Novel mutations target distinct subgroups of medulloblastoma

Giles Robinson; Matthew Parker; Tanya A Kranenburg; Charles Lu; Xiang Chen; Li Ding; Timothy N Phoenix; Erin Hedlund; Lei Wei; Xiaoyan Zhu; Nader Chalhoub; Suzanne J Baker; Robert Huether; Richard Kriwacki; Natasha Curley; Radhika Thiruvenkatam; Jianmin Wang; Gang Wu; Michael Rusch; Xin Hong; Jared Becksfort; Pankaj Gupta; Jing Ma; John Easton; Bhavin Vadodaria; Arzu Onar-Thomas; Tong Lin; Shaoyi Li; Stanley Pounds; Steven Paugh; David Zhao; Daisuke Kawauchi; Martine F Roussel; David Finkelstein; David W Ellison; Ching C Lau; Eric Bouffet; Tim Hassall; Sridharan Gururangan; Richard Cohn; Robert S Fulton; Lucinda L Fulton; David J Dooling; Kerri Ochoa; Amar Gajjar; Elaine R Mardis; Richard K Wilson; James R Downing; Jinghui Zhang; Richard J Gilbertson

doi:10.1038/nature11213

Novel mutations target distinct subgroups of medulloblastoma

Giles Robinson, Matthew Parker, Tanya A Kranenburg, Charles Lu, Xiang Chen, Li Ding, Timothy N Phoenix, Erin Hedlund, Lei Wei, Xiaoyan Zhu, Nader Chalhoub, Suzanne J Baker, Robert Huether, Richard Kriwacki, Natasha Curley, Radhika Thiruvenkatam, Jianmin Wang, Gang Wu, Michael Rusch, Xin HongJared Becksfort, Pankaj Gupta, Jing Ma, John Easton, Bhavin Vadodaria, Arzu Onar-Thomas, Tong Lin, Shaoyi Li, Stanley Pounds, Steven Paugh, David Zhao, Daisuke Kawauchi, Martine F Roussel, David Finkelstein, David W Ellison, Ching C Lau, Eric Bouffet, Tim Hassall, Sridharan Gururangan, Richard Cohn, Robert S Fulton, Lucinda L Fulton, David J Dooling, Kerri Ochoa, Amar Gajjar, Elaine R Mardis, Richard K Wilson, James R Downing, Jinghui Zhang, Richard J Gilbertson

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

Abstract

Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.

Original language	English
Pages (from-to)	43-8
Number of pages	6
Journal	Nature
Volume	488
Issue number	7409
DOIs	https://doi.org/10.1038/nature11213
Publication status	Published - 2 Aug 2012

Keywords / Materials (for Non-textual outputs)

Animals
CREB-Binding Protein
Cadherins
Cdh1 Proteins
Cell Cycle Proteins
Cell Lineage
Cerebellar Neoplasms
Child
DEAD-box RNA Helicases
DNA Copy Number Variations
DNA Helicases
DNA Mutational Analysis
Disease Models, Animal
Genome, Human
Genomics
Hedgehog Proteins
Histone Demethylases
Histones
Humans
Medulloblastoma
Methylation
Mice
Mutation
Nuclear Proteins
Phosphatidylinositol 3-Kinases
Transcription Factors
Wnt Proteins
beta Catenin

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10.1038/nature11213

Cite this

Robinson, G., Parker, M., Kranenburg, T. A., Lu, C., Chen, X., Ding, L., Phoenix, T. N., Hedlund, E., Wei, L., Zhu, X., Chalhoub, N., Baker, S. J., Huether, R., Kriwacki, R., Curley, N., Thiruvenkatam, R., Wang, J., Wu, G., Rusch, M., ... Gilbertson, R. J. (2012). Novel mutations target distinct subgroups of medulloblastoma. Nature, 488(7409), 43-8. https://doi.org/10.1038/nature11213

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title = "Novel mutations target distinct subgroups of medulloblastoma",

abstract = "Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.",

keywords = "Animals, CREB-Binding Protein, Cadherins, Cdh1 Proteins, Cell Cycle Proteins, Cell Lineage, Cerebellar Neoplasms, Child, DEAD-box RNA Helicases, DNA Copy Number Variations, DNA Helicases, DNA Mutational Analysis, Disease Models, Animal, Genome, Human, Genomics, Hedgehog Proteins, Histone Demethylases, Histones, Humans, Medulloblastoma, Methylation, Mice, Mutation, Nuclear Proteins, Phosphatidylinositol 3-Kinases, Transcription Factors, Wnt Proteins, beta Catenin",

