The whole-genome landscape of medulloblastoma subtypes

Paul A. Northcott; Ivo Buchhalter; A. Sorana Morrissy; Volker Hovestadt; Joachim Weischenfeldt; Tobias Ehrenberger; Susanne Gröbner; Maia Segura-Wang; Thomas Zichner; Vasilisa A. Rudneva; Hans Jörg Warnatz; Nikos Sidiropoulos; Aaron H. Phillips; Steven Schumacher; Kortine Kleinheinz; Sebastian M. Waszak; Serap Erkek; David T.W. Jones; Barbara C. Worst; Marcel Kool; Marc Zapatka; Natalie Jäger; Lukas Chavez; Barbara Hutter; Matthias Bieg; Nagarajan Paramasivam; Michael Heinold; Zuguang Gu; Naveed Ishaque; Christina Jäger-Schmidt; Charles D. Imbusch; Alke Jugold; Daniel Hübschmann; Thomas Risch; Vyacheslav Amstislavskiy; Francisco German Rodriguez Gonzalez; Ursula D. Weber; Stephan Wolf; Giles W. Robinson; Xin Zhou; Gang Wu; David Finkelstein; Yanling Liu; Florence M.G. Cavalli; Betty Luu; Vijay Ramaswamy; Xiaochong Wu; Jan Koster; Marina Ryzhova; Yoon Jae Cho; Scott L. Pomeroy; Christel Herold-Mende; Martin Schuhmann; Martin Ebinger; Linda M. Liau; Jaume Mora; Roger E. McLendon; Nada Jabado; Toshihiro Kumabe; Eric Chuah; Yussanne Ma; Richard A. Moore; Andrew J. Mungall; Karen L. Mungall; Nina Thiessen; Kane Tse; Tina Wong; Steven J.M. Jones; Olaf Witt; Till Milde; Andreas Von Deimling; David Capper; Andrey Korshunov; Marie Laure Yaspo; Richard Kriwacki; Amar Gajjar; Jinghui Zhang; Rameen Beroukhim; Ernest Fraenkel; Jan O. Korbel; Benedikt Brors; Matthias Schlesner; Roland Eils; Marco A. Marra; Stefan M. Pfister; Michael D. Taylor; Peter Lichter

doi:10.1038/nature22973

The whole-genome landscape of medulloblastoma subtypes

Paul A. Northcott, Ivo Buchhalter, A. Sorana Morrissy, Volker Hovestadt, Joachim Weischenfeldt, Tobias Ehrenberger, Susanne Gröbner, Maia Segura-Wang, Thomas Zichner, Vasilisa A. Rudneva, Hans Jörg Warnatz, Nikos Sidiropoulos, Aaron H. Phillips, Steven Schumacher, Kortine Kleinheinz, Sebastian M. Waszak, Serap Erkek, David T.W. Jones, Barbara C. Worst, Marcel KoolMarc Zapatka, Natalie Jäger, Lukas Chavez, Barbara Hutter, Matthias Bieg, Nagarajan Paramasivam, Michael Heinold, Zuguang Gu, Naveed Ishaque, Christina Jäger-Schmidt, Charles D. Imbusch, Alke Jugold, Daniel Hübschmann, Thomas Risch, Vyacheslav Amstislavskiy, Francisco German Rodriguez Gonzalez, Ursula D. Weber, Stephan Wolf, Giles W. Robinson, Xin Zhou, Gang Wu, David Finkelstein, Yanling Liu, Florence M.G. Cavalli, Betty Luu, Vijay Ramaswamy, Xiaochong Wu, Jan Koster, Marina Ryzhova, Yoon Jae Cho, Scott L. Pomeroy, Christel Herold-Mende, Martin Schuhmann, Martin Ebinger, Linda M. Liau, Jaume Mora, Roger E. McLendon, Nada Jabado, Toshihiro Kumabe, Eric Chuah, Yussanne Ma, Richard A. Moore, Andrew J. Mungall, Karen L. Mungall, Nina Thiessen, Kane Tse, Tina Wong, Steven J.M. Jones, Olaf Witt, Till Milde, Andreas Von Deimling, David Capper, Andrey Korshunov, Marie Laure Yaspo, Richard Kriwacki, Amar Gajjar, Jinghui Zhang, Rameen Beroukhim, Ernest Fraenkel, Jan O. Korbel, Benedikt Brors, Matthias Schlesner, Roland Eils, Marco A. Marra, Stefan M. Pfister^*, Michael D. Taylor, Peter Lichter

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

Original language	English
Journal	Nature
Volume	547
Issue number	7663
Pages (from-to)	311-317
Number of pages	7
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature22973
Publication status	Published - 19 Jul 2017

