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1. Divergent clonal selection dominates medulloblastoma at recurrence

Author

Morrissy, A Sorana, Garzia, Livia, Shih, David JH, Zuyderduyn, Scott, Huang, Xi, Skowron, Patryk, Remke, Marc, Cavalli, Florence MG, Ramaswamy, Vijay, Lindsay, Patricia E, Jelveh, Salomeh, Donovan, Laura K, Wang, Xin, Luu, Betty, Zayne, Kory, Li, Yisu, Mayoh, Chelsea, Thiessen, Nina, Mercier, Eloi, Mungall, Karen L, Ma, Yusanne, Tse, Kane, Zeng, Thomas, Shumansky, Karey, Roth, Andrew JL, Shah, Sohrab, Farooq, Hamza, Kijima, Noriyuki, Holgado, Borja L, Lee, John JY, Matan-Lithwick, Stuart, Liu, Jessica, Mack, Stephen C, Manno, Alex, Michealraj, KA, Nor, Carolina, Peacock, John, Qin, Lei, Reimand, Juri, Rolider, Adi, Thompson, Yuan Y, Wu, Xiaochong, Pugh, Trevor, Ally, Adrian, Bilenky, Mikhail, Butterfield, Yaron SN, Carlsen, Rebecca, Cheng, Young, Chuah, Eric, Corbett, Richard D, Dhalla, Noreen, He, An, Lee, Darlene, Li, Haiyan I, Long, William, Mayo, Michael, Plettner, Patrick, Qian, Jenny Q, Schein, Jacqueline E, Tam, Angela, Wong, Tina, Birol, Inanc, Zhao, Yongjun, Faria, Claudia C, Pimentel, José, Nunes, Sofia, Shalaby, Tarek, Grotzer, Michael, Pollack, Ian F, Hamilton, Ronald L, Li, Xiao-Nan, Bendel, Anne E, Fults, Daniel W, Walter, Andrew W, Kumabe, Toshihiro, Tominaga, Teiji, Collins, V Peter, Cho, Yoon-Jae, Hoffman, Caitlin, Lyden, David, Wisoff, Jeffrey H, Garvin, James H, Stearns, Duncan S, Massimi, Luca, Schüller, Ulrich, Sterba, Jaroslav, Zitterbart, Karel, Puget, Stephanie, Ayrault, Olivier, Dunn, Sandra E, Tirapelli, Daniela PC, Carlotti, Carlos G, Wheeler, Helen, Hallahan, Andrew R, Ingram, Wendy, MacDonald, Tobey J, Olson, Jeffrey J, Van Meir, Erwin G, Lee, Ji-Yeoun, and Wang, Kyu-Chang

Subjects
Pediatric, Biotechnology, Genetics, Brain Disorders, Human Genome, Brain Cancer, Rare Diseases, Cancer, Animals, Cerebellar Neoplasms, Clone Cells, Craniospinal Irradiation, DNA Mutational Analysis, Disease Models, Animal, Drosophila melanogaster, Female, Genome, Human, Humans, Male, Medulloblastoma, Mice, Molecular Targeted Therapy, Neoplasm Recurrence, Local, Radiotherapy, Image-Guided, Selection, Genetic, Signal Transduction, Xenograft Model Antitumor Assays, General Science & Technology
Abstract

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (

Published
2016

2. Cytogenetic prognostication within medulloblastoma subgroups.

Author

Shih, David, Northcott, Paul, Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian, Garzia, Livia, Peacock, John, Mack, Stephen, Wu, Xiaochong, Rolider, Adi, Morrissy, A, Cavalli, Florence, Jones, David, Zitterbart, Karel, Faria, Claudia, Schüller, Ulrich, Kren, Leos, Kumabe, Toshihiro, Tominaga, Teiji, Shin Ra, Young, Garami, Miklós, Hauser, Peter, Chan, Jennifer, Robinson, Shenandoah, Bognár, László, Klekner, Almos, Saad, Ali, Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael, Thompson, Reid, Bailey, Simon, Lindsey, Janet, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna, Scherer, Stephen, Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey, Rubin, Joshua, de Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James, Gajjar, Amar, Packer, Roger, Fan, Xing, Muraszko, Karin, Vibhakar, Rajeev, Eberhart, Charles, Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert, Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian, Rutkowski, Stefan, Pomeroy, Scott, French, Pim, Kloosterhof, Nanne, Kros, Johan, Van Meir, Erwin, Clifford, Steven, Bourdeaut, Franck, Delattre, Olivier, Doz, François, Hawkins, Cynthia, Malkin, David, Grajkowska, Wieslawa, Perek-Polnik, Marta, Bouffet, Eric, Rutka, James, Pfister, Stefan, Taylor, Michael, Gupta, Nalin, Phillips, Joanna, Weiss, William, and Liau, Linda

