Subgroup-specific structural variation across 1,000 medulloblastoma genomes

PA Northcott; DJH Shih; J Peacock; L Garzia; AS Morrissy; T Zichner; AM Stutz; A Korshunov; J Reimand; SE Schumacher; R Beroukhim; DW Ellison; CR Marshall; AC Lionel; S Mack; A Dubuc; Y Yao; V Ramaswamy; B Luu; A Rolider; FMG Cavalli; X Wang; M Remke; XC Wu; RYB Chiu; A Chu; E Chuah; RD Corbett; GR Hoad; SD Jackman; YS Li; A Lo; KL Mungall; KM Nip; JQ Qian; AGJ Raymond; N Thiessen; RJ Varhol; I Birol; RA Moore; AJ Mungall; R van der Holt; D Kawauchi; MF Roussel; Mirjam Kool; DTW Jones; H Witt; A Fernandez-L; AM Kenney; RJ Wechsler-Reya; P Dirks; T Aviv; WA Grajkowska; M Perek-Polnik; CC Haberler; O Delattre; SS Reynaud; FF Doz; SS Pernet-Fattet; BK Cho; SK Kim; KC Wang; W Scheurlen; CG Eberhart; M Fevre-Montange; A Jouvet; IF Pollack; X Fan; KM Muraszko; GY Gillespie; C Di Rocco; L Massimi; Erna Michiels; Nanne Kloosterhof; Pim French; J.M. Kros; JM Olson; RG Ellenbogen; K Zitterbart; L Kren; RC Thompson; MK Cooper; B Lach; RE McLendon; DD Bigner; A Fontebasso; S Albrecht; N Jabado; JC Lindsey; S Bailey; N Gupta; WA Weiss; L Bognar; A Klekner; TE Van Meter; T Kumabe; T Tominaga; SK Elbabaa; JR Leonard; JB Rubin; LM Liau; EG van Meir; M Fouladi; H Nakamura; G Cinalli; M Garami; P Hauser; AG Saad; A Iolascon; S Jung; CG Carlotti; R Vibhakar; YS Ra; S Robinson; M Zollo; CC Faria; JA Chan; ML Levy; PHB Sorensen; M Meyerson; SL Pomeroy; YJ Cho; GD Bader; U Tabori; CE Hawkins; E Bouffet; SW Scherer; JT Rutka; D Malkin; SC Clifford; SJM Jones; JO Korbel; SM Pfister; MA Marra; MD Taylor

doi:10.1038/nature11327

Subgroup-specific structural variation across 1,000 medulloblastoma genomes

PA Northcott, DJH Shih, J Peacock, L Garzia, AS Morrissy, T Zichner, AM Stutz, A Korshunov, J Reimand, SE Schumacher, R Beroukhim, DW Ellison, CR Marshall, AC Lionel, S Mack, A Dubuc, Y Yao, V Ramaswamy, B Luu, A RoliderFMG Cavalli, X Wang, M Remke, XC Wu, RYB Chiu, A Chu, E Chuah, RD Corbett, GR Hoad, SD Jackman, YS Li, A Lo, KL Mungall, KM Nip, JQ Qian, AGJ Raymond, N Thiessen, RJ Varhol, I Birol, RA Moore, AJ Mungall, R van der Holt, D Kawauchi, MF Roussel, Mirjam Kool, DTW Jones, H Witt, A Fernandez-L, AM Kenney, RJ Wechsler-Reya, P Dirks, T Aviv, WA Grajkowska, M Perek-Polnik, CC Haberler, O Delattre, SS Reynaud, FF Doz, SS Pernet-Fattet, BK Cho, SK Kim, KC Wang, W Scheurlen, CG Eberhart, M Fevre-Montange, A Jouvet, IF Pollack, X Fan, KM Muraszko, GY Gillespie, C Di Rocco, L Massimi, Erna Michiels, Nanne Kloosterhof, Pim French, J.M. Kros, JM Olson, RG Ellenbogen, K Zitterbart, L Kren, RC Thompson, MK Cooper, B Lach, RE McLendon, DD Bigner, A Fontebasso, S Albrecht, N Jabado, JC Lindsey, S Bailey, N Gupta, WA Weiss, L Bognar, A Klekner, TE Van Meter, T Kumabe, T Tominaga, SK Elbabaa, JR Leonard, JB Rubin, LM Liau, EG van Meir, M Fouladi, H Nakamura, G Cinalli, M Garami, P Hauser, AG Saad, A Iolascon, S Jung, CG Carlotti, R Vibhakar, YS Ra, S Robinson, M Zollo, CC Faria, JA Chan, ML Levy, PHB Sorensen, M Meyerson, SL Pomeroy, YJ Cho, GD Bader, U Tabori, CE Hawkins, E Bouffet, SW Scherer, JT Rutka, D Malkin, SC Clifford, SJM Jones, JO Korbel, SM Pfister, MA Marra, MD Taylor

Research output: Contribution to journal › Article › Academic › peer-review

717 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 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.