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The whole-genome landscape of medulloblastoma subtypesFinal published version, 9.48 MBLicence: CC BY

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Northcott, P. A., Buchhalter, I., Morrissy, A. S., Hovestadt, V., Weischenfeldt, J., Ehrenberger, T., Gröbner, S., Segura-Wang, M., Zichner, T., Rudneva, V. A., Warnatz, H. J., Sidiropoulos, N., Phillips, A. H., Schumacher, S., Kleinheinz, K., Waszak, S. M., Erkek, S., Jones, D. T. W., Worst, B. C., ... Lichter, P. (2017). The whole-genome landscape of medulloblastoma subtypes. Nature, 547(7663), 311-317. https://doi.org/10.1038/nature22973

The whole-genome landscape of medulloblastoma subtypes. / Northcott, Paul A.; Buchhalter, Ivo; Morrissy, A. Sorana; Hovestadt, Volker; Weischenfeldt, Joachim; Ehrenberger, Tobias; Gröbner, Susanne; Segura-Wang, Maia; Zichner, Thomas; Rudneva, Vasilisa A.; Warnatz, Hans Jörg; Sidiropoulos, Nikos; Phillips, Aaron H.; Schumacher, Steven; Kleinheinz, Kortine; Waszak, Sebastian M.; Erkek, Serap; Jones, David T.W.; Worst, Barbara C.; Kool, Marcel; Zapatka, Marc; Jäger, Natalie; Chavez, Lukas; Hutter, Barbara; Bieg, Matthias; Paramasivam, Nagarajan; Heinold, Michael; Gu, Zuguang; Ishaque, Naveed; Jäger-Schmidt, Christina; Imbusch, Charles D.; Jugold, Alke; Hübschmann, Daniel; Risch, Thomas; Amstislavskiy, Vyacheslav; Gonzalez, Francisco German Rodriguez; Weber, Ursula D.; Wolf, Stephan; Robinson, Giles W.; Zhou, Xin; Wu, Gang; Finkelstein, David; Liu, Yanling; Cavalli, Florence M.G.; Luu, Betty; Ramaswamy, Vijay; Wu, Xiaochong; Koster, Jan; Ryzhova, Marina; Cho, Yoon Jae; Pomeroy, Scott L.; Herold-Mende, Christel; Schuhmann, Martin; Ebinger, Martin; Liau, Linda M.; Mora, Jaume; McLendon, Roger E.; Jabado, Nada; Kumabe, Toshihiro; Chuah, Eric; Ma, Yussanne; Moore, Richard A.; Mungall, Andrew J.; Mungall, Karen L.; Thiessen, Nina; Tse, Kane; Wong, Tina; Jones, Steven J.M.; Witt, Olaf; Milde, Till; Von Deimling, Andreas; Capper, David; Korshunov, Andrey; Yaspo, Marie Laure; Kriwacki, Richard; Gajjar, Amar; Zhang, Jinghui; Beroukhim, Rameen; Fraenkel, Ernest; Korbel, Jan O.; Brors, Benedikt; Schlesner, Matthias; Eils, Roland; Marra, Marco A.; Pfister, Stefan M.; Taylor, Michael D.; Lichter, Peter.

In: Nature, Vol. 547, No. 7663, 19.07.2017, p. 311-317.

Research output: Contribution to journal › Journal article › Research › peer-review

Northcott, PA, Buchhalter, I, Morrissy, AS, Hovestadt, V, Weischenfeldt, J, Ehrenberger, T, Gröbner, S, Segura-Wang, M, Zichner, T, Rudneva, VA, Warnatz, HJ, Sidiropoulos, N, Phillips, AH, Schumacher, S, Kleinheinz, K, Waszak, SM, Erkek, S, Jones, DTW, Worst, BC, Kool, M, Zapatka, M, Jäger, N, Chavez, L, Hutter, B, Bieg, M, Paramasivam, N, Heinold, M, Gu, Z, Ishaque, N, Jäger-Schmidt, C, Imbusch, CD, Jugold, A, Hübschmann, D, Risch, T, Amstislavskiy, V, Gonzalez, FGR, Weber, UD, Wolf, S, Robinson, GW, Zhou, X, Wu, G, Finkelstein, D, Liu, Y, Cavalli, FMG, Luu, B, Ramaswamy, V, Wu, X, Koster, J, Ryzhova, M, Cho, YJ, Pomeroy, SL, Herold-Mende, C, Schuhmann, M, Ebinger, M, Liau, LM, Mora, J, McLendon, RE, Jabado, N, Kumabe, T, Chuah, E, Ma, Y, Moore, RA, Mungall, AJ, Mungall, KL, Thiessen, N, Tse, K, Wong, T, Jones, SJM, Witt, O, Milde, T, Von Deimling, A, Capper, D, Korshunov, A, Yaspo, ML, Kriwacki, R, Gajjar, A, Zhang, J, Beroukhim, R, Fraenkel, E, Korbel, JO, Brors, B, Schlesner, M, Eils, R, Marra, MA, Pfister, SM, Taylor, MD & Lichter, P 2017, 'The whole-genome landscape of medulloblastoma subtypes', Nature, vol. 547, no. 7663, pp. 311-317. https://doi.org/10.1038/nature22973