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

3. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma

Author

Dubuc, Adrian M, Remke, Marc, Korshunov, Andrey, Northcott, Paul A, Zhan, Shing H, Mendez-Lago, Maria, Kool, Marcel, Jones, David TW, Unterberger, Alexander, Morrissy, A Sorana, Shih, David, Peacock, John, Ramaswamy, Vijay, Rolider, Adi, Wang, Xin, Witt, Hendrik, Hielscher, Thomas, Hawkins, Cynthia, Vibhakar, Rajeev, Croul, Sidney, Rutka, James T, Weiss, William A, Jones, Steven JM, Eberhart, Charles G, Marra, Marco A, Pfister, Stefan M, and Taylor, Michael D

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Pediatric, Human Genome, Brain Disorders, Cancer, Genetics, Rare Diseases, Pediatric Cancer, Brain Cancer, Base Sequence, Cerebellar Neoplasms, Cohort Studies, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Genome, Histone Demethylases, Histone Methyltransferases, Histone-Lysine N-Methyltransferase, Humans, Lysine, Male, Medulloblastoma, Methylation, Mutation, Neoplasm Proteins, Nuclear Proteins, Polymorphism, Single Nucleotide, MLL2, KDM6A, Histone lysine methylation, PRC2, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

Recent sequencing efforts have described the mutational landscape of the pediatric brain tumor medulloblastoma. Although MLL2 is among the most frequent somatic single nucleotide variants (SNV), the clinical and biological significance of these mutations remains uncharacterized. Through targeted re-sequencing, we identified mutations of MLL2 in 8 % (14/175) of MBs, the majority of which were loss of function. Notably, we also report mutations affecting the MLL2-binding partner KDM6A, in 4 % (7/175) of tumors. While MLL2 mutations were independent of age, gender, histological subtype, M-stage or molecular subgroup, KDM6A mutations were most commonly identified in Group 4 MBs, and were mutually exclusive with MLL2 mutations. Immunohistochemical staining for H3K4me3 and H3K27me3, the chromatin effectors of MLL2 and KDM6A activity, respectively, demonstrated alterations of the histone code in 24 % (53/220) of MBs across all subgroups. Correlating these MLL2- and KDM6A-driven histone marks with prognosis, we identified populations of MB with improved (K4+/K27-) and dismal (K4-/K27-) outcomes, observed primarily within Group 3 and 4 MBs. Group 3 and 4 MBs demonstrate somatic copy number aberrations, and transcriptional profiles that converge on modifiers of H3K27-methylation (EZH2, KDM6A, KDM6B), leading to silencing of PRC2-target genes. As PRC2-mediated aberrant methylation of H3K27 has recently been targeted for therapy in other diseases, it represents an actionable target for a substantial percentage of medulloblastoma patients with aggressive forms of the disease.