Original language	English
Pages (from-to)	49-56
Number of pages	8
Journal	Nature
Volume	488
Issue number	7409
DOIs	https://doi.org/10.1038/nature11327
Publication status	Published - 2012

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Northcott, PA., Shih, DJH., Peacock, J., Garzia, L., Morrissy, AS., Zichner, T., Stutz, 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., ... Taylor, MD. (2012). Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature, 488(7409), 49-56. https://doi.org/10.1038/nature11327

@article{e92d8a69c09e47f4890950517a3013ba,

title = "Subgroup-specific structural variation across 1,000 medulloblastoma genomes",

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.",

author = "PA Northcott and DJH Shih and J Peacock and L Garzia and AS Morrissy and T Zichner and AM Stutz and A Korshunov and J Reimand and SE Schumacher and R Beroukhim and DW Ellison and CR Marshall and AC Lionel and S Mack and A Dubuc and Y Yao and V Ramaswamy and B Luu and A Rolider and FMG Cavalli and X Wang and M Remke and XC Wu and RYB Chiu and A Chu and E Chuah and RD Corbett and GR Hoad and SD Jackman and YS Li and A Lo and KL Mungall and KM Nip and JQ Qian and AGJ Raymond and N Thiessen and RJ Varhol and I Birol and RA Moore and AJ Mungall and {van der Holt}, R and D Kawauchi and MF Roussel and Mirjam Kool and DTW Jones and H Witt and A Fernandez-L and AM Kenney and RJ Wechsler-Reya and P Dirks and T Aviv and WA Grajkowska and M Perek-Polnik and CC Haberler and O Delattre and SS Reynaud and FF Doz and SS Pernet-Fattet and BK Cho and SK Kim and KC Wang and W Scheurlen and CG Eberhart and M Fevre-Montange and A Jouvet and IF Pollack and X Fan and KM Muraszko and GY Gillespie and {Di Rocco}, C and L Massimi and Erna Michiels and Nanne Kloosterhof and Pim French and J.M. Kros and JM Olson and RG Ellenbogen and K Zitterbart and L Kren and RC Thompson and MK Cooper and B Lach and RE McLendon and DD Bigner and A Fontebasso and S Albrecht and N Jabado and JC Lindsey and S Bailey and N Gupta and WA Weiss and L Bognar and A Klekner and {Van Meter}, TE and T Kumabe and T Tominaga and SK Elbabaa and JR Leonard and JB Rubin and LM Liau and {van Meir}, EG and M Fouladi and H Nakamura and G Cinalli and M Garami and P Hauser and AG Saad and A Iolascon and S Jung and CG Carlotti and R Vibhakar and YS Ra and S Robinson and M Zollo and CC Faria and JA Chan and ML Levy and PHB Sorensen and M Meyerson and SL Pomeroy and YJ Cho and GD Bader and U Tabori and CE Hawkins and E Bouffet and SW Scherer and JT Rutka and D Malkin and SC Clifford and SJM Jones and JO Korbel and SM Pfister and MA Marra and MD Taylor",

year = "2012",

doi = "10.1038/nature11327",

language = "English",

volume = "488",

pages = "49--56",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7409",

}

Northcott, PA, Shih, DJH, Peacock, J, Garzia, L, Morrissy, AS, Zichner, T, Stutz, 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, XC, Chiu, RYB, Chu, A, Chuah, E, Corbett, RD, Hoad, GR, Jackman, SD, Li, YS, Lo, A, Mungall, KL, Nip, KM, Qian, JQ, Raymond, AGJ, Thiessen, N, Varhol, RJ, Birol, I, Moore, RA, Mungall, AJ, van der 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, Fevre-Montange, M, Jouvet, A, Pollack, IF, Fan, X, Muraszko, KM, Gillespie, GY, Di Rocco, C, Massimi, L, Michiels, E, Kloosterhof, N, French, P, 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, Bognar, 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, A, Jung, S, Carlotti, CG, Vibhakar, R, Ra, YS, 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. 488, no. 7409, pp. 49-56. https://doi.org/10.1038/nature11327