Northcott, Paul A. ; Buchhalter, Ivo ; Morrissy, A. Sorana ; Hovestadt, Volker ; Weischenfeldt, Joachim ; Ehrenberger, Tobias ; Gröbner, Susanne ; Segura-Wang, Maia ; Zichner, Thomas ; Rudneva, Vasilisa A. ; Warnatz, Hans Jörg ; Sidiropoulos, Nikos ; Phillips, Aaron H. ; Schumacher, Steven ; Kleinheinz, Kortine ; Waszak, Sebastian M. ; Erkek, Serap ; Jones, David T.W. ; Worst, Barbara C. ; Kool, Marcel ; Zapatka, Marc ; Jäger, Natalie ; Chavez, Lukas ; Hutter, Barbara ; Bieg, Matthias ; Paramasivam, Nagarajan ; Heinold, Michael ; Gu, Zuguang ; Ishaque, Naveed ; Jäger-Schmidt, Christina ; Imbusch, Charles D. ; Jugold, Alke ; Hübschmann, Daniel ; Risch, Thomas ; Amstislavskiy, Vyacheslav ; Gonzalez, Francisco German Rodriguez ; Weber, Ursula D. ; Wolf, Stephan ; Robinson, Giles W. ; Zhou, Xin ; Wu, Gang ; Finkelstein, David ; Liu, Yanling ; Cavalli, Florence M.G. ; Luu, Betty ; Ramaswamy, Vijay ; Wu, Xiaochong ; Koster, Jan ; Ryzhova, Marina ; Cho, Yoon Jae ; Pomeroy, Scott L. ; Herold-Mende, Christel ; Schuhmann, Martin ; Ebinger, Martin ; Liau, Linda M. ; Mora, Jaume ; McLendon, Roger E. ; Jabado, Nada ; Kumabe, Toshihiro ; Chuah, Eric ; Ma, Yussanne ; Moore, Richard A. ; Mungall, Andrew J. ; Mungall, Karen L. ; Thiessen, Nina ; Tse, Kane ; Wong, Tina ; Jones, Steven J.M. ; Witt, Olaf ; Milde, Till ; Von Deimling, Andreas ; Capper, David ; Korshunov, Andrey ; Yaspo, Marie Laure ; Kriwacki, Richard ; Gajjar, Amar ; Zhang, Jinghui ; Beroukhim, Rameen ; Fraenkel, Ernest ; Korbel, Jan O. ; Brors, Benedikt ; Schlesner, Matthias ; Eils, Roland ; Marra, Marco A. ; Pfister, Stefan M. ; Taylor, Michael D. ; Lichter, Peter. / The whole-genome landscape of medulloblastoma subtypes. In: Nature. 2017 ; Vol. 547, No. 7663. pp. 311-317.

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title = "The whole-genome landscape of medulloblastoma subtypes",