Published
2013

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

Author

Northcott, Paul, Shih, David, Peacock, John, Garzia, Livia, Morrissy, A, Zichner, Thomas, Stütz, Adrian, Korshunov, Andrey, Reimand, Jüri, Schumacher, Steven, Beroukhim, Rameen, Ellison, David, Marshall, Christian, Lionel, Anath, Mack, Stephen, Dubuc, Adrian, Yao, Yuan, Ramaswamy, Vijay, Luu, Betty, Rolider, Adi, Cavalli, Florence, Wang, Xin, Remke, Marc, Wu, Xiaochong, Chiu, Readman, Chu, Andy, Chuah, Eric, Corbett, Richard, Hoad, Gemma, Jackman, Shaun, Li, Yisu, Lo, Allan, Mungall, Karen, Nip, Ka, Qian, Jenny, Raymond, Anthony, Thiessen, Nina, Varhol, Richard, Birol, Inanc, Moore, Richard, Mungall, Andrew, Holt, Robert, Kawauchi, Daisuke, Roussel, Martine, Kool, Marcel, Jones, David, Witt, Hendrick, Fernandez-L, Africa, Kenney, Anna, Wechsler-Reya, Robert, Dirks, Peter, Aviv, Tzvi, Grajkowska, Wieslawa, Perek-Polnik, Marta, Haberler, Christine, Delattre, Olivier, Reynaud, Stéphanie, Doz, François, Pernet-Fattet, Sarah, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Scheurlen, Wolfram, Eberhart, Charles, Fèvre-Montange, Michelle, Jouvet, Anne, Pollack, Ian, Fan, Xing, Muraszko, Karin, Gillespie, G, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna, Kloosterhof, Nanne, French, Pim, Kros, Johan, Olson, James, Ellenbogen, Richard, Zitterbart, Karel, Kren, Leos, Thompson, Reid, Cooper, Michael, Lach, Boleslaw, McLendon, Roger, Bigner, Darell, Fontebasso, Adam, Albrecht, Steffen, Jabado, Nada, Lindsey, Janet, Bailey, Simon, Van Meir, Erwin, Fouladi, Maryam, Nakamura, Hideo, Cinalli, Giuseppe, Garami, Miklós, Hauser, Peter, Saad, Ali, Iolascon, Achille, Jung, Shin, and Carlotti, Carlos

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

5. Regulation of major cellulosomal endoglucanases of Clostridium thermocellum differs from that of a prominent cellulosomal xylanase

Author

Dror, Tali W., Rolider, Adi, Bayer, Edward A., Lamed, Raphael, and Shoham, Yuval

Subjects
Bacterial genetics -- Research, Bacteriology -- Research, Clostridium -- Research, Clostridium -- Genetic aspects, Biological sciences
Abstract

The expression of scaffoldin-anchoring genes and one of the major processive endoglucanases (CelS) from the cellulosome of Clostridium thermocellum has been shown to be dependent on the growth rate. For the present work, we studied the gene regulation of selected cellulosomal endoglucanases and a major xylanase in order to examine the previously observed substrate-linked alterations in cellulosome composition. For this purpose, the transcript levels of genes encoding endoglucanases CelB, CelG, and CelD and the family 10 xylanase XynC were determined in batch cultures, grown on either cellobiose or cellulose, and in carbon-limited continuous cultures at different dilution rates. Under all conditions tested, the transcript levels of celB and celG were at least 10-fold higher than that of celD. Like the major processive endoglucanase CelS, the transcript levels of these endoglucanase genes were also dependent on the growth rate. Thus, at a rate of 0.04 [h.sup.-1], the levels of celB, celG, and celD were threefold higher than those obtained in cultures grown at maximal rates (0.35 [h.sup.-1]) on cellobiose. In contrast, no clear correlation was observed between the transcript level of xynC and the growth rate--the levels remained relatively high, fluctuating between 30 and 50 transcripts per cell. The results suggest that the regulation of C. thermocellum endoglucanases is similar to that of the processive endoglucanase celS but differs from that of a major cellulosomal xylanase in that expression of the latter enzyme is independent of the growth rate.

Published
2005

6. Regulation of expression of scaffoldin-related genes in Clostridium thermocellum

Author

Dror, Tali W., Rolider, Adi, Bayer, Edward A., Lamed, Raphael, and Shoham, Yuval

Subjects
Genetic regulation -- Physiological aspects, Nitrogen -- Physiological aspects, Carbon -- Physiological aspects, Genetic transcription -- Physiological aspects, Messenger RNA -- Genetic aspects, Bacterial proteins -- Genetic aspects, Cellulose -- Physiological aspects, Solution (Chemistry), Clostridium -- Genetic aspects, Bacteriology -- Research, Biological sciences
Abstract

