Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Paul A. Northcott, David J.H. Shih, John Peacock, Livia Garzia, A. Sorana Morrissy, Thomas Zichner, Adrian M. Stútz, Andrey Korshunov, Júri Reimand, Steven E. Schumacher, Rameen Beroukhim, David W. Ellison, Christian R. Marshall, Anath C. Lionel, Stephen MacK, Adrian Dubuc, Yuan Yao, Vijay Ramaswamy, Betty Luu, Adi Rolider & 115 others Florence M.G. Cavalli, Xin Wang, Marc Remke, Xiaochong Wu, Readman Y.B. Chiu, Andy Chu, Eric Chuah, Richard D. Corbett, Gemma R. Hoad, Shaun D. Jackman, Yisu Li, Allan Lo, Karen L. Mungall, Ka Ming Nip, Jenny Q. Qian, Anthony G.J. Raymond, Nina Thiessen, Richard J. Varhol, Inanc Birol, Richard A. Moore, Andrew J. Mungall, Robert Holt, Daisuke Kawauchi, Martine F. Roussel, Marcel Kool, David T.W. Jones, Hendrick Witt, Africa Fernandez-L, Anna M. Kenney, Robert J. Wechsler-Reya, Peter Dirks, Tzvi Aviv, Wieslawa A. Grajkowska, Marta Perek-Polnik, Christine C. Haberler, Olivier Delattre, Stéphanie S. Reynaud, François F. Doz, Sarah S. Pernet-Fattet, Byung Kyu Cho, Seung Ki Kim, Kyu Chang Wang, Wolfram Scheurlen, Charles G. Eberhart, Michelle Fèvre-Montange, Anne Jouvet, Ian F. Pollack, Xing Fan, Karin M. Muraszko, G. Yancey Gillespie, Concezio Di Rocco, Luca Massimi, Erna M.C. Michiels, Nanne K. Kloosterhof, Pim J. French, Johan M. Kros, James M. Olson, Richard G. Ellenbogen, Karel Zitterbart, Leos Kren, Reid C. Thompson, Michael K. Cooper, Boleslaw Lach, Roger E. McLendon, Darell D. Bigner, Adam Fontebasso, Steffen Albrecht, Nada Jabado, Janet C. Lindsey, Simon Bailey, Nalin Gupta, William A. Weiss, László Bognár, Almos Klekner, Timothy E. Van Meter, Toshihiro Kumabe, Teiji Tominaga, Samer K. Elbabaa, Jeffrey R. Leonard, Joshua B. Rubin, Linda M. Liau, Erwin G. Van Meir, Maryam Fouladi, Hideo Nakamura, Giuseppe Cinalli, Miklós Garami, Peter Hauser, Ali Saad, Achille Iolascon, Shin Jung, Carlos G. Carlotti, Rajeev Vibhakar, Young Shin Ra, Shenandoah Robinson, Massimo Zollo, Claudia C. Faria, Jennifer A. Chan, Michael L. Levy, Poul H.B. Sorensen, Matthew Meyerson, Scott L. Pomeroy, Yoon Jae Cho, Gary D. Bader, Uri Tabori, Cynthia E. Hawkins, Eric Bouffet, Stephen W. Scherer, James T. Rutka, David Malkin, Steven C. Clifford, Steven J.M. Jones, Jan O. Korbel, Stefan M. Pfister, Marco A. Marra, Michael D. Taylor

Research output: Contribution to journalArticle

398 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)49-56
Number of pages8
JournalNature
Volume487
Issue number7409
DOIs
StatePublished - Aug 2 2012

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Medulloblastoma
Genome
Brain Neoplasms
Sample Size
Parkinson Disease
Therapeutics
Radiation
Pediatrics
Drug Therapy
Brain
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Northcott, P. A., Shih, D. J. H., Peacock, J., Garzia, L., Sorana Morrissy, A., Zichner, T., ... Taylor, M. D. (2012). Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature, 487(7409), 49-56. https://doi.org/10.1038/nature11327

