Jae Cho, Massimo Zollo, Robert J. Wechsler-Reya, Steven E. Schumacher, Xing Fan, Michael J. Levy, Wolfram Scheurlen, Young Shin Ra, Adrian M. Stütz, William A. Weiss, Simon Bailey, Rajeev Vibhakar, Giuseppe Cinalli, Toshihiro Kumabe, Marco A. Marra, Christian R. Marshall, Eric Bouffet, Luca Massimi, Scott L. Pomeroy, Sarah S. Pernet-Fattet, Andrew J. Mungall, James T. Rutka, G. Yancey Gillespie, Charles G. Eberhart, Peter Hauser, Andy Chu, Jüri Reimand, Xiaochong Wu, Adi Rolider, Xin Wang, Stephen W. Scherer, Reid C. Thompson, Ka Ming Nip, Anne Jouvet, Timothy E. Van Meter, Robert A. Holt, Anthony Raymond, Livia Garzia, Teiji Tominaga, Erwin G. Van Meir, John Peacock, Michael D. Taylor, Achille Iolascon, Roger E. McLendon, Andrey Korshunov, Stephen C. Mack, Nada Jabado, Readman Chiu, Africa Fernandez-L, Eric Chuah, Richard Varhol, Hideo Nakamura, Samer K. Elbabaa, Uri Tabori, Peter B. Dirks, Gary D. Bader, Linda M. Liau, François Doz, Allan Lo, Janet C. Lindsey, Adrian M. Dubuc, Michelle Fèvre-Montange, David T.W. Jones, Carlos Gilberto Carlotti, Ali G. Saad, Steffen Albrecht, Michael K. Cooper, Karen Mungall, Daisuke Kawauchi, A. Sorana Morrissy, Boleslaw Lach, Karel Zitterbart, Joshua B. Rubin, Matthew Meyerson, Florence M.G. Cavalli, Yisu Li, Shenandoah Robinson, Marta Perek-Polnik, Olivier Delattre, David Malkin, Almos Klekner, James M. Olson, Steven J.M. Jones, Thomas Zichner, David W. Ellison, Seung-Ki Kim, Vijay Ramaswamy, Anath C. Lionel, David Shih, Jeffrey R. Leonard, Concezio Di Rocco, Pulmonary Medicine, Pediatrics, Neurology, Pathology, Northcott, Pa, Shih, Dj, Peacock, J, Garzia, L, Morrissy, A, Zichner, T, Stütz, Am, Korshunov, A, Reimand, J, Schumacher, Se, Beroukhim, R, Ellison, Dw, Marshall, Cr, Lionel, Ac, Mack, S, Dubuc, A, Yao, Y, Ramaswamy, V, Luu, B, Rolider, A, Cavalli, Fm, Wang, X, Remke, M, Wu, X, Chiu, Ry, Chu, A, Chuah, E, Corbett, Rd, Hoad, Gr, Jackman, Sd, Li, Y, Lo, A, Mungall, Kl, Nip, Km, Qian, Jq, Raymond, Ag, Thiessen, Nt, Varhol, Rj, Birol, I, Moore, Ra, Mungall, Aj, Holt, R, Kawauchi, D, Roussel, Mf, Kool, M, Jones, Dt, Witt, H, Fernandez L., A, Kenney, Am, Wechsler Reya, Rj, Dirks, P, Aviv, T, Grajkowska, Wa, Perek Polnik, M, Haberler, Cc, Delattre, O, Reynaud, S, Doz, Ff, Pernet Fattet, S, Cho, Bk, Kim, Sk, Wang, Kc, Scheurlen, W, Eberhart, Cg, Fèvre Montange, M, Jouvet, A, Pollack, If, Fan, X, Muraszko, Km, Gillespie, Gy, Di Rocco, C, Massimi, L, Michiels, Em, Kloosterhof, Nk, French, Pj, Kros, Jm, Olson, Jm, Ellenbogen, Rg, Zitterbart, K, Kren, L, Thompson, Rc, Cooper, Mk, Lach, B, Mclendon, Re, Bigner, Dd, Fontebasso, A, Albrecht, S, Jabado, N, Lindsey, Jc, Bailey, S, Gupta, N, Weiss, Wa, Bognár, L, Klekner, A, Van Meter, Te, Kumabe, T, Tominaga, T, Elbabaa, Sk, Leonard, Jr, Rubin, Jb, Liau, Lm, Van Meir, Eg, Fouladi, M, Nakamura, H, Cinalli, G, Garami, M, Hauser, P, Saad, Ag, Iolascon, Achille, Jung, S, Carlotti, Cg, Vibhakar, R, Ra, Y, Robinson, S, Zollo, Massimo, Faria, Cc, Chan, Ja, Levy, Ml, Sorensen, Ph, Meyerson, M, Pomeroy, Sl, Cho, Yj, Bader, Gd, Tabori, U, Hawkins, Ce, Bouffet, E, Scherer, Sw, Rutka, Jt, Malkin, D, Clifford, Sc, Jones, Sj, Korbel, Jo, Pfister, Sm, Marra, Ma, and Taylor, M. D.