Clostridium thermocellum produces an extracellular multienzyme complex, termed the cellulosome, that allows efficient solubilization of crystalline cellulose. The complex is organized around a large noncatalytic protein subunit, termed CipA or scaffoldin, and is found either free in the supernatant or cell bound. The binding of the complex to the cell is mediated by three cell surface anchoring proteins, OlpB, Orf2p, and SdbA, that interact with the CipA scaffoldin. The transcriptional level of the olpB, orf2, sdbA, and cipA genes was determined quantitatively by RNase protection assays in batch and continuous cultures, under carbon and nitrogen limitation. The mRNA level of olpB, orf2, and cipA varied with growth rate, reaching 40 to 60 transcripts per cell under carbon limitation at a low growth rate of 0.04 [h.sup.-1] and 2 to 10 transcripts per cell at a growth rate of 0.35 [h.sup.-1] in batch culture. The mRNA level of sdbA was about three transcripts per cell and was not influenced by growth rate. Primer extension analysis revealed two major transcriptional start sites, at -81 and -50 bp, upstream of the translational start site of the cipA gene. The potential promoters exhibited homology to the known sigma factors [[sigma].sup.A] and [[sigma].sup.L] ([[sigma].sup.54]) of Bacillus subtilis. Transcription from the [[sigma].sup.L]-like promoter was found under all growth conditions, whereas transcription from the [[sigma].sup.A]-like promoter was significant only under carbon limitation. The overall expression level obtained in the primer extension analysis was in good agreement with the results of the RNase-protection assays.

Published
2003

7. Regulation of the cellulosomal celS (cel48A) gene of Clostridium thermocellum is growth rate dependent

Author

Dror, Tali W., Morag, Ely, Rolider, Adi, Bayer, Edward A., Lamed, Raphael, and Shoham, Yuval

Subjects
Microbiological synthesis -- Genetic aspects, Microbiological synthesis -- Physiological aspects, Gene expression -- Physiological aspects, Bacterial growth -- Physiological aspects, Biological sciences
Abstract

Results show that the cellulosomal gene celS is regulated by growth rate in Clostridium thermocellum. The gene encoded product CelS exhibits exoglucanase activity. Data indicae that the amount of CelS produced by cellobiose-grown cultures is lower than that of cellulose-grown cultures.