Subgroup-specific structural variation across 1,000 medulloblastoma genomes. / Northcott, Paul A.; Shih, David J.H.; Peacock, John; Garzia, Livia; Sorana Morrissy, A.; Zichner, Thomas; Stútz, Adrian M.; Korshunov, Andrey; Reimand, Júri; 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 M.G.; Wang, Xin; Remke, Marc; Wu, Xiaochong; Chiu, Readman Y.B.; Chu, Andy; Chuah, Eric; Corbett, Richard D.; Hoad, Gemma R.; Jackman, Shaun D.; Li, Yisu; Lo, Allan; Mungall, Karen L.; Ming Nip, Ka; Qian, Jenny Q.; Raymond, Anthony G.J.; Thiessen, Nina; Varhol, Richard J.; Birol, Inanc; Moore, Richard A.; Mungall, Andrew J.; Holt, Robert; Kawauchi, Daisuke; Roussel, Martine F.; Kool, Marcel; Jones, David T.W.; 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.; Yancey Gillespie, G.; Di Rocco, Concezio; Massimi, Luca; Michiels, Erna M.C.; 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.; Rubin, Joshua B.; Liau, Linda M.; Van Meir, Erwin G.; Fouladi, Maryam; Nakamura, Hideo; Cinalli, Giuseppe; Garami, Miklós; Hauser, Peter; Saad, Ali; Iolascon, Achille; Jung, Shin; Carlotti, Carlos G.; Vibhakar, Rajeev; Shin Ra, Young; Robinson, Shenandoah; Zollo, Massimo; Faria, Claudia C.; Chan, Jennifer A.; Levy, Michael L.; Sorensen, Poul H.B.; Meyerson, Matthew; Pomeroy, Scott L.; Cho, Yoon Jae; Bader, Gary D.; Tabori, Uri; Hawkins, Cynthia E.; Bouffet, Eric; Scherer, Stephen W.; Rutka, James T.; Malkin, David; Clifford, Steven C.; Jones, Steven J.M.; Korbel, Jan O.; Pfister, Stefan M.; Marra, Marco A.; Taylor, Michael D.

In: Nature, Vol. 487, No. 7409, 02.08.2012, p. 49-56.