Subjects
DNA Copy Number Variations, Oncogene Proteins, Fusion, medicine.medical_treatment, Genes, myc, Nerve Tissue Proteins, Biology, Bioinformatics, medulloblastoma, Article, Translocation, Genetic, Targeted therapy, Structural variation, 03 medical and health sciences, 0302 clinical medicine, Transforming Growth Factor beta, Gene Duplication, Gene duplication, medicine, Humans, Hedgehog Proteins, Cerebellar Neoplasms, Child, 030304 developmental biology, Medulloblastoma, 0303 health sciences, Multidisciplinary, Chromothripsis, PROTEÍNAS DE TRANSPORTE (GENÉTICA), Genome, Human, NF-kappa B, Cancer, Proteins, Genomics, medicine.disease, Human genetics, 3. Good health, PVT1, 030220 oncology & carcinogenesis, Genomic Structural Variation, RNA, Long Noncoding, Carrier Proteins, Signal Transduction
Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4 alpha. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-beta signalling in Group 3, and NF-kappa B signalling in Group 4, suggest future avenues for rational, targeted therapy.

Published
2012

11. Author Correction: Failure of human rhombic lip differentiation underlies medulloblastoma formation.

Author

Hendrikse LD, Haldipur P, Saulnier O, Millman J, Sjoboen AH, Erickson AW, Ong W, Gordon V, Coudière-Morrison L, Mercier AL, Shokouhian M, Suárez RA, Ly M, Borlase S, Scott DS, Vladoiu MC, Farooq H, Sirbu O, Nakashima T, Nambu S, Funakoshi Y, Bahcheli A, Diaz-Mejia JJ, Golser J, Bach K, Phuong-Bao T, Skowron P, Wang EY, Kumar SA, Balin P, Visvanathan A, Lee JJY, Ayoub R, Chen X, Chen X, Mungall KL, Luu B, Bérubé P, Wang YC, Pfister SM, Kim SK, Delattre O, Bourdeaut F, Doz F, Masliah-Planchon J, Grajkowska WA, Loukides J, Dirks P, Fèvre-Montange M, Jouvet A, French PJ, Kros JM, Zitterbart K, Bailey SD, Eberhart CG, Rao AAN, Giannini C, Olson JM, Garami M, Hauser P, Phillips JJ, Ra YS, de Torres C, Mora J, Li KKW, Ng HK, Poon WS, Pollack IF, López-Aguilar E, Gillespie GY, Van Meter TE, Shofuda T, Vibhakar R, Thompson RC, Cooper MK, Rubin JB, Kumabe T, Jung S, Lach B, Iolascon A, Ferrucci V, de Antonellis P, Zollo M, Cinalli G, Robinson S, Stearns DS, Van Meir EG, Porrati P, Finocchiaro G, Massimino M, Carlotti CG, Faria CC, Roussel MF, Boop F, Chan JA, Aldinger KA, Razavi F, Silvestri E, McLendon RE, Thompson EM, Ansari M, Garre ML, Chico F, Eguía P, Pérezpeña M, Morrissy AS, Cavalli FMG, Wu X, Daniels C, Rich JN, Jones SJM, Moore RA, Marra MA, Huang X, Reimand J, Sorensen PH, Wechsler-Reya RJ, Weiss WA, Pugh TJ, Garzia L, Kleinman CL, Stein LD, Jabado N, Malkin D, Ayrault O, Golden JA, Ellison DW, Doble B, Ramaswamy V, Werbowetski-Ogilvie TE, Suzuki H, Millen KJ, and Taylor MD

Published
2022
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12. Failure of human rhombic lip differentiation underlies medulloblastoma formation.