Published
2003

8. Divergent clonal selection dominates medulloblastoma at recurrence

Author

Morrissy, A. Sorana, Garzia, Livia, Shih, David J. H., Zuyderduyn, Scott, Huang, Xi, Skowron, Patryk, Remke, Marc, Cavalli, Florence M. G., Ramaswamy, Vijay, Lindsay, Patricia E., Jelveh, Salomeh, Donovan, Laura K., Wang, Xin, Luu, Betty, Zayne, Kory, Li, Yisu, Mayoh, Chelsea, Thiessen, Nina, Mercier, Eloi, Mungall, Karen L., Ma, Yusanne, Tse, Kane, Zeng, Thoma, Shumansky, Karey, Roth, Andrew J. L., Shah, Sohrab, Farooq, Hamza, Kijima, Noriyuki, Holgado, Borja L., Lee, John J. Y., Matan-Lithwick, Stuart, Liu, Jessica, Mack, Stephen C., Manno, Alex, Michealraj, K. A., Nor, Carolina, Peacock, John, Qin, Lei, Reimand, Juri, Rolider, Adi, Thompson, Yuan Y., Wu, Xiaochong, Pugh, Trevor, Ally, Adrian, Bilenky, Mikhail, Butterfield, Yaron S. N., Carlsen, Rebecca, Cheng, Young, Chuah, Eric, Corbett, Richard D., Dhalla, Noreen, He, An, Lee, Darlene, Li, Haiyan I., Long, William, Mayo, Michael, Plettner, Patrick, Qian, Jenny Q., Schein, Jacqueline E., Tam, Angela, Wong, Tina, Birol, Inanc, Zhao, Yongjun, Faria, Claudia C., Pimentel, José, Nunes, Sofia, Shalaby, Tarek, Grotzer, Michael, Pollack, Ian F., Hamilton, Ronald L., Li, Xiao-Nan, Bendel, Anne E., Fults, Daniel W., Walter, Andrew W., Kumabe, Toshihiro, Tominaga, Teiji, Collins, V. Peter, Cho, Yoon-Jae, Hoffman, Caitlin, Lyden, David, Wisoff, Jeffrey H., Garvin, James H., Stearns, Duncan S., Massimi, Luca, Schüller, Ulrich, Sterba, Jaroslav, Zitterbart, Karel, Puget, Stephanie, Ayrault, Olivier, Dunn, Sandra E., Tirapelli, Daniela P. C., Carlotti, Carlos G., Wheeler, Helen, Hallahan, Andrew R., Ingram, Wendy, Macdonald, Tobey J., Olson, Jeffrey J., Van Meir, Erwin G., Lee, Ji-Yeoun, Wang, Kyu-Chang, Kim, Seung-Ki, Cho, Byung-Kyu, Pietsch, Torsten, Fleischhack, Gudrun, Tippelt, Stephan, Ra, Young Shin, Bailey, Simon, Lindsey, Janet C., Clifford, Steven C., Eberhart, Charles G., Cooper, Michael K., Packer, Roger J., Massimino, Maura, Garre, Maria Luisa, Bartels, Ute, Tabori, Uri, Hawkins, Cynthia E., Dirks, Peter, Bouffet, Eric, Rutka, James T., Wechsler-Reya, Robert J., Weiss, William A., Collier, Lara S., Dupuy, Adam J., Korshunov, Andrey, Jones, David T. W., Kool, Marcel, Northcott, Paul A., Pfister, Stefan M., Largaespada, David A., Mungall, Andrew J., Moore, Richard A., Jabado, Nada, Bader, Gary D., Jones, Steven J. M., Malkin, David, Marra, Marco A., Taylor, Michael D., Morrissy, A. Sorana, Garzia, Livia, Shih, David J. H., Zuyderduyn, Scott, Huang, Xi, Skowron, Patryk, Remke, Marc, Cavalli, Florence M. G., Ramaswamy, Vijay, Lindsay, Patricia E., Jelveh, Salomeh, Donovan, Laura K., Wang, Xin, Luu, Betty, Zayne, Kory, Li, Yisu, Mayoh, Chelsea, Thiessen, Nina, Mercier, Eloi, Mungall, Karen L., Ma, Yusanne, Tse, Kane, Zeng, Thoma, Shumansky, Karey, Roth, Andrew J. L., Shah, Sohrab, Farooq, Hamza, Kijima, Noriyuki, Holgado, Borja L., Lee, John J. Y., Matan-Lithwick, Stuart, Liu, Jessica, Mack, Stephen C., Manno, Alex, Michealraj, K. A., Nor, Carolina, Peacock, John, Qin, Lei, Reimand, Juri, Rolider, Adi, Thompson, Yuan Y., Wu, Xiaochong, Pugh, Trevor, Ally, Adrian, Bilenky, Mikhail, Butterfield, Yaron S. N., Carlsen, Rebecca, Cheng, Young, Chuah, Eric, Corbett, Richard D., Dhalla, Noreen, He, An, Lee, Darlene, Li, Haiyan I., Long, William, Mayo, Michael, Plettner, Patrick, Qian, Jenny Q., Schein, Jacqueline E., Tam, Angela, Wong, Tina, Birol, Inanc, Zhao, Yongjun, Faria, Claudia C., Pimentel, José, Nunes, Sofia, Shalaby, Tarek, Grotzer, Michael, Pollack, Ian F., Hamilton, Ronald L., Li, Xiao-Nan, Bendel, Anne E., Fults, Daniel W., Walter, Andrew W., Kumabe, Toshihiro, Tominaga, Teiji, Collins, V. Peter, Cho, Yoon-Jae, Hoffman, Caitlin, Lyden, David, Wisoff, Jeffrey H., Garvin, James H., Stearns, Duncan S., Massimi, Luca, Schüller, Ulrich, Sterba, Jaroslav, Zitterbart, Karel, Puget, Stephanie, Ayrault, Olivier, Dunn, Sandra E., Tirapelli, Daniela P. C., Carlotti, Carlos G., Wheeler, Helen, Hallahan, Andrew R., Ingram, Wendy, Macdonald, Tobey J., Olson, Jeffrey J., Van Meir, Erwin G., Lee, Ji-Yeoun, Wang, Kyu-Chang, Kim, Seung-Ki, Cho, Byung-Kyu, Pietsch, Torsten, Fleischhack, Gudrun, Tippelt, Stephan, Ra, Young Shin, Bailey, Simon, Lindsey, Janet C., Clifford, Steven C., Eberhart, Charles G., Cooper, Michael K., Packer, Roger J., Massimino, Maura, Garre, Maria Luisa, Bartels, Ute, Tabori, Uri, Hawkins, Cynthia E., Dirks, Peter, Bouffet, Eric, Rutka, James T., Wechsler-Reya, Robert J., Weiss, William A., Collier, Lara S., Dupuy, Adam J., Korshunov, Andrey, Jones, David T. W., Kool, Marcel, Northcott, Paul A., Pfister, Stefan M., Largaespada, David A., Mungall, Andrew J., Moore, Richard A., Jabado, Nada, Bader, Gary D., Jones, Steven J. M., Malkin, David, Marra, Marco A., and Taylor, Michael D.