Research output: Contribution to journalArticle

Northcott, PA, Shih, DJH, Peacock, J, Garzia, L, Sorana Morrissy, A, Zichner, T, Stútz, AM, Korshunov, A, Reimand, J, Schumacher, SE, Beroukhim, R, Ellison, DW, Marshall, CR, Lionel, AC, MacK, S, Dubuc, A, Yao, Y, Ramaswamy, V, Luu, B, Rolider, A, Cavalli, FMG, Wang, X, Remke, M, Wu, X, Chiu, RYB, Chu, A, Chuah, E, Corbett, RD, Hoad, GR, Jackman, SD, Li, Y, Lo, A, Mungall, KL, Ming Nip, K, Qian, JQ, Raymond, AGJ, Thiessen, N, Varhol, RJ, Birol, I, Moore, RA, Mungall, AJ, Holt, R, Kawauchi, D, Roussel, MF, Kool, M, Jones, DTW, Witt, H, Fernandez-L, A, Kenney, AM, Wechsler-Reya, RJ, Dirks, P, Aviv, T, Grajkowska, WA, Perek-Polnik, M, Haberler, CC, Delattre, O, Reynaud, SS, Doz, FF, Pernet-Fattet, SS, Cho, BK, Kim, SK, Wang, KC, Scheurlen, W, Eberhart, CG, Fèvre-Montange, M, Jouvet, A, Pollack, IF, Fan, X, Muraszko, KM, Yancey Gillespie, G, Di Rocco, C, Massimi, L, Michiels, EMC, Kloosterhof, NK, French, PJ, Kros, JM, Olson, JM, Ellenbogen, RG, Zitterbart, K, Kren, L, Thompson, RC, 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, A, Iolascon, A, Jung, S, Carlotti, CG, Vibhakar, R, Shin Ra, Y, Robinson, S, Zollo, M, Faria, CC, Chan, JA, Levy, ML, Sorensen, PHB, Meyerson, M, Pomeroy, SL, Cho, YJ, Bader, GD, Tabori, U, Hawkins, CE, Bouffet, E, Scherer, SW, Rutka, JT, Malkin, D, Clifford, SC, Jones, SJM, Korbel, JO, Pfister, SM, Marra, MA & Taylor, MD 2012, 'Subgroup-specific structural variation across 1,000 medulloblastoma genomes', Nature, vol. 487, no. 7409, pp. 49-56. https://doi.org/10.1038/nature11327
Northcott PA, Shih DJH, Peacock J, Garzia L, Sorana Morrissy A, Zichner T et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012 Aug 2;487(7409):49-56. https://doi.org/10.1038/nature11327
Northcott, Paul A. ; Shih, David J.H. ; Peacock, John ; Garzia, Livia ; Sorana Morrissy, A. ; Zichner, Thomas ; Stútz, Adrian M. ; Korshunov, Andrey ; Reimand, Júri ; 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 M.G. ; Wang, Xin ; Remke, Marc ; Wu, Xiaochong ; Chiu, Readman Y.B. ; Chu, Andy ; Chuah, Eric ; Corbett, Richard D. ; Hoad, Gemma R. ; Jackman, Shaun D. ; Li, Yisu ; Lo, Allan ; Mungall, Karen L. ; Ming Nip, Ka ; Qian, Jenny Q. ; Raymond, Anthony G.J. ; Thiessen, Nina ; Varhol, Richard J. ; Birol, Inanc ; Moore, Richard A. ; Mungall, Andrew J. ; Holt, Robert ; Kawauchi, Daisuke ; Roussel, Martine F. ; Kool, Marcel ; Jones, David T.W. ; 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. ; Yancey Gillespie, G. ; Di Rocco, Concezio ; Massimi, Luca ; Michiels, Erna M.C. ; 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. ; Rubin, Joshua B. ; Liau, Linda M. ; Van Meir, Erwin G. ; Fouladi, Maryam ; Nakamura, Hideo ; Cinalli, Giuseppe ; Garami, Miklós ; Hauser, Peter ; Saad, Ali ; Iolascon, Achille ; Jung, Shin ; Carlotti, Carlos G. ; Vibhakar, Rajeev ; Shin Ra, Young ; Robinson, Shenandoah ; Zollo, Massimo ; Faria, Claudia C. ; Chan, Jennifer A. ; Levy, Michael L. ; Sorensen, Poul H.B. ; Meyerson, Matthew ; Pomeroy, Scott L. ; Cho, Yoon Jae ; Bader, Gary D. ; Tabori, Uri ; Hawkins, Cynthia E. ; Bouffet, Eric ; Scherer, Stephen W. ; Rutka, James T. ; Malkin, David ; Clifford, Steven C. ; Jones, Steven J.M. ; Korbel, Jan O. ; Pfister, Stefan M. ; Marra, Marco A. ; Taylor, Michael D. / Subgroup-specific structural variation across 1,000 medulloblastoma genomes. In: Nature. 2012 ; Vol. 487, No. 7409. pp. 49-56.