author = "Giles Robinson and Matthew Parker and Kranenburg, {Tanya A} and Charles Lu and Xiang Chen and Li Ding and Phoenix, {Timothy N} and Erin Hedlund and Lei Wei and Xiaoyan Zhu and Nader Chalhoub and Baker, {Suzanne J} and Robert Huether and Richard Kriwacki and Natasha Curley and Radhika Thiruvenkatam and Jianmin Wang and Gang Wu and Michael Rusch and Xin Hong and Jared Becksfort and Pankaj Gupta and Jing Ma and John Easton and Bhavin Vadodaria and Arzu Onar-Thomas and Tong Lin and Shaoyi Li and Stanley Pounds and Steven Paugh and David Zhao and Daisuke Kawauchi and Roussel, {Martine F} and David Finkelstein and Ellison, {David W} and Lau, {Ching C} and Eric Bouffet and Tim Hassall and Sridharan Gururangan and Richard Cohn and Fulton, {Robert S} and Fulton, {Lucinda L} and Dooling, {David J} and Kerri Ochoa and Amar Gajjar and Mardis, {Elaine R} and Wilson, {Richard K} and Downing, {James R} and Jinghui Zhang and Gilbertson, {Richard J}",

year = "2012",

month = aug,

day = "2",

doi = "10.1038/nature11213",

language = "English",

volume = "488",

pages = "43--8",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7409",

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Robinson, G, Parker, M, Kranenburg, TA, Lu, C, Chen, X, Ding, L, Phoenix, TN, Hedlund, E, Wei, L, Zhu, X, Chalhoub, N, Baker, SJ, Huether, R, Kriwacki, R, Curley, N, Thiruvenkatam, R, Wang, J, Wu, G, Rusch, M, Hong, X, Becksfort, J, Gupta, P, Ma, J, Easton, J, Vadodaria, B, Onar-Thomas, A, Lin, T, Li, S, Pounds, S, Paugh, S, Zhao, D, Kawauchi, D, Roussel, MF, Finkelstein, D, Ellison, DW, Lau, CC, Bouffet, E, Hassall, T, Gururangan, S, Cohn, R, Fulton, RS, Fulton, LL, Dooling, DJ, Ochoa, K, Gajjar, A, Mardis, ER, Wilson, RK, Downing, JR, Zhang, J & Gilbertson, RJ 2012, 'Novel mutations target distinct subgroups of medulloblastoma', Nature, vol. 488, no. 7409, pp. 43-8. https://doi.org/10.1038/nature11213

TY - JOUR

T1 - Novel mutations target distinct subgroups of medulloblastoma

AU - Robinson, Giles

AU - Parker, Matthew

AU - Kranenburg, Tanya A

AU - Lu, Charles

AU - Chen, Xiang

AU - Ding, Li

AU - Phoenix, Timothy N

AU - Hedlund, Erin

AU - Wei, Lei

AU - Zhu, Xiaoyan

AU - Chalhoub, Nader

AU - Baker, Suzanne J

AU - Huether, Robert

AU - Kriwacki, Richard

AU - Curley, Natasha

AU - Thiruvenkatam, Radhika

AU - Wang, Jianmin

AU - Wu, Gang

AU - Rusch, Michael

AU - Hong, Xin

AU - Becksfort, Jared

AU - Gupta, Pankaj

AU - Ma, Jing

AU - Easton, John

AU - Vadodaria, Bhavin

AU - Onar-Thomas, Arzu

AU - Lin, Tong

AU - Li, Shaoyi

AU - Pounds, Stanley

AU - Paugh, Steven

AU - Zhao, David

AU - Kawauchi, Daisuke

AU - Roussel, Martine F

AU - Finkelstein, David

AU - Ellison, David W

AU - Lau, Ching C

AU - Bouffet, Eric

AU - Hassall, Tim

AU - Gururangan, Sridharan

AU - Cohn, Richard

AU - Fulton, Robert S

AU - Fulton, Lucinda L

AU - Dooling, David J

AU - Ochoa, Kerri

AU - Gajjar, Amar

AU - Mardis, Elaine R

AU - Wilson, Richard K

AU - Downing, James R

AU - Zhang, Jinghui

AU - Gilbertson, Richard J

PY - 2012/8/2

Y1 - 2012/8/2

N2 - Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.

AB - Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.

KW - Animals

KW - CREB-Binding Protein

KW - Cadherins

KW - Cdh1 Proteins

KW - Cell Cycle Proteins

KW - Cell Lineage

KW - Cerebellar Neoplasms

KW - Child

KW - DEAD-box RNA Helicases

KW - DNA Copy Number Variations

KW - DNA Helicases

KW - DNA Mutational Analysis

KW - Disease Models, Animal

KW - Genome, Human

KW - Genomics

KW - Hedgehog Proteins

KW - Histone Demethylases

KW - Histones

KW - Humans

KW - Medulloblastoma

KW - Methylation

KW - Mice

KW - Mutation

KW - Nuclear Proteins

KW - Phosphatidylinositol 3-Kinases

KW - Transcription Factors

KW - Wnt Proteins

KW - beta Catenin

U2 - 10.1038/nature11213

DO - 10.1038/nature11213

M3 - Article

C2 - 22722829

SN - 0028-0836

VL - 488

SP - 43

EP - 48

JO - Nature

JF - Nature

IS - 7409

ER -

Novel mutations target distinct subgroups of medulloblastoma

Abstract

Keywords / Materials (for Non-textual outputs)

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Cite this