Abstract

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

Published
2016

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

Author

Northcott, Paul A, Shih, David JH, Peacock, John, Garzia, Livia, Morrissy, A Sorana, Zichner, Thomas, Stütz, Adrian M, Korshunov, Andrey, Reimand, Jüri, Schumacher, Steven E, Beroukhim, Rameen, Ellison, David W, Marshall, Christian R, Lionel, Anath C, Mack, Stephen, Dubuc, Adrian, Yao, Yuan, Ramaswamy, Vijay, Luu, Betty, Rolider, Adi, Cavalli, Florence MG, Wang, Xin, Remke, Marc, Wu, Xiaochong, Chiu, Readman YB, Chu, Andy, Chuah, Eric, Corbett, Richard D, Hoad, Gemma R, Jackman, Shaun D, Li, Yisu, Lo, Allan, Mungall, Karen L, Nip, Ka Ming, Qian, Jenny Q, Raymond, Anthony GJ, Thiessen, Nina T, Varhol, Richard J, Birol, Inanc, Moore, Richard A, Mungall, Andrew J, Holt, Robert, Kawauchi, Daisuke, Roussel, Martine F, Kool, Marcel, Jones, David TW, Witt, Hendrick, Fernandez-L, Africa, Kenney, Anna M, Wechsler-Reya, Robert J, Dirks, Peter, Aviv, Tzvi, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Haberler, Christine C, Delattre, Olivier, Reynaud, Stéphanie S, Doz, François F, Pernet-Fattet, Sarah S, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Scheurlen, Wolfram, Eberhart, Charles G, Fèvre-Montange, Michelle, Jouvet, Anne, Pollack, Ian F, Fan, Xing, Muraszko, Karin M, Gillespie, G Yancey, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Kloosterhof, Nanne K, French, Pim J, Kros, Johan M, Olson, James M, Ellenbogen, Richard G, Zitterbart, Karel, Kren, Leos, Thompson, Reid C, Cooper, Michael K, Lach, Boleslaw, McLendon, Roger E, Bigner, Darell D, Fontebasso, Adam, Albrecht, Steffen, Jabado, Nada, Lindsey, Janet C, Bailey, Simon, Gupta, Nalin, Weiss, William A, Bognár, László, Klekner, Almos, Van Meter, Timothy E, Kumabe, Toshihiro, Tominaga, Teiji, Elbabaa, Samer K, Leonard, Jeffrey R, and Rubin, Joshua B

Subjects
Pediatric Research Initiative, DNA Copy Number Variations, Pediatric Cancer, General Science & Technology, Translocation, Nerve Tissue Proteins, Rare Diseases, Genetic, Transforming Growth Factor beta, Gene Duplication, Genetics, Humans, Hedgehog Proteins, Cerebellar Neoplasms, Fusion, Child, Cancer, Oncogene Proteins, Pediatric, Genome, NF-kappa B, Neurosciences, Proteins, Genomics, myc, Brain Disorders, Brain Cancer, Genes, 5.1 Pharmaceuticals, Genomic Structural Variation, RNA, Long Noncoding, Development of treatments and therapeutic interventions, Carrier Proteins, Medulloblastoma, Signal Transduction, Human
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