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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.",
author = "Northcott, {Paul A.} and Shih, {David J.H.} and John Peacock and Livia Garzia and {Sorana Morrissy}, A. and Thomas Zichner and St{\'u}tz, {Adrian M.} and Andrey Korshunov and J{\'u}ri Reimand and Schumacher, {Steven E.} and Rameen Beroukhim and Ellison, {David W.} and Marshall, {Christian R.} and Lionel, {Anath C.} and Stephen MacK and Adrian Dubuc and Yuan Yao and Vijay Ramaswamy and Betty Luu and Adi Rolider and Cavalli, {Florence M.G.} and Xin Wang and Marc Remke and Xiaochong Wu and Chiu, {Readman Y.B.} and Andy Chu and Eric Chuah and Corbett, {Richard D.} and Hoad, {Gemma R.} and Jackman, {Shaun D.} and Yisu Li and Allan Lo and Mungall, {Karen L.} and {Ming Nip}, Ka and Qian, {Jenny Q.} and Raymond, {Anthony G.J.} and Nina Thiessen and Varhol, {Richard J.} and Inanc Birol and Moore, {Richard A.} and Mungall, {Andrew J.} and Robert Holt and Daisuke Kawauchi and Roussel, {Martine F.} and Marcel Kool and Jones, {David T.W.} and Hendrick Witt and Africa Fernandez-L and Kenney, {Anna M.} and Wechsler-Reya, {Robert J.} and Peter Dirks and Tzvi Aviv and Grajkowska, {Wieslawa A.} and Marta Perek-Polnik and Haberler, {Christine C.} and Olivier Delattre and Reynaud, {St{\'e}phanie S.} and Doz, {Fran{\cc}ois F.} and Pernet-Fattet, {Sarah S.} and Cho, {Byung Kyu} and Kim, {Seung Ki} and Wang, {Kyu Chang} and Wolfram Scheurlen and Eberhart, {Charles G.} and Michelle F{\`e}vre-Montange and Anne Jouvet and Pollack, {Ian F.} and Xing Fan and Muraszko, {Karin M.} and {Yancey Gillespie}, G. and {Di Rocco}, Concezio and Luca Massimi and Michiels, {Erna M.C.} and Kloosterhof, {Nanne K.} and French, {Pim J.} and Kros, {Johan M.} and Olson, {James M.} and Ellenbogen, {Richard G.} and Karel Zitterbart and Leos Kren and Thompson, {Reid C.} and Cooper, {Michael K.} and Boleslaw Lach and McLendon, {Roger E.} and Bigner, {Darell D.} and Adam Fontebasso and Steffen Albrecht and Nada Jabado and Lindsey, {Janet C.} and Simon Bailey and Nalin Gupta and Weiss, {William A.} and L{\'a}szl{\'o} Bogn{\'a}r and Almos Klekner and {Van Meter}, {Timothy E.} and Toshihiro Kumabe and Teiji Tominaga and Elbabaa, {Samer K.} and Leonard, {Jeffrey R.} and Rubin, {Joshua B.} and Liau, {Linda M.} and {Van Meir}, {Erwin G.} and Maryam Fouladi and Hideo Nakamura and Giuseppe Cinalli and Mikl{\'o}s Garami and Peter Hauser and Ali Saad and Achille Iolascon and Shin Jung and Carlotti, {Carlos G.} and Rajeev Vibhakar and {Shin Ra}, Young and Shenandoah Robinson and Massimo Zollo and Faria, {Claudia C.} and Chan, {Jennifer A.} and Levy, {Michael L.} and Sorensen, {Poul H.B.} and Matthew Meyerson and Pomeroy, {Scott L.} and Cho, {Yoon Jae} and Bader, {Gary D.} and Uri Tabori and Hawkins, {Cynthia E.} and Eric Bouffet and Scherer, {Stephen W.} and Rutka, {James T.} and David Malkin and Clifford, {Steven C.} and Jones, {Steven J.M.} and Korbel, {Jan O.} and Pfister, {Stefan M.} and Marra, {Marco A.} and Taylor, {Michael D.}",
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T1 - Subgroup-specific structural variation across 1,000 medulloblastoma genomes