abstract = "Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.",

author = "Northcott, {Paul A.} and Ivo Buchhalter and Morrissy, {A. Sorana} and Volker Hovestadt and Joachim Weischenfeldt and Tobias Ehrenberger and Susanne Gr{\"o}bner and Maia Segura-Wang and Thomas Zichner and Rudneva, {Vasilisa A.} and Warnatz, {Hans J{\"o}rg} and Nikos Sidiropoulos and Phillips, {Aaron H.} and Steven Schumacher and Kortine Kleinheinz and Waszak, {Sebastian M.} and Serap Erkek and Jones, {David T.W.} and Worst, {Barbara C.} and Marcel Kool and Marc Zapatka and Natalie J{\"a}ger and Lukas Chavez and Barbara Hutter and Matthias Bieg and Nagarajan Paramasivam and Michael Heinold and Zuguang Gu and Naveed Ishaque and Christina J{\"a}ger-Schmidt and Imbusch, {Charles D.} and Alke Jugold and Daniel H{\"u}bschmann and Thomas Risch and Vyacheslav Amstislavskiy and Gonzalez, {Francisco German Rodriguez} and Weber, {Ursula D.} and Stephan Wolf and Robinson, {Giles W.} and Xin Zhou and Gang Wu and David Finkelstein and Yanling Liu and Cavalli, {Florence M.G.} and Betty Luu and Vijay Ramaswamy and Xiaochong Wu and Jan Koster and Marina Ryzhova and Cho, {Yoon Jae} and Pomeroy, {Scott L.} and Christel Herold-Mende and Martin Schuhmann and Martin Ebinger and Liau, {Linda M.} and Jaume Mora and McLendon, {Roger E.} and Nada Jabado and Toshihiro Kumabe and Eric Chuah and Yussanne Ma and Moore, {Richard A.} and Mungall, {Andrew J.} and Mungall, {Karen L.} and Nina Thiessen and Kane Tse and Tina Wong and Jones, {Steven J.M.} and Olaf Witt and Till Milde and {Von Deimling}, Andreas and David Capper and Andrey Korshunov and Yaspo, {Marie Laure} and Richard Kriwacki and Amar Gajjar and Jinghui Zhang and Rameen Beroukhim and Ernest Fraenkel and Korbel, {Jan O.} and Benedikt Brors and Matthias Schlesner and Roland Eils and Marra, {Marco A.} and Pfister, {Stefan M.} and Taylor, {Michael D.} and Peter Lichter",

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T1 - The whole-genome landscape of medulloblastoma subtypes

AU - Northcott, Paul A.

AU - Buchhalter, Ivo

AU - Morrissy, A. Sorana

AU - Hovestadt, Volker

AU - Weischenfeldt, Joachim

AU - Ehrenberger, Tobias

AU - Gröbner, Susanne

AU - Segura-Wang, Maia

AU - Zichner, Thomas

AU - Rudneva, Vasilisa A.

AU - Warnatz, Hans Jörg

AU - Sidiropoulos, Nikos

AU - Phillips, Aaron H.

AU - Schumacher, Steven

AU - Kleinheinz, Kortine

AU - Waszak, Sebastian M.

AU - Erkek, Serap

AU - Jones, David T.W.

AU - Worst, Barbara C.

AU - Kool, Marcel

AU - Zapatka, Marc

AU - Jäger, Natalie

AU - Chavez, Lukas

AU - Hutter, Barbara

AU - Bieg, Matthias

AU - Paramasivam, Nagarajan

AU - Heinold, Michael

AU - Gu, Zuguang

AU - Ishaque, Naveed

AU - Jäger-Schmidt, Christina

AU - Imbusch, Charles D.

AU - Jugold, Alke

AU - Hübschmann, Daniel

AU - Risch, Thomas

AU - Amstislavskiy, Vyacheslav

AU - Gonzalez, Francisco German Rodriguez

AU - Weber, Ursula D.

AU - Wolf, Stephan

AU - Robinson, Giles W.

AU - Zhou, Xin

AU - Wu, Gang

AU - Finkelstein, David

AU - Liu, Yanling

AU - Cavalli, Florence M.G.

AU - Luu, Betty

AU - Ramaswamy, Vijay

AU - Wu, Xiaochong

AU - Koster, Jan

AU - Ryzhova, Marina

AU - Cho, Yoon Jae

AU - Pomeroy, Scott L.

AU - Herold-Mende, Christel

AU - Schuhmann, Martin

AU - Ebinger, Martin

AU - Liau, Linda M.

AU - Mora, Jaume

AU - McLendon, Roger E.

AU - Jabado, Nada

AU - Kumabe, Toshihiro

AU - Chuah, Eric

AU - Ma, Yussanne

AU - Moore, Richard A.

AU - Mungall, Andrew J.

AU - Mungall, Karen L.

AU - Thiessen, Nina

AU - Tse, Kane

AU - Wong, Tina

AU - Jones, Steven J.M.

AU - Witt, Olaf

AU - Milde, Till

AU - Von Deimling, Andreas

AU - Capper, David

AU - Korshunov, Andrey

AU - Yaspo, Marie Laure

AU - Kriwacki, Richard

AU - Gajjar, Amar

AU - Zhang, Jinghui

AU - Beroukhim, Rameen

AU - Fraenkel, Ernest

AU - Korbel, Jan O.

AU - Brors, Benedikt

AU - Schlesner, Matthias

AU - Eils, Roland

AU - Marra, Marco A.

AU - Pfister, Stefan M.

AU - Taylor, Michael D.

AU - Lichter, Peter

PY - 2017/7/19

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N2 - Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

AB - Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

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