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1. Biallelic EPCAM deletions induce tissue-specific DNA repair deficiency and cancer predisposition

Author: Forster, V. J., Aronson, M., Zhang, C., Chung, J., Sudhaman, S., Galati, M. A., Kelly, J., Negm, L., Ercan, A. B., Stengs, L., Durno, C., Edwards, M., Komosa, M., Oldfield, L. E., Nunes, N. M., Pedersen, S., Wellum, J., Siddiqui, I., Bianchi, V., Weil, B. R., Fox, V. L., Pugh, T. J., Kamihara, J., and Tabori, U.
Published: 2024
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2. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

Author: Mack, SC, Witt, H, Piro, RM, Gu, L, Zuyderduyn, S, Stütz, AM, Wang, X, Gallo, M, Garzia, L, Zayne, K, Zhang, X, Ramaswamy, V, Jäger, N, Jones, DTW, Sill, M, Pugh, TJ, Ryzhova, M, Wani, KM, Shih, DJH, Head, R, Remke, M, Bailey, SD, Zichner, T, Faria, CC, Barszczyk, M, Stark, S, Seker-Cin, H, Hutter, S, Johann, P, Bender, S, Hovestadt, V, Tzaridis, T, Dubuc, AM, Northcott, PA, Peacock, J, Bertrand, KC, Agnihotri, S, Cavalli, FMG, Clarke, I, Nethery-Brokx, K, Creasy, CL, Verma, SK, Koster, J, Wu, X, Yao, Y, Milde, T, Sin-Chan, P, Zuccaro, J, Lau, L, Pereira, S, Castelo-Branco, P, Hirst, M, Marra, MA, Roberts, SS, Fults, D, Massimi, L, Cho, YJ, Van Meter, T, Grajkowska, W, Lach, B, Kulozik, AE, von Deimling, A, Witt, O, Scherer, SW, Fan, X, Muraszko, KM, Kool, M, Pomeroy, SL, Gupta, N, Phillips, J, Huang, A, Tabori, U, Hawkins, C, Malkin, D, Kongkham, PN, Weiss, WA, Jabado, N, Rutka, JT, Bouffet, E, Korbel, JO, Lupien, M, Aldape, KD, Bader, GD, Eils, R, Lichter, P, Dirks, PB, Pfister, SM, Korshunov, A, and Taylor, MD
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Pediatric, Human Genome, Rare Diseases, Animals, Brain Neoplasms, CpG Islands, DNA Methylation, Embryonic Stem Cells, Ependymoma, Epigenesis, Genetic, Epigenomics, Female, Gene Expression Regulation, Neoplastic, Gene Silencing, Histones, Humans, Infant, Mice, Mice, Inbred NOD, Mice, SCID, Mutation, Phenotype, Polycomb Repressive Complex 2, Prognosis, Rhombencephalon, Xenograft Model Antitumor Assays, General Science & Technology
Abstract: Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
Published: 2014

3. Concomitant IDH wild‐type glioblastoma and IDH1‐mutant anaplastic astrocytoma in a patient with constitutional mismatch repair deficiency syndrome

Author: Galuppini, F., Opocher, E., Tabori, U., Mammi, I., Edwards, M., Campbell, B., Kelly, J., Viel, A., Quaia, M., Rivieri, F., DʼAvella, D., Arcella, A., Giangaspero, F., Fassan, M., and Gardiman, M. P.
Published: 2018
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4. T2-FLAIR Mismatch Sign in Pediatric Low-Grade Glioma.

Author: Wagner, M. W., Nobre, L., Namdar, K., Khalvati, F., Tabori, U., Hawkins, C., and Ertl-Wagner, B. B.
Published: 2023
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5. Radiomics of Pediatric Low-Grade Gliomas: Toward a Pretherapeutic Differentiation of BRAF-Mutated and BRAF-Fused Tumors

Author: Wagner, M W, Hainc, N, Khalvati, F, Namdar, K, Figueiredo, L, Sheng, M, Laughlin, S, Shroff, M M, Bouffet, E, Tabori, U, Hawkins, C, Yeom, K W, Ertl-Wagner, B B, and University of Zurich
Subjects: Oncology, medicine.medical_specialty, medicine.diagnostic_test, Receiver operating characteristic, business.industry, Area under the curve, 610 Medicine & health, Retrospective cohort study, Fluid-attenuated inversion recovery, Confidence interval, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Text mining, 10043 Clinic for Neuroradiology, Internal medicine, Cohort, Biopsy, medicine, Radiology, Nuclear Medicine and imaging, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: BACKGROUND AND PURPOSE B-Raf proto-oncogene, serine/threonine kinase (BRAF) status has important implications for prognosis and therapy of pediatric low-grade gliomas. Currently, BRAF status classification relies on biopsy. Our aim was to train and validate a radiomics approach to predict BRAF fusion and BRAF V600E mutation. MATERIALS AND METHODS In this bi-institutional retrospective study, FLAIR MR imaging datasets of 115 pediatric patients with low-grade gliomas from 2 children's hospitals acquired between January 2009 and January 2016 were included and analyzed. Radiomics features were extracted from tumor segmentations, and the predictive model was tested using independent training and testing datasets, with all available tumor types. The model was selected on the basis of a grid search on the number of trees, opting for the best split for a random forest. We used the area under the receiver operating characteristic curve to evaluate model performance. RESULTS The training cohort consisted of 94 pediatric patients with low-grade gliomas (mean age, 9.4 years; 45 boys), and the external validation cohort comprised 21 pediatric patients with low-grade gliomas (mean age, 8.37 years; 12 boys). A 4-fold cross-validation scheme predicted BRAF status with an area under the curve of 0.75 (SD, 0.12) (95% confidence interval, 0.62-0.89) on the internal validation cohort. By means of the optimal hyperparameters determined by 4-fold cross-validation, the area under the curve for the external validation was 0.85. Age and tumor location were significant predictors of BRAF status (P values = .04 and
Published: 2021
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6. Clinical characteristics and clinical evolution of a large cohort of pediatric patients with primary central nervous system (cns) tumors and tropomyosin receptor kinase (trk) fusion.

Author: Lamoureux A.-A., Fisher M., Lemelle L., Pfaff E., Kramm C., De Wilde B., Kazanowska B., Hutter C., Pfister S.M., Sturm D., Jones D., Orbach D., Pierron G., Raskin S., Drilon A., Diamond E., Harada G., Zapotocky M., Ellezam B., Weil A.G., Venne D., Barritault M., Leblond P., Coltin H., Hammad R., Tabori U., Hawkins C., Hansford J.R., Meyran D., Erker C., McFadden K., Sato M., Gottardo N.G., Dholaria H., Noroxe D.S., Goto H., Ziegler D.S., Lin F.Y., Parsons D.W., Lindsay H., Wong T.-T., Liu Y.-L., Wu K.-S., Franson A.F., Hwang E., Aguilar-Bonilla A., Cheng S., Cacciotti C., Massimino M., Schiavello E., Wood P., Hoffman L.M., Cappellano A., Lassaletta A., Van Damme A., Llort A., Gerber N.U., Ceruso M.S., Bendel A.E., Skrypek M., Hamideh D., Mushtaq N., Walter A., Jabado N., Alsahlawi A., Farmer J.-P., Abadi C.C., Mueller S., Mazewski C., Aguilera D., Robison N., O'Halloran K., Abbou S., Berlanga P., Geoerger B., Ora I., Moertel C.L., Razis E.D., Vernadou A., Doz F., Laetsch T.W., Perreault S., Lamoureux A.-A., Fisher M., Lemelle L., Pfaff E., Kramm C., De Wilde B., Kazanowska B., Hutter C., Pfister S.M., Sturm D., Jones D., Orbach D., Pierron G., Raskin S., Drilon A., Diamond E., Harada G., Zapotocky M., Ellezam B., Weil A.G., Venne D., Barritault M., Leblond P., Coltin H., Hammad R., Tabori U., Hawkins C., Hansford J.R., Meyran D., Erker C., McFadden K., Sato M., Gottardo N.G., Dholaria H., Noroxe D.S., Goto H., Ziegler D.S., Lin F.Y., Parsons D.W., Lindsay H., Wong T.-T., Liu Y.-L., Wu K.-S., Franson A.F., Hwang E., Aguilar-Bonilla A., Cheng S., Cacciotti C., Massimino M., Schiavello E., Wood P., Hoffman L.M., Cappellano A., Lassaletta A., Van Damme A., Llort A., Gerber N.U., Ceruso M.S., Bendel A.E., Skrypek M., Hamideh D., Mushtaq N., Walter A., Jabado N., Alsahlawi A., Farmer J.-P., Abadi C.C., Mueller S., Mazewski C., Aguilera D., Robison N., O'Halloran K., Abbou S., Berlanga P., Geoerger B., Ora I., Moertel C.L., Razis E.D., Vernadou A., Doz F., Laetsch T.W., and Perreault S.
Abstract: BACKGROUND: TRK fusions are detected in less than 3% of CNS tumors. Given their rarity, there are limited data on the clinical course of these patients. METHOD(S): We contacted 166 oncology centers worldwide to retrieve data on patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, NTRK gene fusion, treatment modalities and outcomes. Patients less than 18 years of age at diagnosis were included in this analysis. RESULT(S): Seventy-three pediatric patients with TRK fusion-driven primary CNS tumors were identified. Median age at diagnosis was 2.4 years (range 0.0-17.8) and 60.2 % were male. NTRK2 gene fusions were found in 37 patients (50.7%), NTRK1 and NTRK3 aberrations were detected in 19 (26.0%) and 17 (23.3%), respectively. Tumor types included 38 high-grade gliomas (HGG; 52.1%), 20 low-grade gliomas (LGG; 27.4%), 4 embryonal tumors (5.5%) and 11 others (15.1%). Median follow-up was 46.5 months (range 3-226). During the course of their disease, a total of 62 (84.9%) patients underwent surgery with a treatment intent, 50 (68.5%) patients received chemotherapy, 35 (47.9%) patients received radiation therapy, while 34 (46.6%) patients received NTRK inhibitors (3 as first line treatment). Twenty-four (32.9%) had no progression including 9 LGG (45%) and 9 HGG (23.6%). At last follow-up, only one (5.6%-18 evaluable) patient with LGG died compared to 11 with HGG (35.5%-31 evaluable). For LGG the median progression-free survival (PFS) after the first line of treatment was 17 months (95% CI: 0.0-35.5) and median overall survival (OS) was not reached. For patients with HGG the median PFS was 30 months (95% CI: 11.9-48.1) and median OS was 182 months (95% CI 20.2-343.8). CONCLUSION(S): We report the largest cohort of pediatric patients with TRK fusion-driven primary CNS tumors. These results will help us to better understand clinical evolution and compare outcomes with ongoing clinical trials.
Published: 2022

7. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Author: Das, A, Sudhaman, S, Morgenstern, D, Coblentz, A, Chung, J, Stone, SC, Alsafwani, N, Liu, ZA, Abu Al Karsaneh, O, Soleimani, S, Ladany, H, Chen, D, Zatzman, M, Cabric, V, Nobre, L, Bianchi, V, Edwards, M, Nahum, LCS, Ercan, AB, Nabbi, A, Constantini, S, Dvir, R, Yalon-Oren, M, Campino, GA, Caspi, S, Larouche, V, Reddy, A, Osborn, M, Mason, G, Lindhorst, S, Bronsema, A, Magimairajan, V, Opocher, E, De Mola, RL, Sabel, M, Frojd, C, Sumerauer, D, Samuel, D, Cole, K, Chiaravalli, S, Massimino, M, Tomboc, P, Ziegler, DS, George, B, Van Damme, A, Hijiya, N, Gass, D, McGee, RB, Mordechai, O, Bowers, DC, Laetsch, TW, Lossos, A, Blumenthal, DT, Sarosiek, T, Yen, LY, Knipstein, J, Bendel, A, Hoffman, LM, Luna-Fineman, S, Zimmermann, S, Scheers, I, Nichols, KE, Zapotocky, M, Hansford, JR, Maris, JM, Dirks, P, Taylor, MD, Kulkarni, A, Shroff, M, Tsang, DS, Villani, A, Xu, W, Aronson, M, Durno, C, Shlien, A, Malkin, D, Getz, G, Maruvka, YE, Ohashi, PS, Hawkins, C, Pugh, TJ, Bouffet, E, Tabori, U, Das, A, Sudhaman, S, Morgenstern, D, Coblentz, A, Chung, J, Stone, SC, Alsafwani, N, Liu, ZA, Abu Al Karsaneh, O, Soleimani, S, Ladany, H, Chen, D, Zatzman, M, Cabric, V, Nobre, L, Bianchi, V, Edwards, M, Nahum, LCS, Ercan, AB, Nabbi, A, Constantini, S, Dvir, R, Yalon-Oren, M, Campino, GA, Caspi, S, Larouche, V, Reddy, A, Osborn, M, Mason, G, Lindhorst, S, Bronsema, A, Magimairajan, V, Opocher, E, De Mola, RL, Sabel, M, Frojd, C, Sumerauer, D, Samuel, D, Cole, K, Chiaravalli, S, Massimino, M, Tomboc, P, Ziegler, DS, George, B, Van Damme, A, Hijiya, N, Gass, D, McGee, RB, Mordechai, O, Bowers, DC, Laetsch, TW, Lossos, A, Blumenthal, DT, Sarosiek, T, Yen, LY, Knipstein, J, Bendel, A, Hoffman, LM, Luna-Fineman, S, Zimmermann, S, Scheers, I, Nichols, KE, Zapotocky, M, Hansford, JR, Maris, JM, Dirks, P, Taylor, MD, Kulkarni, A, Shroff, M, Tsang, DS, Villani, A, Xu, W, Aronson, M, Durno, C, Shlien, A, Malkin, D, Getz, G, Maruvka, YE, Ohashi, PS, Hawkins, C, Pugh, TJ, Bouffet, E, and Tabori, U
Abstract: Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.
Published: 2022

8. HGG-11. Clinical characteristics and clinical evolution of a large cohort of pediatric patients with primary central nervous system (CNS) tumors and tropomyosin receptor kinase (TRK) fusion.

Author: Lamoureux, A-A, Fisher, M, Lemelle, L, Pfaff, E, Kramm, C, De Wilde, B, Kazanowska, B, Hutter, C, Pfister, SM, Sturm, D, Jones, D, Orbach, D, Pierron, G, Raskin, S, Drilon, A, Diamond, E, Harada, G, Zapotocky, M, Ellezam, B, Weil, AG, Venne, D, Barritault, M, Leblond, P, Coltin, H, Hammad, R, Tabori, U, Hawkins, C, Hansford, JR, Meyran, D, Erker, C, McFadden, K, Sato, M, Gottardo, NG, Dholaria, H, Nørøxe, DS, Goto, H, Ziegler, DS, Lin, FY, Parsons, DW, Lindsay, H, Wong, T-T, Liu, Y-L, Wu, K-S, Franson, AF, Hwang, E, Aguilar-Bonilla, A, Cheng, S, Cacciotti, C, Massimino, M, Schiavello, E, Wood, P, Hoffman, LM, Cappellano, A, Lassaletta, A, Van Damme, A, Llort, A, Gerber, NU, Ceruso, MS, Bendel, AE, Skrypek, M, Hamideh, D, Mushtaq, N, Walter, A, Jabado, N, Alsahlawi, A, Farmer, J-P, Abadi, CC, Mueller, S, Mazewski, C, Aguilera, D, Robison, N, O’Halloran, K, Abbou, S, Berlanga, P, Geoerger, B, Øra, I, Moertel, CL, Razis, ED, Vernadou, A, Doz, F, Laetsch, TW, Perreault, S, Lamoureux, A-A, Fisher, M, Lemelle, L, Pfaff, E, Kramm, C, De Wilde, B, Kazanowska, B, Hutter, C, Pfister, SM, Sturm, D, Jones, D, Orbach, D, Pierron, G, Raskin, S, Drilon, A, Diamond, E, Harada, G, Zapotocky, M, Ellezam, B, Weil, AG, Venne, D, Barritault, M, Leblond, P, Coltin, H, Hammad, R, Tabori, U, Hawkins, C, Hansford, JR, Meyran, D, Erker, C, McFadden, K, Sato, M, Gottardo, NG, Dholaria, H, Nørøxe, DS, Goto, H, Ziegler, DS, Lin, FY, Parsons, DW, Lindsay, H, Wong, T-T, Liu, Y-L, Wu, K-S, Franson, AF, Hwang, E, Aguilar-Bonilla, A, Cheng, S, Cacciotti, C, Massimino, M, Schiavello, E, Wood, P, Hoffman, LM, Cappellano, A, Lassaletta, A, Van Damme, A, Llort, A, Gerber, NU, Ceruso, MS, Bendel, AE, Skrypek, M, Hamideh, D, Mushtaq, N, Walter, A, Jabado, N, Alsahlawi, A, Farmer, J-P, Abadi, CC, Mueller, S, Mazewski, C, Aguilera, D, Robison, N, O’Halloran, K, Abbou, S, Berlanga, P, Geoerger, B, Øra, I, Moertel, CL, Razis, ED, Vernadou, A, Doz, F, Laetsch, TW, and Perreault, S
Abstract: BACKGROUND: TRK fusions are detected in less than 3% of CNS tumors. Given their rarity, there are limited data on the clinical course of these patients. METHODS: We contacted 166 oncology centers worldwide to retrieve data on patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, NTRK gene fusion, treatment modalities and outcomes. Patients less than 18 years of age at diagnosis were included in this analysis. RESULTS: Seventy-three pediatric patients with TRK fusion-driven primary CNS tumors were identified. Median age at diagnosis was 2.4 years (range 0.0–17.8) and 60.2 % were male. NTRK2 gene fusions were found in 37 patients (50.7%), NTRK1 and NTRK3 aberrations were detected in 19 (26.0%) and 17 (23.3%), respectively. Tumor types included 38 high-grade gliomas (HGG; 52.1%), 20 low-grade gliomas (LGG; 27.4%), 4 embryonal tumors (5.5%) and 11 others (15.1%). Median follow-up was 46.5 months (range 3-226). During the course of their disease, a total of 62 (84.9%) patients underwent surgery with a treatment intent, 50 (68.5%) patients received chemotherapy, 35 (47.9%) patients received radiation therapy, while 34 (46.6%) patients received NTRK inhibitors (3 as first line treatment). Twenty-four (32.9%) had no progression including 9 LGG (45%) and 9 HGG (23.6%). At last follow-up, only one (5.6%-18 evaluable) patient with LGG died compared to 11 with HGG (35.5%-31 evaluable). For LGG the median progression-free survival (PFS) after the first line of treatment was 17 months (95% CI: 0.0-35.5) and median overall survival (OS) was not reached. For patients with HGG the median PFS was 30 months (95% CI: 11.9-48.1) and median OS was 182 months (95% CI 20.2-343.8). CONCLUSIONS: We report the largest cohort of pediatric patients with TRK fusion-driven primary CNS tumors. These results will help us to better understand clinical evolution and compare outcomes with ongoing clinical trials.
Published: 2022