AU - Northcott, Paul A.

AU - Shih, David J.H.

AU - Peacock, John

AU - Garzia, Livia

AU - Sorana Morrissy, A.

AU - Zichner, Thomas

AU - Stútz, Adrian M.

AU - Korshunov, Andrey

AU - Reimand, Júri

AU - Schumacher, Steven E.

AU - Beroukhim, Rameen

AU - Ellison, David W.

AU - Marshall, Christian R.

AU - Lionel, Anath C.

AU - MacK, Stephen

AU - Dubuc, Adrian

AU - Yao, Yuan

AU - Ramaswamy, Vijay

AU - Luu, Betty

AU - Rolider, Adi

AU - Cavalli, Florence M.G.

AU - Wang, Xin

AU - Remke, Marc

AU - Wu, Xiaochong

AU - Chiu, Readman Y.B.

AU - Chu, Andy

AU - Chuah, Eric

AU - Corbett, Richard D.

AU - Hoad, Gemma R.

AU - Jackman, Shaun D.

AU - Li, Yisu

AU - Lo, Allan

AU - Mungall, Karen L.

AU - Ming Nip, Ka

AU - Qian, Jenny Q.

AU - Raymond, Anthony G.J.

AU - Thiessen, Nina

AU - Varhol, Richard J.

AU - Birol, Inanc

AU - Moore, Richard A.

AU - Mungall, Andrew J.

AU - Holt, Robert

AU - Kawauchi, Daisuke

AU - Roussel, Martine F.

AU - Kool, Marcel

AU - Jones, David T.W.

AU - Witt, Hendrick

AU - Fernandez-L, Africa

AU - Kenney, Anna M.

AU - Wechsler-Reya, Robert J.

AU - Dirks, Peter

AU - Aviv, Tzvi

AU - Grajkowska, Wieslawa A.

AU - Perek-Polnik, Marta

AU - Haberler, Christine C.

AU - Delattre, Olivier

AU - Reynaud, Stéphanie S.

AU - Doz, François F.

AU - Pernet-Fattet, Sarah S.

AU - Cho, Byung Kyu

AU - Kim, Seung Ki

AU - Wang, Kyu Chang

AU - Scheurlen, Wolfram

AU - Eberhart, Charles G.

AU - Fèvre-Montange, Michelle

AU - Jouvet, Anne

AU - Pollack, Ian F.

AU - Fan, Xing

AU - Muraszko, Karin M.

AU - Yancey Gillespie, G.

AU - Di Rocco, Concezio

AU - Massimi, Luca

AU - Michiels, Erna M.C.

AU - Kloosterhof, Nanne K.

AU - French, Pim J.

AU - Kros, Johan M.

AU - Olson, James M.

AU - Ellenbogen, Richard G.

AU - Zitterbart, Karel

AU - Kren, Leos

AU - Thompson, Reid C.

AU - Cooper, Michael K.

AU - Lach, Boleslaw

AU - McLendon, Roger E.

AU - Bigner, Darell D.

AU - Fontebasso, Adam

AU - Albrecht, Steffen

AU - Jabado, Nada

AU - Lindsey, Janet C.

AU - Bailey, Simon

AU - Gupta, Nalin

AU - Weiss, William A.

AU - Bognár, László

AU - Klekner, Almos

AU - Van Meter, Timothy E.

AU - Kumabe, Toshihiro

AU - Tominaga, Teiji

AU - Elbabaa, Samer K.

AU - Leonard, Jeffrey R.

AU - Rubin, Joshua B.

AU - Liau, Linda M.

AU - Van Meir, Erwin G.

AU - Fouladi, Maryam

AU - Nakamura, Hideo

AU - Cinalli, Giuseppe

AU - Garami, Miklós

AU - Hauser, Peter

AU - Saad, Ali

AU - Iolascon, Achille

AU - Jung, Shin

AU - Carlotti, Carlos G.

AU - Vibhakar, Rajeev

AU - Shin Ra, Young

AU - Robinson, Shenandoah

AU - Zollo, Massimo

AU - Faria, Claudia C.

AU - Chan, Jennifer A.

AU - Levy, Michael L.

AU - Sorensen, Poul H.B.

AU - Meyerson, Matthew

AU - Pomeroy, Scott L.

AU - Cho, Yoon Jae

AU - Bader, Gary D.

AU - Tabori, Uri

AU - Hawkins, Cynthia E.

AU - Bouffet, Eric

AU - Scherer, Stephen W.

AU - Rutka, James T.

AU - Malkin, David

AU - Clifford, Steven C.

AU - Jones, Steven J.M.

AU - Korbel, Jan O.

AU - Pfister, Stefan M.

AU - Marra, Marco A.

AU - Taylor, Michael D.

PY - 2012/8/2

Y1 - 2012/8/2

N2 - 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.

AB - 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.

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