Author

Hendrikse LD, Haldipur P, Saulnier O, Millman J, Sjoboen AH, Erickson AW, Ong W, Gordon V, Coudière-Morrison L, Mercier AL, Shokouhian M, Suárez RA, Ly M, Borlase S, Scott DS, Vladoiu MC, Farooq H, Sirbu O, Nakashima T, Nambu S, Funakoshi Y, Bahcheli A, Diaz-Mejia JJ, Golser J, Bach K, Phuong-Bao T, Skowron P, Wang EY, Kumar SA, Balin P, Visvanathan A, Lee JJY, Ayoub R, Chen X, Chen X, Mungall KL, Luu B, Bérubé P, Wang YC, Pfister SM, Kim SK, Delattre O, Bourdeaut F, Doz F, Masliah-Planchon J, Grajkowska WA, Loukides J, Dirks P, Fèvre-Montange M, Jouvet A, French PJ, Kros JM, Zitterbart K, Bailey SD, Eberhart CG, Rao AAN, Giannini C, Olson JM, Garami M, Hauser P, Phillips JJ, Ra YS, de Torres C, Mora J, Li KKW, Ng HK, Poon WS, Pollack IF, López-Aguilar E, Gillespie GY, Van Meter TE, Shofuda T, Vibhakar R, Thompson RC, Cooper MK, Rubin JB, Kumabe T, Jung S, Lach B, Iolascon A, Ferrucci V, de Antonellis P, Zollo M, Cinalli G, Robinson S, Stearns DS, Van Meir EG, Porrati P, Finocchiaro G, Massimino M, Carlotti CG, Faria CC, Roussel MF, Boop F, Chan JA, Aldinger KA, Razavi F, Silvestri E, McLendon RE, Thompson EM, Ansari M, Garre ML, Chico F, Eguía P, Pérezpeña M, Morrissy AS, Cavalli FMG, Wu X, Daniels C, Rich JN, Jones SJM, Moore RA, Marra MA, Huang X, Reimand J, Sorensen PH, Wechsler-Reya RJ, Weiss WA, Pugh TJ, Garzia L, Kleinman CL, Stein LD, Jabado N, Malkin D, Ayrault O, Golden JA, Ellison DW, Doble B, Ramaswamy V, Werbowetski-Ogilvie TE, Suzuki H, Millen KJ, and Taylor MD

Subjects
Cell Lineage, Cerebellum embryology, Cerebellum pathology, Core Binding Factor alpha Subunits genetics, Hedgehog Proteins metabolism, Histone Demethylases, Humans, Ki-67 Antigen metabolism, Muscle Proteins, Mutation, Otx Transcription Factors deficiency, Otx Transcription Factors genetics, Repressor Proteins, T-Box Domain Proteins metabolism, Transcription Factors, Cell Differentiation genetics, Cerebellar Neoplasms classification, Cerebellar Neoplasms genetics, Cerebellar Neoplasms pathology, Medulloblastoma classification, Medulloblastoma genetics, Medulloblastoma pathology, Metencephalon embryology, Metencephalon pathology
Abstract

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1-4 . Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5-8 . By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10 . However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4 . Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES + KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2022
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13. The transcriptional landscape of Shh medulloblastoma.