9. Re-Evaluating Surgery and Re-Irradiation for Locally Recurrent Pediatric Ependymoma — a Multi-Institutional Study

Author: Mak, D.Y., primary, Laperriere, N.J., additional, Ramaswamy, V., additional, Bouffet, E., additional, Murray, J.C., additional, McNall-Knapp, R., additional, Bielamowicz, K., additional, Paulino, A.C., additional, Zaky, W., additional, McGovern, S.L., additional, Okcu, F., additional, Tabori, U., additional, Dirks, P.B., additional, Taylor, M.D., additional, Tsang, D.S.C., additional, and Bavle, A., additional
Published: 2021
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10. Hearing Loss After Radiation and Chemotherapy for Central Nervous System and Head and Neck Tumors in Children

Author: Keilty, D., primary, Khandwala, M., additional, Liu, Z., additional, Papioannou, V., additional, Bouffet, E., additional, Hodgson, D., additional, Yee, R., additional, Laperriere, N.J., additional, Ahmed, S., additional, Mabbott, D., additional, Cushing, S.L., additional, Ramaswamy, V., additional, Tabori, U., additional, Huang, A., additional, Bartels, U., additional, and Tsang, D., additional
Published: 2021
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11. NASPGHAN Annual Meeting Abstracts

Author: Durno, C, Ercan, A, Aronson, M, Villani, A, Bouffet, E, Erdman, S, Scheers, Isabelle, Bronsema, A, Tabori, U, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique
Subjects: and Child Health, Pediatrics, Perinatology and Child Health, Gastroenterology, Pediatrics, Perinatology
Abstract: Background: Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome causing intestinal polyposis and a high risk of early onset gastrointestinal, brain, and hematological cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. Aim: Our aim was to determine if surveillance affects outcome. The primary outcome measure was overall survival. The secondary outcome measure was detection of new cancers. Methods: Patients referred to the International Replication Repair Consortium undergo genetic testing to confirm CMMRD. All individuals were diagnosed with CMMRD through diagnostic criteria by the genetic counsellor at the consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging studies was recommended and initiated internationally on Jan 1, 2012. Protocol included upper endoscopy, colonoscopy, video capsule endoscopy and/or magnetic resonance enterography, and brain MRI. Whole-body MRI was recommended as of Jan 1, 2018. Surveillance questionnaire was sent to the responsible physician with diagnostic fields completed by the registry coordinator as a double check of reliability. Survival analyses was completed using an as-treated approach. Results: Cancer and surveillance data was collected from 64 (50%) of 127 CMMRD individuals registered in the Consortium from 41 countries. There were 114 tumours reported in 60 patients including 55 brain, 28 gastrointestinal (GI), 17 hematological and 14 other malignancies. Surveillance data was available on 110 cancers; 16 were incidental cancers, 68 were symptomatic and 26 were discovered through surveillance. Surveillance identified 13 GI cancers, 11 brain, and 2 hematological malignancies. The gastrointestinal cancers included 5 colorectal, 7 small bowel, and one gastric. Four patients were unaffected. Five-year overall survival was 95% for tumors discovered by surveillance, compared to 43% for symptomatic tumors (p=0.001). Overall survival for gastrointestinal tumors identified by surveillance was 100% (n=13) compared to 79% (n=19) for symptomatic lesions (p=0.1). Similarly, 5-year survival was 83+/-15% and 32+/-7% for surveillance and non-surveillance of brain tumors (p=0.03). Median age at diagnosis of gastrointestinal cancer was 14.6 years (range 9.0-50.6 years). Conclusion: These data support a survival benefit in CMMRD patients undergoing a surveillance protocol.
Published: 2019
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12. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma

Author: Kumar, R, Smith, KS, Deng, M, Terhune, C, Robinson, GW, Orr, BA, Liu, APY, Lin, T, Billups, CA, Chintagumpala, M, Bowers, DC, Hassall, TE, Hansford, JR, Khuong-Quang, DA, Crawford, JR, Bendel, AE, Gururangan, S, Schroeder, K, Bouffet, E, Bartels, U, Fisher, MJ, Cohn, R, Partap, S, Kellie, SJ, McCowage, G, Paulino, AC, Rutkowski, S, Fleischhack, G, Dhall, G, Klesse, LJ, Leary, S, Nazarian, J, Kool, M, Wesseling, P, Ryzhova, M, Zheludkova, O, Golanov, A, McLendon, RE, Packer, RJ, Dunham, C, Hukin, J, Fouladi, M, Faria, CC, Pimentel, J, Walter, AW, Jabado, N, Cho, Y-J, Perreault, S, Croul, SE, Zapotocky, M, Hawkins, C, Tabori, U, Taylor, MD, Pfister, SM, Klimo, P, Boop, FA, Ellison, DW, Merchant, TE, Onar-Thomas, A, Korshunov, A, Jones, DTW, Gajjar, A, Ramaswamy, V, Northcott, PA, Kumar, R, Smith, KS, Deng, M, Terhune, C, Robinson, GW, Orr, BA, Liu, APY, Lin, T, Billups, CA, Chintagumpala, M, Bowers, DC, Hassall, TE, Hansford, JR, Khuong-Quang, DA, Crawford, JR, Bendel, AE, Gururangan, S, Schroeder, K, Bouffet, E, Bartels, U, Fisher, MJ, Cohn, R, Partap, S, Kellie, SJ, McCowage, G, Paulino, AC, Rutkowski, S, Fleischhack, G, Dhall, G, Klesse, LJ, Leary, S, Nazarian, J, Kool, M, Wesseling, P, Ryzhova, M, Zheludkova, O, Golanov, A, McLendon, RE, Packer, RJ, Dunham, C, Hukin, J, Fouladi, M, Faria, CC, Pimentel, J, Walter, AW, Jabado, N, Cho, Y-J, Perreault, S, Croul, SE, Zapotocky, M, Hawkins, C, Tabori, U, Taylor, MD, Pfister, SM, Klimo, P, Boop, FA, Ellison, DW, Merchant, TE, Onar-Thomas, A, Korshunov, A, Jones, DTW, Gajjar, A, Ramaswamy, V, and Northcott, PA
Abstract: PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular ta
Published: 2021

13. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

Author: Durno, C, Ercan, AB, Bianchi, V, Edwards, M, Aronson, M, Galati, M, Atenafu, EG, Abebe-Campino, G, Al-Battashi, A, Alharbi, M, Azad, VF, Baris, HN, Basel, D, Bedgood, R, Bendel, A, Ben-Shachar, S, Blumenthal, DT, Blundell, M, Bornhorst, M, Bronsema, A, Cairney, E, Rhode, S, Caspi, S, Chamdin, A, Chiaravalli, S, Constantini, S, Crooks, B, Das, A, Dvir, R, Farah, R, Foulkes, WD, Frenkel, Z, Gallinger, B, Gardner, S, Gass, D, Ghalibafian, M, Gilpin, C, Goldberg, Y, Goudie, C, Hamid, SA, Hampel, H, Hansford, JR, Harlos, C, Hijiya, N, Hsu, S, Kamihara, J, Kebudi, R, Knipstein, J, Koschmann, C, Kratz, C, Larouche, V, Lassaletta, A, Lindhorst, S, Ling, SC, Link, MP, De Mola, RL, Luiten, R, Lurye, M, Maciaszek, JL, MagimairajanIssai, V, Maher, OM, Massimino, M, McGee, RB, Mushtaq, N, Mason, G, Newmark, M, Nicholas, G, Nichols, KE, Nicolaides, T, Opocher, E, Osborn, M, Oshrine, B, Pearlman, R, Pettee, D, Rapp, J, Rashid, M, Reddy, A, Reichman, L, Remke, M, Robbins, G, Roy, S, Sabel, M, Samuel, D, Scheers, I, Schneider, KW, Sen, S, Stearns, D, Sumerauer, D, Swallow, C, Taylor, L, Thomas, G, Toledano, H, Tomboc, P, Van Damme, A, Winer, I, Yalon, M, Yen, LY, Zapotocky, M, Zelcer, S, Ziegler, DS, Zimmermann, S, Hawkins, C, Malkin, D, Bouffet, E, Villani, A, Tabori, U, Durno, C, Ercan, AB, Bianchi, V, Edwards, M, Aronson, M, Galati, M, Atenafu, EG, Abebe-Campino, G, Al-Battashi, A, Alharbi, M, Azad, VF, Baris, HN, Basel, D, Bedgood, R, Bendel, A, Ben-Shachar, S, Blumenthal, DT, Blundell, M, Bornhorst, M, Bronsema, A, Cairney, E, Rhode, S, Caspi, S, Chamdin, A, Chiaravalli, S, Constantini, S, Crooks, B, Das, A, Dvir, R, Farah, R, Foulkes, WD, Frenkel, Z, Gallinger, B, Gardner, S, Gass, D, Ghalibafian, M, Gilpin, C, Goldberg, Y, Goudie, C, Hamid, SA, Hampel, H, Hansford, JR, Harlos, C, Hijiya, N, Hsu, S, Kamihara, J, Kebudi, R, Knipstein, J, Koschmann, C, Kratz, C, Larouche, V, Lassaletta, A, Lindhorst, S, Ling, SC, Link, MP, De Mola, RL, Luiten, R, Lurye, M, Maciaszek, JL, MagimairajanIssai, V, Maher, OM, Massimino, M, McGee, RB, Mushtaq, N, Mason, G, Newmark, M, Nicholas, G, Nichols, KE, Nicolaides, T, Opocher, E, Osborn, M, Oshrine, B, Pearlman, R, Pettee, D, Rapp, J, Rashid, M, Reddy, A, Reichman, L, Remke, M, Robbins, G, Roy, S, Sabel, M, Samuel, D, Scheers, I, Schneider, KW, Sen, S, Stearns, D, Sumerauer, D, Swallow, C, Taylor, L, Thomas, G, Toledano, H, Tomboc, P, Van Damme, A, Winer, I, Yalon, M, Yen, LY, Zapotocky, M, Zelcer, S, Ziegler, DS, Zimmermann, S, Hawkins, C, Malkin, D, Bouffet, E, Villani, A, and Tabori, U
Abstract: PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
Published: 2021

14. Clinical phenotypes and prognostic features of embryonal tumours with multi-layered rosettes: a Rare Brain Tumor Registry study.

Author: Khan, S, Solano-Paez, P, Suwal, T, Lu, M, Al-Karmi, S, Ho, B, Mumal, I, Shago, M, Hoffman, LM, Dodgshun, A, Nobusawa, S, Tabori, U, Bartels, U, Ziegler, DS, Hansford, JR, Ramaswamy, V, Hawkins, C, Dufour, C, André, N, Bouffet, E, Huang, A, Rare Brain Tumor Registry, Khan, S, Solano-Paez, P, Suwal, T, Lu, M, Al-Karmi, S, Ho, B, Mumal, I, Shago, M, Hoffman, LM, Dodgshun, A, Nobusawa, S, Tabori, U, Bartels, U, Ziegler, DS, Hansford, JR, Ramaswamy, V, Hawkins, C, Dufour, C, André, N, Bouffet, E, Huang, A, and Rare Brain Tumor Registry
Abstract: BACKGROUND: Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease. METHODS: Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors. FINDINGS: 159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18-36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 [73%] of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47-68) at 6 months and 31% (21-42) at 2 years; overall survival was 29% (20-38) at 2 years an
Published: 2021

15. 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

16. HGG-20. DIAGNOSTIC AND BIOLOGICAL ROLE OF METHYLATION PATTERNS IN REPLICATION REPAIR DEFICIENT HIGH GRADE GLIOMAS

Author: Dodgshun, A, Fukuoka, K, Edwards, M, Bianchi, V, Sexton-Oates, A, Larouche, V, Magimairajan, V, Lindhorst, S, Yalon, M, Mason, G, Crooks, B, Constantini, S, Massimino, M, Chiaravalli, S, Ramdas, J, Mason, W, Shamvil, A, Farah, R, Van Damme, A, Opocher, E, Hamid, SA, Ziegler, D, Samuel, D, Cole, KA, Tomboc, P, Stearns, D, Thomas, G, Lossos, A, Sullivan, M, Hansford, JR, Jones, D, Mackay, A, Jones, C, Ramaswamy, V, Hawkins, C, Bouffet, E, Tabori, U, Dodgshun, A, Fukuoka, K, Edwards, M, Bianchi, V, Sexton-Oates, A, Larouche, V, Magimairajan, V, Lindhorst, S, Yalon, M, Mason, G, Crooks, B, Constantini, S, Massimino, M, Chiaravalli, S, Ramdas, J, Mason, W, Shamvil, A, Farah, R, Van Damme, A, Opocher, E, Hamid, SA, Ziegler, D, Samuel, D, Cole, KA, Tomboc, P, Stearns, D, Thomas, G, Lossos, A, Sullivan, M, Hansford, JR, Jones, D, Mackay, A, Jones, C, Ramaswamy, V, Hawkins, C, Bouffet, E, and Tabori, U
Abstract: Replication repair deficiency (RRD) is an important driving mechanism of pediatric high grade glioma (pHGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although pHGG present specific patterns of DNA methylation corresponding to driving oncogenic processes, methylation patterns have not been well studied in RRD tumors. We analyzed 52 RRD pHGG using either 450k or 850k methylation arrays. These arrays were compared with 234 PHGG driven by other genetic or epigenetic mechanisms and 10 additional pHGG samples known to be hypermutant. RRD pHGG displayed a methylation pattern corresponding to specific secondary mutations such as IDH1 and H3K27M. Strikingly, RRD pHGG lacking these known secondary mutations largely clustered together with a poorly described group previously labelled Wild type-C. Most of the hypermutant tumors clustered in a similar location suggesting undiagnosed RRD may be a driving force for tumors clustering in this location. Analysis of methylation patterns revealed that RRD pHGG displayed a unique CpG Island Demethylator Phenotype in contrast to the Methylator Phenotype described in other cancers. This effect was most concentrated at gene promotors. Prominent demethylation was observed in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism and cellular organization. These data suggest that methylation profiles may provide diagnostic information for the detection of RRD pHGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide novel impact of hypermutation and RRD on the cancer epigenome.
Published: 2020

17. Multilineage hematopoietic engraftment after allogeneic peripheral blood stem cell transplantation without conditioning in SCID patients

Author: Bielorai, B, Trakhtenbrot, L, Amariglio, N, Rothman, R, Tabori, U, Dallal, I, Golan, H, Neumann, Y, Reichart, M, Kaplinsky, C, Rechavi, G, and Toren, A
Published: 2004
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18. Erratum: A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases (S0092867418301156 (2018) 172(5) (1050–1062.e14) (S0092867418301156) (10.1016/j.cell.2018.01.038))

Author: Garzia L., Kijima N., Morrissy A. S., De Antonellis P., Guerreiro-Stucklin A., Holgado B. L., Wu X., Wang X., Parsons M., Zayne K., Manno A., Kuzan-Fischer C., Nor C., Donovan L. K., Liu J., Qin L., Garancher A., Liu K. -W., Mansouri S., Luu B., Thompson Y. Y., Ramaswamy V., Peacock J., Farooq H., Skowron P., Shih D. J. H., Li A., Ensan S., Robbins C. S., Cybulsky M., Mitra S., Ma Y., Moore R., Mungall A., Cho Y. -J., Weiss W. A., Chan J. A., Hawkins C. E., Massimino M., Jabado N., Zapotocky M., Sumerauer D., Bouffet E., Dirks P., Tabori U., Sorensen P. H. B., Brastianos P. K., Aldape K., Jones S. J. M., Marra M. A., Woodgett J. R., Wechsler-Reya R. J., Fults D. W., Taylor M. D., Garzia, L., Kijima, N., Morrissy, A. S., De Antonellis, P., Guerreiro-Stucklin, A., Holgado, B. L., Wu, X., Wang, X., Parsons, M., Zayne, K., Manno, A., Kuzan-Fischer, C., Nor, C., Donovan, L. K., Liu, J., Qin, L., Garancher, A., Liu, K. -W., Mansouri, S., Luu, B., Thompson, Y. Y., Ramaswamy, V., Peacock, J., Farooq, H., Skowron, P., Shih, D. J. H., Li, A., Ensan, S., Robbins, C. S., Cybulsky, M., Mitra, S., Ma, Y., Moore, R., Mungall, A., Cho, Y. -J., Weiss, W. A., Chan, J. A., Hawkins, C. E., Massimino, M., Jabado, N., Zapotocky, M., Sumerauer, D., Bouffet, E., Dirks, P., Tabori, U., Sorensen, P. H. B., Brastianos, P. K., Aldape, K., Jones, S. J. M., Marra, M. A., Woodgett, J. R., Wechsler-Reya, R. J., Fults, D. W., and Taylor, M. D.
Abstract: (Cell 172, 1050–1062; February 22, 2018) It has come to our attention that in preparing the final version of the manuscript, we made a mistake in the legend for Figure 6. The figure includes 4 major panels labeled A, B, C and D, and we inadvertently included descriptions for panels A, B, C, D, and E. The information in the Figure 6E legend describes panel 6D and should have been labeled as such, and the text labeled 6D should have been deleted. The error has been corrected online, and we apologize for any confusion we may have caused.
Published: 2018