TY - JOUR

T1 - Subgroup-specific structural variation across 1,000 medulloblastoma genomes

AU - Northcott, PA

AU - Shih, DJH

AU - Peacock, J

AU - Garzia, L

AU - Morrissy, AS

AU - Zichner, T

AU - Stutz, AM

AU - Korshunov, A

AU - Reimand, J

AU - Schumacher, SE

AU - Beroukhim, R

AU - Ellison, DW

AU - Marshall, CR

AU - Lionel, AC

AU - Mack, S

AU - Dubuc, A

AU - Yao, Y

AU - Ramaswamy, V

AU - Luu, B

AU - Rolider, A

AU - Cavalli, FMG

AU - Wang, X

AU - Remke, M

AU - Wu, XC

AU - Chiu, RYB

AU - Chu, A

AU - Chuah, E

AU - Corbett, RD

AU - Hoad, GR

AU - Jackman, SD

AU - Li, YS

AU - Lo, A

AU - Mungall, KL

AU - Nip, KM

AU - Qian, JQ

AU - Raymond, AGJ

AU - Thiessen, N

AU - Varhol, RJ

AU - Birol, I

AU - Moore, RA

AU - Mungall, AJ

AU - van der Holt, R

AU - Kawauchi, D

AU - Roussel, MF

AU - Kool, Mirjam

AU - Jones, DTW

AU - Witt, H

AU - Fernandez-L, A

AU - Kenney, AM

AU - Wechsler-Reya, RJ

AU - Dirks, P

AU - Aviv, T

AU - Grajkowska, WA

AU - Perek-Polnik, M

AU - Haberler, CC

AU - Delattre, O

AU - Reynaud, SS

AU - Doz, FF

AU - Pernet-Fattet, SS

AU - Cho, BK

AU - Kim, SK

AU - Wang, KC

AU - Scheurlen, W

AU - Eberhart, CG

AU - Fevre-Montange, M

AU - Jouvet, A

AU - Pollack, IF

AU - Fan, X

AU - Muraszko, KM

AU - Gillespie, GY

AU - Di Rocco, C

AU - Massimi, L

AU - Michiels, Erna

AU - Kloosterhof, Nanne

AU - French, Pim

AU - Kros, J.M.

AU - Olson, JM

AU - Ellenbogen, RG

AU - Zitterbart, K

AU - Kren, L

AU - Thompson, RC

AU - Cooper, MK

AU - Lach, B

AU - McLendon, RE

AU - Bigner, DD

AU - Fontebasso, A

AU - Albrecht, S

AU - Jabado, N

AU - Lindsey, JC

AU - Bailey, S

AU - Gupta, N

AU - Weiss, WA

AU - Bognar, L

AU - Klekner, A

AU - Van Meter, TE

AU - Kumabe, T

AU - Tominaga, T

AU - Elbabaa, SK

AU - Leonard, JR

AU - Rubin, JB

AU - Liau, LM

AU - van Meir, EG

AU - Fouladi, M

AU - Nakamura, H

AU - Cinalli, G

AU - Garami, M

AU - Hauser, P

AU - Saad, AG

AU - Iolascon, A

AU - Jung, S

AU - Carlotti, CG

AU - Vibhakar, R

AU - Ra, YS

AU - Robinson, S

AU - Zollo, M

AU - Faria, CC

AU - Chan, JA

AU - Levy, ML

AU - Sorensen, PHB

AU - Meyerson, M

AU - Pomeroy, SL

AU - Cho, YJ

AU - Bader, GD

AU - Tabori, U

AU - Hawkins, CE

AU - Bouffet, E

AU - Scherer, SW

AU - Rutka, JT

AU - Malkin, D

AU - Clifford, SC

AU - Jones, SJM

AU - Korbel, JO

AU - Pfister, SM

AU - Marra, MA

AU - Taylor, MD

PY - 2012

Y1 - 2012

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 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.

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 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.

U2 - 10.1038/nature11327

DO - 10.1038/nature11327

M3 - Article

C2 - 22832581

SN - 0028-0836

VL - 488

SP - 49

EP - 56

JO - Nature

JF - Nature

IS - 7409

ER -

Subgroup-specific structural variation across 1,000 medulloblastoma genomes

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