Author

Skowron P, Farooq H, Cavalli FMG, Morrissy AS, Ly M, Hendrikse LD, Wang EY, Djambazian H, Zhu H, Mungall KL, Trinh QM, Zheng T, Dai S, Stucklin ASG, Vladoiu MC, Fong V, Holgado BL, Nor C, Wu X, Abd-Rabbo D, Bérubé P, Wang YC, Luu B, Suarez RA, Rastan A, Gillmor AH, Lee JJY, Zhang XY, Daniels C, Dirks P, Malkin D, Bouffet E, Tabori U, Loukides J, Doz FP, Bourdeaut F, Delattre OO, Masliah-Planchon J, Ayrault O, Kim SK, Meyronet D, Grajkowska WA, Carlotti CG, de Torres C, Mora J, Eberhart CG, Van Meir EG, Kumabe T, French PJ, Kros JM, Jabado N, Lach B, Pollack IF, Hamilton RL, Rao AAN, Giannini C, Olson JM, Bognár L, Klekner A, Zitterbart K, Phillips JJ, Thompson RC, Cooper MK, Rubin JB, Liau LM, Garami M, Hauser P, Li KKW, Ng HK, Poon WS, Yancey Gillespie G, Chan JA, Jung S, McLendon RE, Thompson EM, Zagzag D, Vibhakar R, Ra YS, Garre ML, Schüller U, Shofuda T, Faria CC, López-Aguilar E, Zadeh G, Hui CC, Ramaswamy V, Bailey SD, Jones SJ, Mungall AJ, Moore RA, Calarco JA, Stein LD, Bader GD, Reimand J, Ragoussis J, Weiss WA, Marra MA, Suzuki H, and Taylor MD

Subjects
Adolescent, Adult, Child, Child, Preschool, Female, Gene Regulatory Networks, Genetic Variation, Humans, Infant, Male, Middle Aged, Signal Transduction genetics, Young Adult, Cerebellar Neoplasms genetics, Gene Expression Regulation, Neoplastic, Hedgehog Proteins genetics, Medulloblastoma genetics, Transcriptome
Abstract

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

Published
2021
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14. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.

Author

Nobre L, Zapotocky M, Khan S, Fukuoka K, Fonseca A, McKeown T, Sumerauer D, Vicha A, Grajkowska WA, Trubicka J, Li KKW, Ng HK, Massimi L, Lee JY, Kim SK, Zelcer S, Vasiljevic A, Faure-Conter C, Hauser P, Lach B, van Veelen-Vincent ML, French PJ, Van Meir EG, Weiss WA, Gupta N, Pollack IF, Hamilton RL, Nageswara Rao AA, Giannini C, Rubin JB, Moore AS, Chambless LB, Vibhakar R, Ra YS, Massimino M, McLendon RE, Wheeler H, Zollo M, Ferruci V, Kumabe T, Faria CC, Sterba J, Jung S, López-Aguilar E, Mora J, Carlotti CG, Olson JM, Leary S, Cain J, Krskova L, Zamecnik J, Hawkins CE, Tabori U, Huang A, Bartels U, Northcott PA, Taylor MD, Yip S, Hansford JR, Bouffet E, and Ramaswamy V

Subjects
Adolescent, Biomarkers, Tumor metabolism, Child, Cyclophosphamide therapeutic use, Female, Humans, Ifosfamide therapeutic use, Male, Medulloblastoma metabolism, Middle Aged, Neoplasm Recurrence, Local metabolism, Progression-Free Survival, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cerebellar Neoplasms drug therapy, Medulloblastoma drug therapy, Neoplasm Recurrence, Local drug therapy
Abstract

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

Published
2020
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15. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.

Author

Suzuki H, Kumar SA, Shuai S, Diaz-Navarro A, Gutierrez-Fernandez A, De Antonellis P, Cavalli FMG, Juraschka K, Farooq H, Shibahara I, Vladoiu MC, Zhang J, Abeysundara N, Przelicki D, Skowron P, Gauer N, Luu B, Daniels C, Wu X, Forget A, Momin A, Wang J, Dong W, Kim SK, Grajkowska WA, Jouvet A, Fèvre-Montange M, Garrè ML, Nageswara Rao AA, Giannini C, Kros JM, French PJ, Jabado N, Ng HK, Poon WS, Eberhart CG, Pollack IF, Olson JM, Weiss WA, Kumabe T, López-Aguilar E, Lach B, Massimino M, Van Meir EG, Rubin JB, Vibhakar R, Chambless LB, Kijima N, Klekner A, Bognár L, Chan JA, Faria CC, Ragoussis J, Pfister SM, Goldenberg A, Wechsler-Reya RJ, Bailey SD, Garzia L, Morrissy AS, Marra MA, Huang X, Malkin D, Ayrault O, Ramaswamy V, Puente XS, Calarco JA, Stein L, and Taylor MD

Subjects
Adolescent, Adult, Alternative Splicing, Hedgehog Proteins metabolism, Humans, Mutation, RNA Splice Sites, RNA Splicing, Cerebellar Neoplasms genetics, Hedgehog Proteins genetics, Medulloblastoma genetics, RNA, Small Nuclear genetics
Abstract

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes 1-3 . Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

Published
2019
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16. Intertumoral Heterogeneity within Medulloblastoma Subgroups.