19. NASPGHAN Annual Meeting Abstracts

Author: UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Durno, C, Ercan, A, Aronson, M, Villani, A, Bouffet, E, Erdman, S, Scheers, Isabelle, Bronsema, A, Tabori, U, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Durno, C, Ercan, A, Aronson, M, Villani, A, Bouffet, E, Erdman, S, Scheers, Isabelle, Bronsema, A, and Tabori, U
Abstract: Background: Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome causing intestinal polyposis and a high risk of early onset gastrointestinal, brain, and hematological cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. Aim: Our aim was to determine if surveillance affects outcome. The primary outcome measure was overall survival. The secondary outcome measure was detection of new cancers. Methods: Patients referred to the International Replication Repair Consortium undergo genetic testing to confirm CMMRD. All individuals were diagnosed with CMMRD through diagnostic criteria by the genetic counsellor at the consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging studies was recommended and initiated internationally on Jan 1, 2012. Protocol included upper endoscopy, colonoscopy, video capsule endoscopy and/or magnetic resonance enterography, and brain MRI. Whole-body MRI was recommended as of Jan 1, 2018. Surveillance questionnaire was sent to the responsible physician with diagnostic fields completed by the registry coordinator as a double check of reliability. Survival analyses was completed using an as-treated approach. Results: Cancer and surveillance data was collected from 64 (50%) of 127 CMMRD individuals registered in the Consortium from 41 countries. There were 114 tumours reported in 60 patients including 55 brain, 28 gastrointestinal (GI), 17 hematological and 14 other malignancies. Surveillance data was available on 110 cancers; 16 were incidental cancers, 68 were symptomatic and 26 were discovered through surveillance. Surveillance identified 13 GI cancers, 11 brain, and 2 hematological malignancies. The gastrointestinal cancers included 5 colorectal, 7 small bowel, and one gastric. Four patients were unaffected. Five-year overall survival was 95% for tumors discovered by surveillance, comp
Published: 2019

20. Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Author: Guerreiro Stucklin, AS, Ryall, S, Fukuoka, K, Zapotocky, M, Lassaletta, A, Li, C, Bridge, T, Kim, B, Arnoldo, A, Kowalski, PE, Zhong, Y, Johnson, M, Ramani, AK, Siddaway, R, Nobre, LF, de Antonellis, P, Dunham, C, Cheng, S, Boué, DR, Finlay, JL, Coven, SL, de Prada, I, Perez-Somarriba, M, Faria, CC, Grotzer, MA, Rushing, E, Sumerauer, D, Zamecnik, J, Krskova, L, Garcia Ariza, M, Cruz, O, Morales La Madrid, A, Solano, P, Terashima, K, Nakano, Y, Ichimura, K, Nagane, M, Sakamoto, H, Gil-da-Costa, MJ, Silva, R, Johnston, DL, Michaud, J, Wilson, B, van Landeghem, FKH, Oviedo, A, McNeely, PD, Crooks, B, Fried, I, Zhukova, N, Hansford, JR, Nageswararao, A, Garzia, L, Shago, M, Brudno, M, Irwin, MS, Bartels, U, Ramaswamy, V, Bouffet, E, Taylor, MD, Tabori, U, Hawkins, C, Guerreiro Stucklin, AS, Ryall, S, Fukuoka, K, Zapotocky, M, Lassaletta, A, Li, C, Bridge, T, Kim, B, Arnoldo, A, Kowalski, PE, Zhong, Y, Johnson, M, Ramani, AK, Siddaway, R, Nobre, LF, de Antonellis, P, Dunham, C, Cheng, S, Boué, DR, Finlay, JL, Coven, SL, de Prada, I, Perez-Somarriba, M, Faria, CC, Grotzer, MA, Rushing, E, Sumerauer, D, Zamecnik, J, Krskova, L, Garcia Ariza, M, Cruz, O, Morales La Madrid, A, Solano, P, Terashima, K, Nakano, Y, Ichimura, K, Nagane, M, Sakamoto, H, Gil-da-Costa, MJ, Silva, R, Johnston, DL, Michaud, J, Wilson, B, van Landeghem, FKH, Oviedo, A, McNeely, PD, Crooks, B, Fried, I, Zhukova, N, Hansford, JR, Nageswararao, A, Garzia, L, Shago, M, Brudno, M, Irwin, MS, Bartels, U, Ramaswamy, V, Bouffet, E, Taylor, MD, Tabori, U, and Hawkins, C
Abstract: Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.
Published: 2019

21. Detection of RAG mutations and prenatal diagnosis in families presenting with either T–B– severe combined immunodeficiency or Omennʼs syndrome

Author: Tabori, U, Mark, Z, Amariglio, N, Etzioni, A, Golan, H, Biloray, B, Toren, A, Rechavi, G, and Dalal, I
Published: 2004

22. Repeat Irradiation for Children with Supratentorial High-Grade Glioma

Author: Oliveira, C., primary, Laperriere, N.J., additional, Bouffet, E., additional, Hawkins, C., additional, Ramaswamy, V., additional, Yee, R., additional, Bartels, U., additional, Tabori, U., additional, Huang, A., additional, Millar, B.A., additional, Crooks, B., additional, Bowes, L., additional, Zelcer, S., additional, and Derek, T., additional
Published: 2019
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23. A275 COMPREHENSIVE GENOMIC ANALYSIS RESULT IN EARLY DETECTION AND IMPLEMENTATION OF IMMUNE CHECK POINT THERAPY TO IMPROVE SURVIVAL FOR PATIENTS WITH INHERITED REPLICATION REPAIR DEFICIENCY GASTROINTESTINAL CANCERS:REPORT FROM THE INTERNATIONAL REPLICATION REPAIR CONSORTIUM

Author: Durno, C, primary, Aronson, M, additional, Edwards, M, additional, Boufett, E, additional, and Tabori, U, additional
Published: 2019
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24. Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 2 and Related Disorders

Author: Evans DGR, Salvador-Hernandez H, Chang VY, Erez A, Voss SD, Druker H, Scott HS, and Tabori U
Subjects: otorhinolaryngologic diseases
Abstract: The neurofibromatoses consist of at least three autosomal-dominant inherited disorders: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. For over 80 years, these conditions were inextricably tied together under generalized neurofibromatosis. In 1987, the localization of NF1 to chromosome 17q and NF2 (bilateral vestibular schwannoma) to 22q led to a consensus conference at Bethesda, Maryland. The two main neurofibromatoses, NF1 and NF2, were formally separated. More recently, the SMARCB1 and LZTR1 genes on 22q have been confirmed as causing a subset of schwannomatosis. The last 26 years have seen a great improvement in understanding of the clinical and molecular features of these conditions as well as insights into management. Childhood presentation of NF2 (often with meningioma) in particular predicts a severe multitumor disease course. Malignancy is rare in NF2, particularly in childhood; however, there are substantial risks from benign and low-grade central nervous system (CNS) tumors necessitating MRI surveillance to optimize management. At least annual brain MRI, including high-resolution images through the auditory meatus, and a clinical examination and auditory assessment are required from diagnosis or from around 10 to 12 years of age if asymptomatic. Spinal imaging at baseline and every 2 to 3 years is advised with more frequent imaging if warranted on the basis of sites of tumor involvement. The malignancy risk in schwannomatosis is not well defined but may include an increased risk of malignant peripheral nerve sheath tumor in SMARCB1 Imaging protocols are also proposed for SMARCB1 and LZTR1 schwannomatosis and SMARCE1-related meningioma predisposition. Clin Cancer Res; 23(12); e54-e61. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
Published: 2017

25. Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood

Author: Achatz MI, Porter CC, Brugières L, Druker H, Frebourg T, Foulkes WD, Kratz CP, Kuiper RP, Hansford JR, Salvador-Hernandez H, Nathanson KL, Kohlmann WK, Doros L, Onel K, Schneider KW, Scollon SR, Tabori U, Tomlinson GE, Evans DGR, and Plon SE
Abstract: Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (APC and MUTYH), juvenile polyposis coli (BMPR1A and SMAD4), Peutz-Jeghers Syndrome (STK11/LKB1), and PTEN hamartoma tumor syndrome (PHTS; PTEN), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series. Clin Cancer Res; 23(13); e107-e14. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
Published: 2017

26. Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1

Author: Evans DGR, Salvador-Hernandez H, Chang VY, Erez A, Voss SD, Schneider KW, Scott HS, Plon SE, and Tabori U
Abstract: Although the neurofibromatoses consist of at least three autosomal dominantly inherited disorders, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, NF1 represents a multisystem pleiotropic condition very different from the other two. NF1 is a genetic syndrome first manifesting in childhood; affecting multiple organs, childhood development, and neurocognitive status; and presenting the clinician with often complex management decisions that require a multidisciplinary approach. Molecular genetic testing (see article for detailed discussion) is recommended to confirm NF1, particularly in children fulfilling only pigmentary features of the diagnostic criteria. Although cancer risk is not the major issue facing an individual with NF1 during childhood, the condition causes significantly increased malignancy risks compared with the general population. Specifically, NF1 is associated with highly elevated risks of juvenile myelomonocytic leukemia, rhabdomyosarcoma, and malignant peripheral nerve sheath tumor as well as substantial risks of noninvasive pilocytic astrocytoma, particularly optic pathway glioma (OPG), which represent a major management issue. Until 8 years of age, clinical assessment for OPG is advised every 6 to 12 months, but routine MRI assessment is not currently advised in asymptomatic individuals with NF1 and no signs of clinical visual pathway disturbance. Routine surveillance for other malignancies is not recommended, but clinicians and parents should be aware of the small risks (
Published: 2017

27. Multiple Brain Developmental Venous Anomalies as a Marker for Constitutional Mismatch Repair Deficiency Syndrome

Author: Shiran, S.I., primary, Ben-Sira, L., additional, Elhasid, R., additional, Roth, J., additional, Tabori, U., additional, Yalon, M., additional, Constantini, S., additional, and Dvir, R., additional
Published: 2018
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28. 13 The genetic landscape of pediatric low-grade gliomas: Incidence, prognosis and response to therapy - a SickKids pLGG Task Force update

Author: Ryall, S, primary, Zapotocky, M, additional, Fukuoka, K, additional, Guerreiro-Stucklin, A, additional, Bennett, J, additional, Arnoldo, A, additional, Kowalski, P, additional, Johnson, M, additional, Lassaletta, A, additional, Bouffet, E, additional, Bartels, U, additional, Ellison, D, additional, Tabori, U, additional, and Hawkins, C, additional
Published: 2018
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29. The clinical and biological dilemma of preleukemia presenting as aplastic anemia with chromosomal translocation t(4;11)

Author: Tabori, U, Burstein, Y, Dvir, R, Rechavi, G, and Toren, A
Published: 2001
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30. Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood

Author: Achatz, M.I., Porter, C.C., Brugieres, L., Druker, H., Frebourg, T., Foulkes, W.D., Kratz, C.P., Kuiper, R.P., Hansford, J.R., Hernandez, H.S., Nathanson, K.L., Kohlmann, W.K., Doros, L., Onel, K., Schneider, K.W, Scollon, S.R., Tabori, U., Tomlinson, G.E., Evans, D.G., Plon, S.E., Achatz, M.I., Porter, C.C., Brugieres, L., Druker, H., Frebourg, T., Foulkes, W.D., Kratz, C.P., Kuiper, R.P., Hansford, J.R., Hernandez, H.S., Nathanson, K.L., Kohlmann, W.K., Doros, L., Onel, K., Schneider, K.W, Scollon, S.R., Tabori, U., Tomlinson, G.E., Evans, D.G., and Plon, S.E.
Abstract: Item does not contain fulltext, Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (APC and MUTYH), juvenile polyposis coli (BMPR1A and SMAD4), Peutz-Jeghers Syndrome (STK11/LKB1), and PTEN hamartoma tumor syndrome (PHTS; PTEN), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series. Clin Cancer Res; 23(13); e107-e14. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
Published: 2017

31. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants

Author: Pajtler, KW, Mack, SC, Ramaswamy, V, Smith, CA, Witt, H, Smith, A, Hansford, JR, von Hoff, K, Wright, KD, Hwang, E, Frappaz, D, Kanemura, Y, Massimino, M, Faure-Conter, C, Modena, P, Tabori, U, Warren, KE, Holland, EC, Ichimura, K, Giangaspero, F, Castel, D, von Deimling, A, Kool, M, Dirks, PB, Grundy, RG, Foreman, NK, Gajjar, A, Korshunov, A, Finlay, J, Gilbertson, RJ, Ellison, DW, Aldape, KD, Merchant, TE, Bouffet, E, Pfister, SM, Taylor, MD, Pajtler, KW, Mack, SC, Ramaswamy, V, Smith, CA, Witt, H, Smith, A, Hansford, JR, von Hoff, K, Wright, KD, Hwang, E, Frappaz, D, Kanemura, Y, Massimino, M, Faure-Conter, C, Modena, P, Tabori, U, Warren, KE, Holland, EC, Ichimura, K, Giangaspero, F, Castel, D, von Deimling, A, Kool, M, Dirks, PB, Grundy, RG, Foreman, NK, Gajjar, A, Korshunov, A, Finlay, J, Gilbertson, RJ, Ellison, DW, Aldape, KD, Merchant, TE, Bouffet, E, Pfister, SM, and Taylor, MD
Abstract: Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth.
Published: 2017

32. D2.1 Volumetric assessment of tumour size changes in paediatric low grade gliomas: comparison with linear measurements and implications for determining response to therapy

Author: D’Arco, F, primary, O’Hare, P, additional, Dashti, F, additional, Lassaletta, A, additional, Loka, T, additional, Bouffet, E, additional, Tabori, U, additional, Thust, S, additional, Messalli, G, additional, Hales, P, additional, and Laughlin, S, additional
Published: 2017
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33. 83 Volumetric assessment of tumour size changes in paediatric low grade gliomas: comparison with linear measurements and implications for determining response to therapy

Author: D’Arco, F, primary, O’Hare, P, additional, Dashti, F, additional, Lassaletta, A, additional, Loka, T, additional, Bouffet, E, additional, Tabori, U, additional, Thust, S, additional, Messalli, G, additional, Hales, P, additional, and Laughlin, S, additional
Published: 2017
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34. Integrated molecular signatures of TERT promoter deregulation predict disease outcomes in non-muscle invasive bladder cancer

Author: Leão, R., primary, Lee, D., additional, Figueiredo, A., additional, Komosa, M., additional, Zhang, C., additional, Apolónio, J., additional, Nunes, N.M., additional, Hermanns, T., additional, Wild, P., additional, Poyet, C., additional, Hamilton, R.J., additional, Castelo-Branco, P., additional, and Tabori, U., additional
Published: 2017
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35. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: A retrospective integrated clinical and molecular analysis

