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Novel mutations target distinct subgroups of medulloblastoma.

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 - Nature (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: St Jude Children's Research Hospital, Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.

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.

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The genomic landscape of medulloblastomaTop: clinical, histologic, gross chromosomal, nuclear CTNNB1 (nCTNNB1), and cohort (discovery or validation) details of 79 medulloblastomas by subgroup. Below: genetic alterations detected in 27 genes of particular interest. Color key at bottom. ANOVA (continuous) or Fisher’s exact (categorical) p-value is shown right. False discovery estimates (FDR) of each mutation are shown right. ***=P<0.0005; **=P<0.005; *=P<0.05; ns=not significant.
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Figure 1: The genomic landscape of medulloblastomaTop: clinical, histologic, gross chromosomal, nuclear CTNNB1 (nCTNNB1), and cohort (discovery or validation) details of 79 medulloblastomas by subgroup. Below: genetic alterations detected in 27 genes of particular interest. Color key at bottom. ANOVA (continuous) or Fisher’s exact (categorical) p-value is shown right. False discovery estimates (FDR) of each mutation are shown right. ***=P<0.0005; **=P<0.005; *=P<0.05; ns=not significant.

Mentions: To identify genetic alterations that drive medulloblastoma, we performed whole genome sequencing (WGS) of DNA from 37 tumours and matched normal blood (discovery cohort). Tumours were subgrouped by gene expression (WNT-subgroup, n=5; SHH-subgroup, n=5; subgroup-3, n=6; subgroup-4, n=19; ‘unclassified’ [profiles not available], n=2. Figure 1; Supplementary Figures 1-3 and Supplementary Table 1). Validation of all putative somatic alterations including single nucleotide variations (SNVs), insertion/deletions (indels) and structural variations (SVs) identified by CREST8, was conducted for 12 tumours using custom capture arrays and Illumina-based DNA sequencing (Supplementary Table 2). Putative coding alterations and SVs were validated in the remaining 25 ‘discovery cohort’ cases by polymerase chain reaction and Sanger-based sequencing. Mutation frequency was determined in a separate ‘validation cohort’ of 56 medulloblastomas (WNT-subgroup, n=6; SHH-subgroup, n=8; subgroup-3, n=11; subgroup-4, n=19; unclassified, n=12; Figure 1, Supplementary Table 1).


Novel mutations target distinct subgroups of medulloblastoma.

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 - Nature (2012)

The genomic landscape of medulloblastomaTop: clinical, histologic, gross chromosomal, nuclear CTNNB1 (nCTNNB1), and cohort (discovery or validation) details of 79 medulloblastomas by subgroup. Below: genetic alterations detected in 27 genes of particular interest. Color key at bottom. ANOVA (continuous) or Fisher’s exact (categorical) p-value is shown right. False discovery estimates (FDR) of each mutation are shown right. ***=P<0.0005; **=P<0.005; *=P<0.05; ns=not significant.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412905&req=5

Figure 1: The genomic landscape of medulloblastomaTop: clinical, histologic, gross chromosomal, nuclear CTNNB1 (nCTNNB1), and cohort (discovery or validation) details of 79 medulloblastomas by subgroup. Below: genetic alterations detected in 27 genes of particular interest. Color key at bottom. ANOVA (continuous) or Fisher’s exact (categorical) p-value is shown right. False discovery estimates (FDR) of each mutation are shown right. ***=P<0.0005; **=P<0.005; *=P<0.05; ns=not significant.
Mentions: To identify genetic alterations that drive medulloblastoma, we performed whole genome sequencing (WGS) of DNA from 37 tumours and matched normal blood (discovery cohort). Tumours were subgrouped by gene expression (WNT-subgroup, n=5; SHH-subgroup, n=5; subgroup-3, n=6; subgroup-4, n=19; ‘unclassified’ [profiles not available], n=2. Figure 1; Supplementary Figures 1-3 and Supplementary Table 1). Validation of all putative somatic alterations including single nucleotide variations (SNVs), insertion/deletions (indels) and structural variations (SVs) identified by CREST8, was conducted for 12 tumours using custom capture arrays and Illumina-based DNA sequencing (Supplementary Table 2). Putative coding alterations and SVs were validated in the remaining 25 ‘discovery cohort’ cases by polymerase chain reaction and Sanger-based sequencing. Mutation frequency was determined in a separate ‘validation cohort’ of 56 medulloblastomas (WNT-subgroup, n=6; SHH-subgroup, n=8; subgroup-3, n=11; subgroup-4, n=19; unclassified, n=12; Figure 1, Supplementary Table 1).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: St Jude Children's Research Hospital, Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.

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.

Show MeSH
Related in: MedlinePlus