Author

Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, Garzia L, Torchia J, Nor C, Morrissy AS, Agnihotri S, Thompson YY, Kuzan-Fischer CM, Farooq H, Isaev K, Daniels C, Cho BK, Kim SK, Wang KC, Lee JY, Grajkowska WA, Perek-Polnik M, Vasiljevic A, Faure-Conter C, Jouvet A, Giannini C, Nageswara Rao AA, Li KKW, Ng HK, Eberhart CG, Pollack IF, Hamilton RL, Gillespie GY, Olson JM, Leary S, Weiss WA, Lach B, Chambless LB, Thompson RC, Cooper MK, Vibhakar R, Hauser P, van Veelen MC, Kros JM, French PJ, Ra YS, Kumabe T, López-Aguilar E, Zitterbart K, Sterba J, Finocchiaro G, Massimino M, Van Meir EG, Osuka S, Shofuda T, Klekner A, Zollo M, Leonard JR, Rubin JB, Jabado N, Albrecht S, Mora J, Van Meter TE, Jung S, Moore AS, Hallahan AR, Chan JA, Tirapelli DPC, Carlotti CG, Fouladi M, Pimentel J, Faria CC, Saad AG, Massimi L, Liau LM, Wheeler H, Nakamura H, Elbabaa SK, Perezpeña-Diazconti M, Chico Ponce de León F, Robinson S, Zapotocky M, Lassaletta A, Huang A, Hawkins CE, Tabori U, Bouffet E, Bartels U, Dirks PB, Rutka JT, Bader GD, Reimand J, Goldenberg A, Ramaswamy V, and Taylor MD

Subjects
Cluster Analysis, Cohort Studies, DNA Copy Number Variations, DNA Methylation, Gene Expression Profiling, Genomics, Humans, Medulloblastoma genetics, Medulloblastoma therapy, Medulloblastoma classification, Precision Medicine
Abstract

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2017
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17. Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease.

Author

Pronicki M, Piekutowska-Abramczuk D, Jurkiewicz E, Rokicki D, Ciara E, Trubicka J, Iwanicka-Pronicka K, Pajdowska M, Migdał M, and Grajkowska WA

Subjects
Basal Ganglia Diseases genetics, Humans, Infant, Newborn, Male, Mutation, Basal Ganglia Diseases pathology, Brain pathology, Membrane Transport Proteins genetics
Abstract

Biotin-thiamine-responsive basal ganglia disease is a severe form of a rare neurogenetic disorder caused by pathogenic molecular variants in the thiamine transporter gene. Nowadays, a potentially effective treatment is known, therefore the early diagnosis is mandatory. The aim of the paper was to assess the contribution of neuropathological and magnetic resonance imaging (MRI) studies to a proper diagnosis. We present the brain study of two Polish patients with SLC19A3 mutations, including (1) an infant with an intriguing "walnut" appearance of the brain autopsied many years before the discovery of the SLC19A3 defect, and (2) a one-year-old patient with clinical features of Leigh syndrome. In patient 2, biotin/thiamine responsiveness was not tested at the time of diagnosis and causal treatment started with one-year delay. The central nervous system lesions found in the patients displayed almost clearly a specific pattern for SLC19A3 defect, as previously proposed in diagnostic criteria. Our study presents a detailed description of neuropathological and MRI findings of both patients. We confirm that the autopsy and/or MRI of the brain is sufficient to qualify a patient with an unknown neuropathological disorder directly for SLC19A3 mutations testing and a prompt trial of specific treatment. .

Published
2017
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18. WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma.

