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

Author

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

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

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

Published
2016

2. Genetic and hypoxic regulation of angiogenesis in gliomas

Author

Dawn E. Post, Van Meir Eg, Daniel J. Brat, Tan C, and Balveen Kaur

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Genotype, Angiogenesis, medicine.medical_treatment, Biology, Fibroblast growth factor, Angiopoietin, chemistry.chemical_compound, medicine, Animals, Humans, Hypoxia, Neovascularization, Pathologic, Brain Neoplasms, Growth factor, Astrocytoma, Glioma, medicine.disease, Phenotype, nervous system diseases, Endothelial stem cell, Vascular endothelial growth factor, Neurology, Oncology, chemistry, Neurology (clinical), Signal Transduction
Abstract

Infiltrative astrocytic neoplasms are by far the most common malignant brain tumors in adults. Clinically, they are highly problematic due to their widely invasive nature which makes a complete resection almost impossible. Biologic progression of these tumors is inevitable and adjuvant therapies are only moderately effective in prolonging survival. Glioblastoma multiforme (GBM; WHO grade IV), the most malignant form of infiltrating astrocytoma, can evolve from a lower grade precursor tumor (secondary GBM) or can present as high grade lesion from the outset, so-called de novo GBM. Molecular genetic investigations suggest that GBMs are comprised of multiple molecular genetic subsets. Notwithstanding the diversity of genetic alterations leading to the GBM phenotype, the vascular changes that evolve in this disease, presumably favoring further growth, are remarkably similar. Underlying genetic alterations in GBM may tilt the balance in favor of an angiogenic phenotype by upregulation of pro-angiogenic factors and down-regulation of angiogenesis inhibitors. Increased vascularity and endothelial cell proliferation in GBMs are also driven by hypoxia-induced expression of pro-angiogenic cytokines, such vascular endothelial growth factor (VEGF). Understanding the contribution of genetic alterations and hypoxia in angiogenic dysregulation in astrocytic neoplasms will lead to the development of better anti-angiogenic therapies for this disease. This review will summarize the properties of angiogenic dysregulation that lead to the highly vascularized nature of these tumors.

Published
2004

3. Genetic modulation of hypoxia induced gene expression and angiogenesis relevance to brain tumors

Author

Daniel J. Brat, Balveen Kaur, and Van Meir Eg

Subjects
Neovascularization, Pathologic, biology, Brain Neoplasms, Angiogenesis, Basic fibroblast growth factor, Astrocytoma, medicine.disease, Gene Expression Regulation, Neoplastic, Vascular endothelial growth factor, chemistry.chemical_compound, HIF1A, chemistry, CDKN2A, Cancer research, biology.protein, medicine, Animals, Humans, PTEN, Hypoxia, neoplasms, Platelet-derived growth factor receptor
Abstract

Angiogenesis is required for the development and biologic progression of infiltrative astrocytomas and takes the form of "microvascular hyperplasia" in glioblastoma multiforme, the most malignant astrocytoma. This pathologic term refers to an abnormal vascular proliferation that is often associated with necrosis and likely originates in hypoxic zones. Both the physiologic response to hypoxia and genetic alterations contribute to this process. The presence of hypoxic regions within an expanding tumor mass leads to upregulation of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), through increased activity of the transcriptional complex HIF-1 (hypoxia-inducible factor-1). HIF-1 mediated gene expression may be directly or indirectly modulated by alterations in oncogenes/tumor suppressor genes that occur during astrocytoma development, including PTEN, TP53, p16(CDKN2A), p14ARF, EGFR, and PDGFR. Genetic alterations are also believed to influence the HIF-independent expression of pro- and anti- angiogenic factors, such as basic fibroblast growth factor (bFGF) and thrombospondin-1 (TSP-1), respectively. Thus, genetic events that occur during the progression of infiltrating astrocytomas promote angiogenesis, both by modulating hypoxia induced gene expression and by regulating of pro- and anti- angiogenic factors.

Published
2003

4. 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

5. CD44 expression and growth factors

Author

Sawamura Y, Van Meir Eg, and Hamada J

Subjects
Gene isoform, Tumor microenvironment, Endothelium, biology, Chemistry, Cell, CD44, Cell biology, Extracellular matrix, Hyaluronan Receptors, medicine.anatomical_structure, Circulating tumor cell, Tumor progression, medicine, biology.protein, Animals, Humans, Growth Substances
Abstract

Soluble factors such as growth factors and cytokines present in the tumor microenvironment regulate a variety of genes associated with malignant properties of tumor cells such as growth, migration, invasion, and metastatic capacities. CD44 is a multi-functional adhesion molecule involved in cell to cell and cell to extracellular matrix interaction, the trapping of growth factors and cytokines, and the regulation of cell traffic. Growth factors and cytokines modify the expression, selective isoform splicing and functions of CD44, resulting in changes in the biological properties of the cells. These include adhesion of circulating tumor cells to endothelium and body cavities, and survival in response to growth factors presented by the CD44 molecule. The modification of CD44 on both tumor and host cells by growth factors may play an important role in tumor progression.

Published
1998

6. Expression of the CD44 adhesion molecule in tumours of the central and peripheral nervous system

Author

Baltuch Gh, de Tribolet N, and Van Meir Eg

Subjects
Adult, Cancer Research, medicine.medical_specialty, Neurology, Lymphoma, Gene Expression, Nervous System, Metastasis, Central Nervous System Neoplasms, Central nervous system disease, Fetus, Peripheral Nervous System Neoplasms, Glioma, Gene expression, Meningeal Neoplasms, medicine, Animals, Humans, Neuroectodermal Tumors, Primitive, biology, CD44, Neuroma, Acoustic, Adhesion, medicine.disease, Immunohistochemistry, Hyaluronan Receptors, medicine.anatomical_structure, Oncology, Peripheral nervous system, Immunology, biology.protein, Cancer research, Neurology (clinical), Meningioma
Published
1995

7. Application of advances in molecular biology to the treatment of brain tumors

Author

Mark R. Gilbert, H. Takeshima, Y. Sawamura, and Meir Eg Van Meir Eg

Subjects
medicine.medical_specialty, Genetic enhancement, medicine.medical_treatment, Brain tumor, Drug design, Apoptosis, Bioinformatics, Viral vector, Diagnosis, Differential, Glioma, Molecular genetics, medicine, Humans, Genes, Tumor Suppressor, Molecular Biology, Neovascularization, Pathologic, business.industry, Brain Neoplasms, Cell Cycle, Genetic Therapy, medicine.disease, Molecular biology, Radiation therapy, Oncology, Identification (biology), business
Abstract

Recent advances in molecular biology have substantially improved our understanding of the molecular genetics of primary brain neoplasms. Soon each histopathologic category of glioma will be further divided into subgroups according to similar genetic background, gene expression profile, and similarity of biologic responses to radiotherapy or chemotherapy. Identification of key molecules that are specifically altered in neoplastic cells will provide candidate molecular targets for tumor treatment. Novel therapeutic tools for targeting tumor cells, such as viral vectors for gene therapy, have been created. In the near future, the accumulation of new knowledge in brain tumor biology and genetics, combined with rational drug design, will revolutionize the treatment of malignant gliomas, which are among the most lethal human cancers.

Published
2000

9. Intertumoral Heterogeneity within Medulloblastoma Subgroups

Author

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

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

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

Published
2017

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

Author

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

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

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

Published
2016

11. 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

12. 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

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