10. PTPS-08HEMATOGENOUS DISSEMINATION OF MEDULLOBLASTOMA METASTASES TO THE LEPTOMENINGES

Author

Garzia, Livia, primary, Kijima, Noriyuki, additional, Morrissy, A., additional, Donovan, Laura, additional, Wu, Xiaochong, additional, Luu, Betty, additional, Ramaswamy, Vijay, additional, Peacock, John, additional, Lopez-Holgado, Borja, additional, Wang, Xin, additional, Cavalli, Florence, additional, Rolider, Adi, additional, Shih, David, additional, Skowron, Patryk, additional, Lee, John, additional, Michealraj, Antony, additional, Malkin, David, additional, Fults, Daniel, additional, Marra, Marco, additional, and Taylor, Michael, additional

Published
2015
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11. Cytogenetic prognostication within medulloblastoma subgroups.

Author

Shih, David JH, Shih, David JH, Northcott, Paul A, Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian M, Garzia, Livia, Peacock, John, Mack, Stephen C, Wu, Xiaochong, Rolider, Adi, Morrissy, A Sorana, Cavalli, Florence MG, Jones, David TW, Zitterbart, Karel, Faria, Claudia C, Schüller, Ulrich, Kren, Leos, Kumabe, Toshihiro, Tominaga, Teiji, Shin Ra, Young, Garami, Miklós, Hauser, Peter, Chan, Jennifer A, Robinson, Shenandoah, Bognár, László, Klekner, Almos, Saad, Ali G, Liau, Linda M, Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael K, Thompson, Reid C, Bailey, Simon, Lindsey, Janet C, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Scherer, Stephen W, Phillips, Joanna J, Gupta, Nalin, Fan, Xing, Muraszko, Karin M, Vibhakar, Rajeev, Eberhart, Charles G, Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert J, Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian F, Weiss, William A, Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey R, Rubin, Joshua B, de Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James M, Gajjar, Amar, Packer, Roger J, Rutkowski, Stefan, Pomeroy, Scott L, French, Pim J, Kloosterhof, Nanne K, Kros, Johan M, Van Meir, Erwin G, Clifford, Steven C, Bourdeaut, Franck, Delattre, Olivier, Doz, François F, Hawkins, Cynthia E, Malkin, David, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Bouffet, Eric, Rutka, James T, Pfister, Stefan M, Taylor, Michael D, Shih, David JH, Shih, David JH, Northcott, Paul A, Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian M, Garzia, Livia, Peacock, John, Mack, Stephen C, Wu, Xiaochong, Rolider, Adi, Morrissy, A Sorana, Cavalli, Florence MG, Jones, David TW, Zitterbart, Karel, Faria, Claudia C, Schüller, Ulrich, Kren, Leos, Kumabe, Toshihiro, Tominaga, Teiji, Shin Ra, Young, Garami, Miklós, Hauser, Peter, Chan, Jennifer A, Robinson, Shenandoah, Bognár, László, Klekner, Almos, Saad, Ali G, Liau, Linda M, Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael K, Thompson, Reid C, Bailey, Simon, Lindsey, Janet C, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Scherer, Stephen W, Phillips, Joanna J, Gupta, Nalin, Fan, Xing, Muraszko, Karin M, Vibhakar, Rajeev, Eberhart, Charles G, Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert J, Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian F, Weiss, William A, Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey R, Rubin, Joshua B, de Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James M, Gajjar, Amar, Packer, Roger J, Rutkowski, Stefan, Pomeroy, Scott L, French, Pim J, Kloosterhof, Nanne K, Kros, Johan M, Van Meir, Erwin G, Clifford, Steven C, Bourdeaut, Franck, Delattre, Olivier, Doz, François F, Hawkins, Cynthia E, Malkin, David, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Bouffet, Eric, Rutka, James T, Pfister, Stefan M, and Taylor, Michael D

Abstract

PurposeMedulloblastoma 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 methodsMolecular 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.ResultsSubgroup 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.ConclusionCombining 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