Author: Thompson, E.M. (Eric M.), Hielscher, T. (Thomas), Bouffet, E. (Eric), Remke, M. (Marc), Luu, P. (Phan), Gururangan, S. (Sridharan), McLendon, R.E. (Roger E.), Bigner, D.D. (Darell), Lipp, E.S. (Eric S.), Perreault, S. (Sebastien), Cho, Y.-J. (Yoon-Jae), Grant, G. (Gerald), Kim, S.-K. (Seung-Ki), Lee, J.Y. (Ji Yeoun), Rao, A.A.N. (Amulya A. Nageswara), Giannini, C. (Caterina), Li, K.K.W. (Kay Ka Wai), Ng, H.-K. (Ho-Keung), Yao, Y. (Yu), Kumabe, T. (Toshihiro), Tominaga, T. (Teiji), Grajkowska, W.A. (Wieslawa), Perek-Polnik, M. (Marta), Low, D.C.Y. (David C.Y.), Seow, W.T. (Wan Tew), Chang, K.T.E. (Kenneth T.E.), Mora, J. (Jaume), Pollack, A. (Aaron), Hamilton, R.L. (Ronald L.), Leary, S. (Sarah), Moore, A.S. (Andrew S.), Ingram, W.J. (Wendy J.), Hallahan, A.R. (Andrew R.), Jouvet, A. (Anne), Fèvre-Montange, M. (Michelle), Vasiljevic, A. (Alexandre), Faure-Conter, C. (Cecile), Shofuda, T. (Tomoko), Kagawa, N. (Naoki), Hashimoto, N. (Naoya), Jabado, N. (Nada), Weil, A.G. (Alexander G.), Gayden, T. (Tenzin), Wataya, T. (Takafumi), Shalaby, T. (Tarek), Grotzer, M. (Michael), Zitterbart, K. (Karel), Sterba, J., Kren, L. (Leos), Hortobágyi, T. (Tibor), Klekner, A. (Almos), Bognár, L. (László), Pócza, T. (Tímea), Hauser, P. (Peter), Schüller, U. (Ulrich), Jung, S. (Shin), Jang, W.-Y. (Woo-Youl), French, P.J. (Pim), Kros, J.M. (Johan), Veelen-Vincent, M.L.C. (Marie-Lise) van, Massimi, L. (Luca), Leonard, J.R. (Jeffrey), Rubin, J.B. (Joshua), Vibhakar, R. (Rajeev), Chambless, L.B. (Lola B.), Cooper, M.K. (Michael), Thompson, R.C. (Reid), Faria, R. (Rui), Carvalho, A. (Alice), Nunes, S. (Sofia), Pimentel, J., Fan, X. (Xing), Muraszko, K.M. (Karin), López-Aguilar, E. (Enrique), Lyden, D. (David), Garzia, L. (Livia), Shih, D.J.H. (David J.), Kijima, N. (Noriyuki), Schneider, C. (Christian), Adamski, J. (Jennifer), Northcott, P.A. (Paul A.), Kool, M. (Marcel), Jones, D. (David), Chan, J.A. (Jennifer A.), Nikolic, A. (Ana), Garre, M.L. (Maria Luisa), Van Meir, E.G. (Erwin G.), Osuka, S. (Satoru), Olson, J.J. (Jeffrey J.), Jahangiri, A. (Arman), Castro, B.A. (Brandyn A.), Gupta, N. (Nalin), Weiss, W.A. (William A.), Moxon-Emre, I. (Iska), Mabbott, D.J. (Donald J.), Lassaletta, A. (Alvaro), Hawkins, C.E. (Cynthia), Tabori, U. (Uri), Drake, J. (James), Kulkarni, A. (Abhaya), Dirks, M. (Maaike), Rutka, J.T. (James), Korshunov, A. (Andrey), Pfister, S.M. (Stefan), Packer, R.J. (Roger J.), Ramaswamy, E.A., Taylor, M.D. (Michael), Thompson, E.M. (Eric M.), Hielscher, T. (Thomas), Bouffet, E. (Eric), Remke, M. (Marc), Luu, P. (Phan), Gururangan, S. (Sridharan), McLendon, R.E. (Roger E.), Bigner, D.D. (Darell), Lipp, E.S. (Eric S.), Perreault, S. (Sebastien), Cho, Y.-J. (Yoon-Jae), Grant, G. (Gerald), Kim, S.-K. (Seung-Ki), Lee, J.Y. (Ji Yeoun), Rao, A.A.N. (Amulya A. Nageswara), Giannini, C. (Caterina), Li, K.K.W. (Kay Ka Wai), Ng, H.-K. (Ho-Keung), Yao, Y. (Yu), Kumabe, T. (Toshihiro), Tominaga, T. (Teiji), Grajkowska, W.A. (Wieslawa), Perek-Polnik, M. (Marta), Low, D.C.Y. (David C.Y.), Seow, W.T. (Wan Tew), Chang, K.T.E. (Kenneth T.E.), Mora, J. (Jaume), Pollack, A. (Aaron), Hamilton, R.L. (Ronald L.), Leary, S. (Sarah), Moore, A.S. (Andrew S.), Ingram, W.J. (Wendy J.), Hallahan, A.R. (Andrew R.), Jouvet, A. (Anne), Fèvre-Montange, M. (Michelle), Vasiljevic, A. (Alexandre), Faure-Conter, C. (Cecile), Shofuda, T. (Tomoko), Kagawa, N. (Naoki), Hashimoto, N. (Naoya), Jabado, N. (Nada), Weil, A.G. (Alexander G.), Gayden, T. (Tenzin), Wataya, T. (Takafumi), Shalaby, T. (Tarek), Grotzer, M. (Michael), Zitterbart, K. (Karel), Sterba, J., Kren, L. (Leos), Hortobágyi, T. (Tibor), Klekner, A. (Almos), Bognár, L. (László), Pócza, T. (Tímea), Hauser, P. (Peter), Schüller, U. (Ulrich), Jung, S. (Shin), Jang, W.-Y. (Woo-Youl), French, P.J. (Pim), Kros, J.M. (Johan), Veelen-Vincent, M.L.C. (Marie-Lise) van, Massimi, L. (Luca), Leonard, J.R. (Jeffrey), Rubin, J.B. (Joshua), Vibhakar, R. (Rajeev), Chambless, L.B. (Lola B.), Cooper, M.K. (Michael), Thompson, R.C. (Reid), Faria, R. (Rui), Carvalho, A. (Alice), Nunes, S. (Sofia), Pimentel, J., Fan, X. (Xing), Muraszko, K.M. (Karin), López-Aguilar, E. (Enrique), Lyden, D. (David), Garzia, L. (Livia), Shih, D.J.H. (David J.), Kijima, N. (Noriyuki), Schneider, C. (Christian), Adamski, J. (Jennifer), Northcott, P.A. (Paul A.), Kool, M. (Marcel), Jones, D. (David), Chan, J.A. (Jennifer A.), Nikolic, A. (Ana), Garre, M.L. (Maria Luisa), Van Meir, E.G. (Erwin G.), Osuka, S. (Satoru), Olson, J.J. (Jeffrey J.), Jahangiri, A. (Arman), Castro, B.A. (Brandyn A.), Gupta, N. (Nalin), Weiss, W.A. (William A.), Moxon-Emre, I. (Iska), Mabbott, D.J. (Donald J.), Lassaletta, A. (Alvaro), Hawkins, C.E. (Cynthia), Tabori, U. (Uri), Drake, J. (James), Kulkarni, A. (Abhaya), Dirks, M. (Maaike), Rutka, J.T. (James), Korshunov, A. (Andrey), Pfister, S.M. (Stefan), Packer, R.J. (Roger J.), Ramaswamy, E.A., and Taylor, M.D. (Michael)
Abstract: 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 (<1·5 cm2 tumour remaining), or sub-total resection (≥1·5 cm2 tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >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 mod
Published: 2016
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36. Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors.

Author: Torchia, J, Golbourn, B, Feng, S, Ho, KC, Sin-Chan, P, Vasiljevic, A, Norman, JD, Guilhamon, P, Garzia, L, Agamez, NR, Lu, M, Chan, TS, Picard, D, de Antonellis, P, Khuong-Quang, D-A, Planello, AC, Zeller, C, Barsyte-Lovejoy, D, Lafay-Cousin, L, Letourneau, L, Bourgey, M, Yu, M, Gendoo, DMA, Dzamba, M, Barszczyk, M, Medina, T, Riemenschneider, AN, Morrissy, AS, Ra, Y-S, Ramaswamy, V, Remke, M, Dunham, CP, Yip, S, Ng, H-K, Lu, J-Q, Mehta, V, Albrecht, S, Pimentel, J, Chan, JA, Somers, GR, Faria, CC, Roque, L, Fouladi, M, Hoffman, LM, Moore, AS, Wang, Y, Choi, SA, Hansford, JR, Catchpoole, D, Birks, DK, Foreman, NK, Strother, D, Klekner, A, Bognár, L, Garami, M, Hauser, P, Hortobágyi, T, Wilson, B, Hukin, J, Carret, A-S, Van Meter, TE, Hwang, EI, Gajjar, A, Chiou, S-H, Nakamura, H, Toledano, H, Fried, I, Fults, D, Wataya, T, Fryer, C, Eisenstat, DD, Scheinemann, K, Fleming, AJ, Johnston, DL, Michaud, J, Zelcer, S, Hammond, R, Afzal, S, Ramsay, DA, Sirachainan, N, Hongeng, S, Larbcharoensub, N, Grundy, RG, Lulla, RR, Fangusaro, JR, Druker, H, Bartels, U, Grant, R, Malkin, D, McGlade, CJ, Nicolaides, T, Tihan, T, Phillips, J, Majewski, J, Montpetit, A, Bourque, G, Bader, GD, Reddy, AT, Gillespie, GY, Warmuth-Metz, M, Rutkowski, S, Tabori, U, Lupien, M, Brudno, M, Schüller, U, Pietsch, T, Judkins, AR, Hawkins, CE, Bouffet, E, Kim, S-K, Dirks, PB, Taylor, MD, Erdreich-Epstein, A, Arrowsmith, CH, De Carvalho, DD, Rutka, JT, Jabado, N, Huang, A, Torchia, J, Golbourn, B, Feng, S, Ho, KC, Sin-Chan, P, Vasiljevic, A, Norman, JD, Guilhamon, P, Garzia, L, Agamez, NR, Lu, M, Chan, TS, Picard, D, de Antonellis, P, Khuong-Quang, D-A, Planello, AC, Zeller, C, Barsyte-Lovejoy, D, Lafay-Cousin, L, Letourneau, L, Bourgey, M, Yu, M, Gendoo, DMA, Dzamba, M, Barszczyk, M, Medina, T, Riemenschneider, AN, Morrissy, AS, Ra, Y-S, Ramaswamy, V, Remke, M, Dunham, CP, Yip, S, Ng, H-K, Lu, J-Q, Mehta, V, Albrecht, S, Pimentel, J, Chan, JA, Somers, GR, Faria, CC, Roque, L, Fouladi, M, Hoffman, LM, Moore, AS, Wang, Y, Choi, SA, Hansford, JR, Catchpoole, D, Birks, DK, Foreman, NK, Strother, D, Klekner, A, Bognár, L, Garami, M, Hauser, P, Hortobágyi, T, Wilson, B, Hukin, J, Carret, A-S, Van Meter, TE, Hwang, EI, Gajjar, A, Chiou, S-H, Nakamura, H, Toledano, H, Fried, I, Fults, D, Wataya, T, Fryer, C, Eisenstat, DD, Scheinemann, K, Fleming, AJ, Johnston, DL, Michaud, J, Zelcer, S, Hammond, R, Afzal, S, Ramsay, DA, Sirachainan, N, Hongeng, S, Larbcharoensub, N, Grundy, RG, Lulla, RR, Fangusaro, JR, Druker, H, Bartels, U, Grant, R, Malkin, D, McGlade, CJ, Nicolaides, T, Tihan, T, Phillips, J, Majewski, J, Montpetit, A, Bourque, G, Bader, GD, Reddy, AT, Gillespie, GY, Warmuth-Metz, M, Rutkowski, S, Tabori, U, Lupien, M, Brudno, M, Schüller, U, Pietsch, T, Judkins, AR, Hawkins, CE, Bouffet, E, Kim, S-K, Dirks, PB, Taylor, MD, Erdreich-Epstein, A, Arrowsmith, CH, De Carvalho, DD, Rutka, JT, Jabado, N, and Huang, A
Abstract: We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.
Published: 2016