Author

Zhukova N, Ramaswamy V, Remke M, Martin DC, Castelo-Branco P, Zhang CH, Fraser M, Tse K, Poon R, Shih DJ, Baskin B, Ray PN, Bouffet E, Dirks P, von Bueren AO, Pfaff E, Korshunov A, Jones DT, Northcott PA, Kool M, Pugh TJ, Pomeroy SL, Cho YJ, Pietsch T, Gessi M, Rutkowski S, Bognár L, Cho BK, Eberhart CG, Conter CF, Fouladi M, French PJ, Grajkowska WA, Gupta N, Hauser P, Jabado N, Vasiljevic A, Jung S, Kim SK, Klekner A, Kumabe T, Lach B, Leonard JR, Liau LM, Massimi L, Pollack IF, Ra YS, Rubin JB, Van Meir EG, Wang KC, Weiss WA, Zitterbart K, Bristow RG, Alman B, Hawkins CE, Malkin D, Clifford SC, Pfister SM, Taylor MD, and Tabori U

Subjects
Adolescent, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Cell Survival radiation effects, Cerebellar Neoplasms mortality, Cerebellar Neoplasms pathology, Cerebellar Neoplasms radiotherapy, Child, Child, Preschool, Cohort Studies, Female, Humans, International Cooperation, Male, Medulloblastoma mortality, Medulloblastoma pathology, Medulloblastoma radiotherapy, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells radiation effects, Radiotherapy adverse effects, Tumor Suppressor Protein p53 metabolism, Young Adult, beta Catenin genetics, beta Catenin metabolism, Cerebellar Neoplasms genetics, Lithium pharmacology, Medulloblastoma genetics, Mutation genetics, Tumor Suppressor Protein p53 genetics, Wnt Proteins metabolism, Wnt Signaling Pathway drug effects
Abstract

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.

Published
2014
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19. Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

Author

Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stütz AM, Korshunov A, Reimand J, Schumacher SE, Beroukhim R, Ellison DW, Marshall CR, Lionel AC, Mack S, Dubuc A, Yao Y, Ramaswamy V, Luu B, Rolider A, Cavalli FM, Wang X, Remke M, Wu X, Chiu RY, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman SD, Li Y, Lo A, Mungall KL, Nip KM, Qian JQ, Raymond AG, Thiessen NT, Varhol RJ, Birol I, Moore RA, Mungall AJ, Holt R, Kawauchi D, Roussel MF, Kool M, Jones DT, Witt H, Fernandez-L A, Kenney AM, Wechsler-Reya RJ, Dirks P, Aviv T, Grajkowska WA, Perek-Polnik M, Haberler CC, Delattre O, Reynaud SS, Doz FF, Pernet-Fattet SS, Cho BK, Kim SK, Wang KC, Scheurlen W, Eberhart CG, Fèvre-Montange M, Jouvet A, Pollack IF, Fan X, Muraszko KM, Gillespie GY, Di Rocco C, Massimi L, Michiels EM, Kloosterhof NK, French PJ, Kros JM, Olson JM, Ellenbogen RG, Zitterbart K, Kren L, Thompson RC, Cooper MK, Lach B, McLendon RE, Bigner DD, Fontebasso A, Albrecht S, Jabado N, Lindsey JC, Bailey S, Gupta N, Weiss WA, Bognár L, Klekner A, Van Meter TE, Kumabe T, Tominaga T, Elbabaa SK, Leonard JR, Rubin JB, Liau LM, Van Meir EG, Fouladi M, Nakamura H, Cinalli G, Garami M, Hauser P, Saad AG, Iolascon A, Jung S, Carlotti CG, Vibhakar R, Ra YS, Robinson S, Zollo M, Faria CC, Chan JA, Levy ML, Sorensen PH, Meyerson M, Pomeroy SL, Cho YJ, Bader GD, Tabori U, Hawkins CE, Bouffet E, Scherer SW, Rutka JT, Malkin D, Clifford SC, Jones SJ, Korbel JO, Pfister SM, Marra MA, and Taylor MD

Subjects
Carrier Proteins genetics, Cerebellar Neoplasms metabolism, Child, DNA Copy Number Variations genetics, Gene Duplication genetics, Genes, myc genetics, Genomics, Hedgehog Proteins metabolism, Humans, Medulloblastoma metabolism, NF-kappa B metabolism, Nerve Tissue Proteins genetics, Oncogene Proteins, Fusion genetics, Proteins genetics, RNA, Long Noncoding, Signal Transduction, Transforming Growth Factor beta metabolism, Translocation, Genetic genetics, Cerebellar Neoplasms classification, Cerebellar Neoplasms genetics, Genome, Human genetics, Genomic Structural Variation genetics, Medulloblastoma classification, Medulloblastoma genetics
Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Published
2012
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