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1. 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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2. 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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3. 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

4. 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

5. Trp53 inactivation leads to earlier phaeochromocytoma formation in pten knockout mice.

Author

Korpershoek E, Kloosterhof NK, Ziel-van der Made A, Korsten H, Oudijk L, Trapman J, Dinjens WN, and de Krijger RR

Subjects
Adrenal Gland Neoplasms enzymology, Adrenal Gland Neoplasms pathology, Adrenal Glands enzymology, Adrenal Glands pathology, Animals, Dopamine beta-Hydroxylase metabolism, Lung Neoplasms enzymology, Lung Neoplasms secondary, Male, Mice, Mice, Knockout, PTEN Phosphohydrolase deficiency, Pheochromocytoma enzymology, Pheochromocytoma pathology, Tumor Suppressor Protein p53 deficiency, Tyrosine 3-Monooxygenase metabolism, Adrenal Gland Neoplasms genetics, Lung Neoplasms genetics, PTEN Phosphohydrolase genetics, Pheochromocytoma genetics, Tumor Suppressor Protein p53 genetics
Abstract

Phaeochromocytomas (PCCs) are benign neuroendocrine tumours of the adrenal medulla. Approximately 10% of PCC patients develop metastases, but this frequency is much higher in specific subtypes of patients. The reliable diagnosis of malignant PCC can only be made after identification of a metastasis. To study the effect of Trp53 inactivation on PCC pathogenesis in Pten KO mice, we investigated the adrenals of a large cohort of mice with conditional monoallelic and biallelic inactivation of Trp53 and Pten. The adrenal weights were determined for all mice, and in a proportion of these mice, immunohistochemistry for tyrosine hydroxylase and dopamine β-hydroxylase was performed on the adrenals and corresponding lungs. Finally, comparative genomic hybridization (CGH) was performed. The histological and immunohistochemical results confirmed that the adrenal tumours were PCCs. Inactivation of one or both alleles of Trp53 resulted in earlier tumour occurrence in the Pten(loxP/loxP) mice as well as in the Pten(loxP/+) mice. In addition, lung metastases were found in up to 67% of mice. The CGH results showed that the most frequent genomic alterations were loss of chromosome 19 (86%) and gain of chromosome 15 (71%). In this study, we have shown that Pten/Trp53 KO mice showed metastatic PCC at high frequency and primary tumours occurred at younger ages in mice with Trp53 inactivation. Therefore, the present model appears to be a suitable model that might allow the preclinical study of new therapeutics for these tumours.

Published
2012
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6. 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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7. The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma.

Author

Bralten LB, Gravendeel AM, Kloosterhof NK, Sacchetti A, Vrijenhoek T, Veltman JA, van den Bent MJ, Kros JM, Hoogenraad CC, Sillevis Smitt PA, and French PJ

Subjects
Cell Movement, Cell Proliferation, DNA Methylation, Glioma mortality, Glioma pathology, Humans, Membrane Proteins physiology, Mutation, Neoplasm Invasiveness, Nerve Tissue Proteins physiology, Nuclear Receptor Coactivator 1 physiology, RNA, Messenger analysis, Brain Neoplasms genetics, Genes, Tumor Suppressor, Glioma genetics, Membrane Proteins genetics, Nerve Tissue Proteins genetics
Abstract

Genomic translocations have been implicated in cancer. In this study, we performed a screen for genetic translocations in gliomas based on exon-level expression profiles. We identified a translocation in the contactin-associated protein-like 2 (CASPR2) gene, encoding a cell adhesion molecule. CASPR2 mRNA was fused to an expressed sequence tag that likely is part of the nuclear receptor coactivator 1 gene. Despite high mRNA expression levels, no CASPR2 fusion protein was detected. In a set of 25 glioblastomas and 22 oligodendrogliomas, mutation analysis identified two additional samples with genetic alterations in the CASPR2 gene and all three identified genetic alterations are likely to reduce CASPR2 protein expression levels. Methylation of the CASPR2 gene was also observed in gliomas and glioma cell lines. CASPR2-overexpressing cells showed decreased proliferation rates, likely because of an increase in apoptosis. Moreover, high CASPR2 mRNA expression level is positively correlated with survival and is an independent prognostic factor. These results indicate that CASPR2 acts as a tumor suppressor gene in glioma.

Published
2010
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8. Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology.

Author

Gravendeel LA, Kouwenhoven MC, Gevaert O, de Rooi JJ, Stubbs AP, Duijm JE, Daemen A, Bleeker FE, Bralten LB, Kloosterhof NK, De Moor B, Eilers PH, van der Spek PJ, Kros JM, Sillevis Smitt PA, van den Bent MJ, and French PJ

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Brain Neoplasms pathology, Child, Cluster Analysis, Female, Gene Expression Profiling, Glioma pathology, Humans, Male, Middle Aged, Prognosis, Reproducibility of Results, Survival Rate, Young Adult, Brain Neoplasms genetics, Glioma genetics
Abstract

Gliomas are the most common primary brain tumors with heterogeneous morphology and variable prognosis. Treatment decisions in patients rely mainly on histologic classification and clinical parameters. However, differences between histologic subclasses and grades are subtle, and classifying gliomas is subject to a large interobserver variability. To improve current classification standards, we have performed gene expression profiling on a large cohort of glioma samples of all histologic subtypes and grades. We identified seven distinct molecular subgroups that correlate with survival. These include two favorable prognostic subgroups (median survival, >4.7 years), two with intermediate prognosis (median survival, 1-4 years), two with poor prognosis (median survival, <1 year), and one control group. The intrinsic molecular subtypes of glioma are different from histologic subgroups and correlate better to patient survival. The prognostic value of molecular subgroups was validated on five independent sample cohorts (The Cancer Genome Atlas, Repository for Molecular Brain Neoplasia Data, GSE12907, GSE4271, and Li and colleagues). The power of intrinsic subtyping is shown by its ability to identify a subset of prognostically favorable tumors within an external data set that contains only histologically confirmed glioblastomas (GBM). Specific genetic changes (epidermal growth factor receptor amplification, IDH1 mutation, and 1p/19q loss of heterozygosity) segregate in distinct molecular subgroups. We identified a subgroup with molecular features associated with secondary GBM, suggesting that different genetic changes drive gene expression profiles. Finally, we assessed response to treatment in molecular subgroups. Our data provide compelling evidence that expression profiling is a more accurate and objective method to classify gliomas than histologic classification. Molecular classification therefore may aid diagnosis and can guide clinical decision making.

Published
2009
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