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Cytogenetic prognostication within medulloblastoma subgroups

DJ. Shih, PA. Northcott, M. Remke, A. Korshunov, V. Ramaswamy, M. Kool, B. Luu, Y. Yao, X. Wang, AM. Dubuc, L. Garzia, J. Peacock, SC. Mack, X. Wu, A. Rolider, AS. Morrissy, FM. Cavalli, DT. Jones, K. Zitterbart, CC. Faria, U. Schüller, L. Kren,...

Journal of clinical oncology. 2014 ; 32 (9) : 886-96.

J. clin. Oncol.
ISSN 1527-7755
Medvik
Source

Language English Country United States

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/bmc14063737

Online Full text

NLK Free Medical Journals from 2004 to 1 year ago
Open Access Digital Library from 1999-01-01

PubMed 24493713
DOI 10.1200/jco.2013.50.9539
Knihovny.cz E-resources

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.

Ali G Saad University of Arkansas for Medical Sciences Little

Boleslaw Lach McMaster University Hamilton Ontario

David J H Shih Marc Remke Vijay Ramaswamy Betty Luu Yuan Yao Xin Wang Adrian M Dubuc Livia Garzia John Peacock Stephen C Mack Xiaochong Wu Adi Rolider A Sorana Morrissy Florence M G Cavalli Claudia C Faria Stephen W Scherer Uri Tabori Cynthia E Hawkins David Malkin Eric Bouffet James T Rutka and Michael D Taylor Hospital for Sick Children

David J H Shih Marc Remke Vijay Ramaswamy Yuan Yao Xin Wang Adrian M Dubuc John Peacock Stephen C Mack and Michael D Taylor University of Toronto Toronto

Jennifer A Chan University of Calgary Calgary Alberta

Ji Yeoun Lee Byung Kyu Cho Seung Ki Kim and Kyu Chang Wang Seoul National University Children's Hospital Seoul

Karel Zitterbart and Leos Kren University Hospital Brno Brno Czech Republic

Karel Zitterbart Masaryk University School of Medicine

László Bognár and Almos Klekner University of Debrecen Medical and Health Science Centre Debrecen Hungary

Paul A Northcott Andrey Korshunov Marcel Kool David T W Jones and Stefan M Pfister German Cancer Research Center

Peter Hauser and Miklós Garami Semmelweis University Budapest

Scott L Pomeroy Harvard Medical School Boston MA

Shenandoah Robinson Boston Children's Hospital

Shin Jung Chonnam National University Research Institute of Medical Sciences Chonnam National University Hwasun Hospital and Medical School Chonnam South Korea

Stefan M Pfister University Hospital Heidelberg Heidelberg

Stefan Rutkowski University Medical Center Hamburg Eppendorf Hamburg Germany

Steffen Albrecht Adam Fontebasso and Nada Jabado McGill University Montreal Quebec Canada

Toshihiro Kumabe and Teiji Tominaga Tohoku University Graduate School of Medicine Sendai Japan

Ulrich Schüller Ludwig Maximilians University Munich

Young Shin Ra University of Ulsan Asan Medical Center

References provided by Crossref.org

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100 1_: $a Shih, David J H $u David J.H. Shih, Marc Remke, Vijay Ramaswamy, Betty Luu, Yuan Yao, Xin Wang, Adrian M. Dubuc, Livia Garzia, John Peacock, Stephen C. Mack, Xiaochong Wu, Adi Rolider, A. Sorana Morrissy, Florence M.G. Cavalli, Claudia C. Faria, Stephen W. Scherer, Uri Tabori, Cynthia E. Hawkins, David Malkin, Eric Bouffet, James T. Rutka, and Michael D. Taylor, Hospital for Sick Children; David J.H. Shih, Marc Remke, Vijay Ramaswamy, Yuan Yao, Xin Wang, Adrian M. Dubuc, John Peacock, Stephen C. Mack, and Michael D. Taylor, University of Toronto, Toronto; Boleslaw Lach, McMaster University, Hamilton, Ontario; Jennifer A. Chan, University of Calgary, Calgary, Alberta; Steffen Albrecht, Adam Fontebasso, and Nada Jabado, McGill University, Montreal, Quebec, Canada; Paul A. Northcott, Andrey Korshunov, Marcel Kool, David T.W. Jones, and Stefan M. Pfister, German Cancer Research Center; Stefan M. Pfister, University Hospital Heidelberg, Heidelberg; Ulrich Schüller, Ludwig-Maximilians-University, Munich; Stefan Rutkowski, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Karel Zitterbart, Masaryk University School of Medicine; Karel Zitterbart and Leos Kren, University Hospital Brno, Brno, Czech Republic; Toshihiro Kumabe and Teiji Tominaga, Tohoku University Graduate School of Medicine, Sendai, Japan; Young Shin Ra, University of Ulsan, Asan Medical Center; Ji-Yeoun Lee, Byung-Kyu Cho, Seung-Ki Kim, and Kyu-Chang Wang, Seoul National University Children's Hospital, Seoul; Shin Jung, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Chonnam, South Korea; Peter Hauser and Miklós Garami, Semmelweis University, Budapest; László Bognár and Almos Klekner, University of Debrecen, Medical and Health Science Centre, Debrecen, Hungary; Shenandoah Robinson, Boston Children's Hospital; Scott L. Pomeroy, Harvard Medical School, Boston, MA; Ali G. Saad, University of Arkansas for Medical Sciences, Little

245 10: $a Cytogenetic prognostication within medulloblastoma subgroups / $c DJ. Shih, PA. Northcott, M. Remke, A. Korshunov, V. Ramaswamy, M. Kool, B. Luu, Y. Yao, X. Wang, AM. Dubuc, L. Garzia, J. Peacock, SC. Mack, X. Wu, A. Rolider, AS. Morrissy, FM. Cavalli, DT. Jones, K. Zitterbart, CC. Faria, U. Schüller, L. Kren, T. Kumabe, T. Tominaga, Y. Shin Ra, M. Garami, P. Hauser, JA. Chan, S. Robinson, L. Bognár, A. Klekner, AG. Saad, LM. Liau, S. Albrecht, A. Fontebasso, G. Cinalli, P. De Antonellis, M. Zollo, MK. Cooper, RC. Thompson, S. Bailey, JC. Lindsey, C. Di Rocco, L. Massimi, EM. Michiels, SW. Scherer, JJ. Phillips, N. Gupta, X. Fan, KM. Muraszko, R. Vibhakar, CG. Eberhart, M. Fouladi, B. Lach, S. Jung, RJ. Wechsler-Reya, M. Fèvre-Montange, A. Jouvet, N. Jabado, IF. Pollack, WA. Weiss, JY. Lee, BK. Cho, SK. Kim, KC. Wang, JR. Leonard, JB. Rubin, C. de Torres, C. Lavarino, J. Mora, YJ. Cho, U. Tabori, JM. Olson, A. Gajjar, RJ. Packer, S. Rutkowski, SL. Pomeroy, PJ. French, NK. Kloosterhof, JM. Kros, EG. Van Meir, SC. Clifford, F. Bourdeaut, O. Delattre, FF. Doz, CE. Hawkins, D. Malkin, WA. Grajkowska, M. Perek-Polnik, E. Bouffet, JT. Rutka, SM. Pfister, MD. Taylor,

520 9_: $a 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.

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