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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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Deregulation of H3K27me3 in subgroup-3 and 4 human and mouse medulloblastoma(a) Top row, SNP profiles of chromosome 7 copy number in medulloblastomas (samples as Figure 1; *=subgroup-3 cases). Second row, expression of EZH2. Subgroup-3 and 4 tumours are ordered left to right by expression level, #=median expression point (Bonferroni corrected p-value of EZH2 expression vs. chromosome 7 gain). Third row, mutation status of KDM6A, CHD7 and ZMYM3 (p-value, Fisher’s exact mutations vs. EZH2 expression). Fourth row, H3K27me3 immunohistochemistry (numbers=colorimetry, p-value ANOVA). (b) H3K27me3 expression (right) in mouse Blbp-Cre ; Ctnnb1+/lox(Ex3) ; Tp53flx/flx (WNT), Ptch1+/−; Tp53−/− (SHH) and Myc ; Ink4c−/− (group 3) medulloblastomas and (left) developing hindbrain. high power views of E14.5 (i) LRL and (ii) upper rhombic lip (URL). IGL=internal granule layer, EGL=external germinal layer. Scale bar=50μm. White arrows in P7 cerebellum pinpoint H3K27me3 cells in the EGL.
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Figure 2: Deregulation of H3K27me3 in subgroup-3 and 4 human and mouse medulloblastoma(a) Top row, SNP profiles of chromosome 7 copy number in medulloblastomas (samples as Figure 1; *=subgroup-3 cases). Second row, expression of EZH2. Subgroup-3 and 4 tumours are ordered left to right by expression level, #=median expression point (Bonferroni corrected p-value of EZH2 expression vs. chromosome 7 gain). Third row, mutation status of KDM6A, CHD7 and ZMYM3 (p-value, Fisher’s exact mutations vs. EZH2 expression). Fourth row, H3K27me3 immunohistochemistry (numbers=colorimetry, p-value ANOVA). (b) H3K27me3 expression (right) in mouse Blbp-Cre ; Ctnnb1+/lox(Ex3) ; Tp53flx/flx (WNT), Ptch1+/−; Tp53−/− (SHH) and Myc ; Ink4c−/− (group 3) medulloblastomas and (left) developing hindbrain. high power views of E14.5 (i) LRL and (ii) upper rhombic lip (URL). IGL=internal granule layer, EGL=external germinal layer. Scale bar=50μm. White arrows in P7 cerebellum pinpoint H3K27me3 cells in the EGL.

Mentions: Hypergeometric distribution analyses revealed selective mutation of histone modifiers in subgroup-3 and 4 medulloblastomas (Supplementary Table 11). Six subgroup-4, one subgroup-3, and one unclassified medulloblastoma contained novel inactivating mutations in KDM6A (Figures 1 and 2; Supplementary Figures 8 and 16). The single female with a KDM6A splice site mutation deleted the second allele that escapes X inactivation25 (subgroup-4 #15), and 57% (n=4/7) of KDM6A-mutant male medulloblastomas deleted chromosome Y, compared with only 6% (n=3/51) of male, KDM6A wild-type tumours (P<0.005, Fisher’s exact; Figure 1). Thus, a two-hit model of KDM6A–UTY tumour suppression appears to operate in subgroup-4 medulloblastomas. Notably, mutations in six other KDM family members (KDM1A, KDM3A, KDM4C, KDM5A, KDM5B and KDM7A) were detected exclusively in subgroup-3 and 4 tumours, implicating broad disruption of lysine demethylation in these medulloblastomas (Figure 1, Supplementary Table 11; Supplementary Figure 16).


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)

Deregulation of H3K27me3 in subgroup-3 and 4 human and mouse medulloblastoma(a) Top row, SNP profiles of chromosome 7 copy number in medulloblastomas (samples as Figure 1; *=subgroup-3 cases). Second row, expression of EZH2. Subgroup-3 and 4 tumours are ordered left to right by expression level, #=median expression point (Bonferroni corrected p-value of EZH2 expression vs. chromosome 7 gain). Third row, mutation status of KDM6A, CHD7 and ZMYM3 (p-value, Fisher’s exact mutations vs. EZH2 expression). Fourth row, H3K27me3 immunohistochemistry (numbers=colorimetry, p-value ANOVA). (b) H3K27me3 expression (right) in mouse Blbp-Cre ; Ctnnb1+/lox(Ex3) ; Tp53flx/flx (WNT), Ptch1+/−; Tp53−/− (SHH) and Myc ; Ink4c−/− (group 3) medulloblastomas and (left) developing hindbrain. high power views of E14.5 (i) LRL and (ii) upper rhombic lip (URL). IGL=internal granule layer, EGL=external germinal layer. Scale bar=50μm. White arrows in P7 cerebellum pinpoint H3K27me3 cells in the EGL.
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Related In: Results  -  Collection

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Figure 2: Deregulation of H3K27me3 in subgroup-3 and 4 human and mouse medulloblastoma(a) Top row, SNP profiles of chromosome 7 copy number in medulloblastomas (samples as Figure 1; *=subgroup-3 cases). Second row, expression of EZH2. Subgroup-3 and 4 tumours are ordered left to right by expression level, #=median expression point (Bonferroni corrected p-value of EZH2 expression vs. chromosome 7 gain). Third row, mutation status of KDM6A, CHD7 and ZMYM3 (p-value, Fisher’s exact mutations vs. EZH2 expression). Fourth row, H3K27me3 immunohistochemistry (numbers=colorimetry, p-value ANOVA). (b) H3K27me3 expression (right) in mouse Blbp-Cre ; Ctnnb1+/lox(Ex3) ; Tp53flx/flx (WNT), Ptch1+/−; Tp53−/− (SHH) and Myc ; Ink4c−/− (group 3) medulloblastomas and (left) developing hindbrain. high power views of E14.5 (i) LRL and (ii) upper rhombic lip (URL). IGL=internal granule layer, EGL=external germinal layer. Scale bar=50μm. White arrows in P7 cerebellum pinpoint H3K27me3 cells in the EGL.
Mentions: Hypergeometric distribution analyses revealed selective mutation of histone modifiers in subgroup-3 and 4 medulloblastomas (Supplementary Table 11). Six subgroup-4, one subgroup-3, and one unclassified medulloblastoma contained novel inactivating mutations in KDM6A (Figures 1 and 2; Supplementary Figures 8 and 16). The single female with a KDM6A splice site mutation deleted the second allele that escapes X inactivation25 (subgroup-4 #15), and 57% (n=4/7) of KDM6A-mutant male medulloblastomas deleted chromosome Y, compared with only 6% (n=3/51) of male, KDM6A wild-type tumours (P<0.005, Fisher’s exact; Figure 1). Thus, a two-hit model of KDM6A–UTY tumour suppression appears to operate in subgroup-4 medulloblastomas. Notably, mutations in six other KDM family members (KDM1A, KDM3A, KDM4C, KDM5A, KDM5B and KDM7A) were detected exclusively in subgroup-3 and 4 tumours, implicating broad disruption of lysine demethylation in these medulloblastomas (Figure 1, Supplementary Table 11; Supplementary Figure 16).

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