37. 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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38. CNS tumours The first study of dabrafenib in pediatric patients with BRAF V600–mutant relapsed or refractory low-grade gliomas

Author: Kieran, M.W., primary, Bouffet, E., additional, Tabori, U., additional, Broniscer, A., additional, Cohen, K., additional, Hansford, J., additional, Geoerger, B., additional, Hingorani, P., additional, Dunkel, I., additional, Russo, M., additional, Tseng, L., additional, Liu, Q., additional, Nebot, N., additional, Whitlock, J., additional, and Hargrave, D., additional
Published: 2016
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39. Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age

Author: Fontebasso, AM, Shirinian, M, Khuong-Quang, D-A, Bechet, D, Gayden, T, Kool, M, De Jay, N, Jacob, K, Gerges, N, Hutter, B, Seker-Cin, H, Witt, H, Montpetit, A, Brunet, S, Lepage, P, Bourret, G, Klekner, A, Bognar, L, Hauser, P, Garami, M, Farmer, J-P, Montes, J-L, Atkinson, J, Lambert, S, Kwan, T, Korshunov, A, Tabori, U, Collins, VP, Albrecht, S, Faury, D, Pfister, SM, Paulus, W, Hasselblatt, M, Jones, DTW, Jabado, N, Fontebasso, AM, Shirinian, M, Khuong-Quang, D-A, Bechet, D, Gayden, T, Kool, M, De Jay, N, Jacob, K, Gerges, N, Hutter, B, Seker-Cin, H, Witt, H, Montpetit, A, Brunet, S, Lepage, P, Bourret, G, Klekner, A, Bognar, L, Hauser, P, Garami, M, Farmer, J-P, Montes, J-L, Atkinson, J, Lambert, S, Kwan, T, Korshunov, A, Tabori, U, Collins, VP, Albrecht, S, Faury, D, Pfister, SM, Paulus, W, Hasselblatt, M, Jones, DTW, and Jabado, N
Abstract: Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.
Published: 2015

40. Concomitant <italic>IDH</italic> wild‐type glioblastoma and <italic>IDH1</italic>‐mutant anaplastic astrocytoma in a patient with constitutional mismatch repair deficiency syndrome.

Author: Galuppini, F., Opocher, E., Tabori, U., Mammi, I., Edwards, M., Campbell, B., Kelly, J., Viel, A., Quaia, M., Rivieri, F., D'Avella, D., Arcella, A., Giangaspero, F., Fassan, M., and Gardiman, M. P.
Subjects: GLIOBLASTOMA multiforme, ISOCITRATE dehydrogenase, ASTROCYTOMAS, HEADACHE, CENTRAL nervous system diseases
Abstract: The article presents a study regarding the concomitant wild-type glioblastoma and isocitrate dehydrogenase (IDH)-mutant anaplastic astrocytoma in a patient with constitutional mismatch repair deficiency syndrome (CMMRD). It cites the case of a 12-year-old girl who was presented with a history of progressive headache and balance disturbances. It also mentions the different laboratory examinations undergone by the patient that lead to her diagnosis.
Published: 2018
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41. Aurora kinase B inhibition as a potential therapy in pediatric glioblastoma including diffuse-intrinsic pontine glioma

Author: Buczkowicz P, Zarghooni M, Bartels U, A, Morrison, Bouffet E, Tabori U, A, Huang, and Hawkins C
Published: 2011
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42. 2503 Hypermethylation of a specific area in the TERT promoter defines a novel risk stratification biomarker for prostate cancer patients submitted to radical prostatectomy

Author: Castelo-Branco, P., primary, Leão, R., additional, De Mello, R.A., additional, Lipman, T., additional, Campbell, B., additional, Price, A., additional, Zhang, C., additional, Buerno, S., additional, Gomes, A., additional, Bristow, R.G., additional, Schweiger, M., additional, Hamilton, R., additional, Zlotta, A., additional, Figueiredo, A., additional, Klocker, H., additional, Sueltmann, H., additional, and Tabori, U., additional
Published: 2015
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43. OT-05 * H3.3-K27M IS A NEGATIVE PROGNOSTIC MARKER IN THALAMIC PEDIATRIC GLIOMA

Author: Ryall, S., primary, Buczkowicz, P., additional, Krishnatry, R., additional, Arnoldo, A., additional, Steinbok, P., additional, Tabori, U., additional, and Hawkins, C., additional
Published: 2015
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44. GE-09 * COMBINED HEREDITARY AND SOMATIC MUTATIONS OF REPLICATION ERROR REPAIR GENES RESULT IN RAPID ONSET OF ULTRA-HYPERMUTATED MALIGNANT BRAIN TUMORS IN CHILDREN

Author: Shlien, A., primary, Campbell, B. B., additional, de Borja, R., additional, Alexandrov, L. B., additional, Merino, D. M., additional, Remke, M., additional, Bakry, D., additional, Dirks, P., additional, Huang, A., additional, Grundy, R. G., additional, Durno, C., additional, Aronson, M., additional, Taylor, M. D., additional, Pursell, Z. F., additional, Pearson, C. E., additional, Malkin, D., additional, Bouffet, E., additional, Hawkins, C., additional, Campbell, P. J., additional, and Tabori, U., additional
Published: 2015
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45. LG-03 * RADIATION THERAPY IS ASSOCIATED WITH INCREASED LATE MORTALITY IN LONG-TERM ADULT SURVIVORS OF CHILDHOOD LOW GRADE GLIOMA: A POPULATION BASED STUDY

Author: Krishnatry, R., primary, Zhukova, N., additional, Stucklin, A. G., additional, Pole, J., additional, Mistry, M., additional, Ramaswamy, V., additional, Bartels, U., additional, Huang, A., additional, Laperriere, N., additional, Dirks, P., additional, Zelcer, S., additional, Silva, M., additional, Johnston, D. L., additional, Scheinemann, K., additional, Hawkins, C., additional, Bandopadhayay, P., additional, Kieran, M. W., additional, Manley, P. E., additional, Bouffet, E., additional, and Tabori, U., additional
Published: 2015
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46. LG-01 * BRAF MUTATION AND CDKN2A DELETION DEFINE A CLINICALLY DISTINCT SUBGROUP OF CHILDHOOD SECONDARY HIGH-GRADE GLIOMA

Author: Mistry, M., primary, Zhukova, N., additional, Merico, D., additional, Rakopoulos, P., additional, Krishnatry, R., additional, Shago, M., additional, Stavropoulos, J., additional, Pole, J., additional, Ray, P., additional, Remke, M., additional, Buczkowicz, P., additional, Ramaswamy, V., additional, Shlien, A., additional, Rutka, J., additional, Dirks, P., additional, Taylor, M., additional, Malkin, D., additional, Bouffet, E., additional, Hawkins, C., additional, and Tabori, U., additional
Published: 2015
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47. 422 TERT promoter methylation is a pan-cancer biomarker with prognostic significance in prostate cancer patients

Author: Leão, R.R., primary, Castelo-Branco, P., additional, Lipman, T., additional, Campbell, B., additional, Price, A., additional, Zhang, C., additional, Buerno, S., additional, Gomes, A., additional, Coelho, H., additional, Bristow, R., additional, Schweiger, M., additional, Hamilton, R.J., additional, Zlotta, A.R., additional, Figueiredo, A., additional, Klocker, H., additional, Sueltman, H., additional, and Tabori, U., additional
Published: 2015
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48. Genetic comparison of pediatric diffuse intrinsic pontine gliomas (DIPG) to high and low grade astrocytomas

Author: Hawkins, C., Buczkowicz, P., Bartels, U., Tabori, U., Fried, I., Zarghooni, M., and Bouffet, E.
Published: 2010
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49. Integrated analysis of copy number alteration and RNA expression profile in pediatric diffuse intrinsic pontine glioma (DIPG)

Author: Hawkins C, Zarghooni, M., Buczkowicz P, Bartels U, I, Fried, Tabori U, and Bouffet E
Published: 2010
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50. 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

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