12. Cytogenetic prognostication within medulloblastoma subgroups

Author

Shih, David J. H., Northcott, Paul A., Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian M., Garzia, Livia, Peacock, John, Mack, Stephen C., Wu, Xiaochong, Rolider, Adi, Morrissy, A. Sorana, Cavalli, Florence M. G., Jones, David T. W., Zitterbart, Karel, Faria, Claudia C., Schüller, Ulrich, Kren, Leo, Kumabe, Toshihiro, Tominaga, Teiji, Ra, Young Shin, Garami, Mikló, Hauser, Peter, Chan, Jennifer A., Robinson, Shenandoah, Bognár, László, Klekner, Almo, Saad, Ali G., Liau, Linda M., Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael K., Thompson, Reid C., Bailey, Simon, Lindsey, Janet C., Di Rocco, Concezio, Massimi, Luca, Michiels, Erna M. C., Scherer, Stephen W., Phillips, Joanna J., Gupta, Nalin, Fan, Xing, Muraszko, Karin M., Vibhakar, Rajeev, Eberhart, Charles G., Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert J., Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian F., Weiss, William A., Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey R., Rubin, Joshua B., De Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James M., Gajjar, Amar, Packer, Roger J., Rutkowski, Stefan, Pomeroy, Scott L., French, Pim J., Kloosterhof, Nanne K., Kros, Johan M., Van Meir, Erwin G., Clifford, Steven C., Bourdeaut, Franck, Delattre, Olivier, Doz, François F., Hawkins, Cynthia E., Malkin, David, Grajkowska, Wieslawa A., Perek-Polnik, Marta, Bouffet, Eric, Rutka, James T., Pfister, Stefan M., Taylor, Michael D., Shih, David J. H., Northcott, Paul A., Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian M., Garzia, Livia, Peacock, John, Mack, Stephen C., Wu, Xiaochong, Rolider, Adi, Morrissy, A. Sorana, Cavalli, Florence M. G., Jones, David T. W., Zitterbart, Karel, Faria, Claudia C., Schüller, Ulrich, Kren, Leo, Kumabe, Toshihiro, Tominaga, Teiji, Ra, Young Shin, Garami, Mikló, Hauser, Peter, Chan, Jennifer A., Robinson, Shenandoah, Bognár, László, Klekner, Almo, Saad, Ali G., Liau, Linda M., Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael K., Thompson, Reid C., Bailey, Simon, Lindsey, Janet C., Di Rocco, Concezio, Massimi, Luca, Michiels, Erna M. C., Scherer, Stephen W., Phillips, Joanna J., Gupta, Nalin, Fan, Xing, Muraszko, Karin M., Vibhakar, Rajeev, Eberhart, Charles G., Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert J., Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian F., Weiss, William A., Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey R., Rubin, Joshua B., De Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James M., Gajjar, Amar, Packer, Roger J., Rutkowski, Stefan, Pomeroy, Scott L., French, Pim J., Kloosterhof, Nanne K., Kros, Johan M., Van Meir, Erwin G., Clifford, Steven C., Bourdeaut, Franck, Delattre, Olivier, Doz, François F., Hawkins, Cynthia E., Malkin, David, Grajkowska, Wieslawa A., Perek-Polnik, Marta, Bouffet, Eric, Rutka, James T., Pfister, Stefan M., and Taylor, Michael D.

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. © 2

Published
2014

13. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma

Author

Dubuc, Adrian M., primary, Remke, Marc, additional, Korshunov, Andrey, additional, Northcott, Paul A., additional, Zhan, Shing H., additional, Mendez-Lago, Maria, additional, Kool, Marcel, additional, Jones, David T. W., additional, Unterberger, Alexander, additional, Morrissy, A. Sorana, additional, Shih, David, additional, Peacock, John, additional, Ramaswamy, Vijay, additional, Rolider, Adi, additional, Wang, Xin, additional, Witt, Hendrik, additional, Hielscher, Thomas, additional, Hawkins, Cynthia, additional, Vibhakar, Rajeev, additional, Croul, Sidney, additional, Rutka, James T., additional, Weiss, William A., additional, Jones, Steven J. M., additional, Eberhart, Charles G., additional, Marra, Marco A., additional, Pfister, Stefan M., additional, and Taylor, Michael D., additional

Published
2012
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