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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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Pik3caE545K accelerates but does not initiate WNT-subgroup medulloblastomaTumour free survival of mice of the indicated genotype. All mice carry the Blbp-cre allele. Log Rank P<0.0001. (b) Hematoxylin and eosin and immunohistochemical stains of indicated tumors. Scale=50 μm.
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Figure 4: Pik3caE545K accelerates but does not initiate WNT-subgroup medulloblastomaTumour free survival of mice of the indicated genotype. All mice carry the Blbp-cre allele. Log Rank P<0.0001. (b) Hematoxylin and eosin and immunohistochemical stains of indicated tumors. Scale=50 μm.

Mentions: Cancer-associated, activating mutations in PIK3CA were detected in a single case each of WNT (PIK3CAQ546K), SHH (PIK3CAH1047R) and subgroup-4 (PIK3CAN345K) medulloblastoma (Figure 1; Supplementary Figure 23). Although PIK3CA mutations are common in adult cancers40 and reported in medulloblastoma41, their role in tumourigenesis remains controversial. In particular it is not known if these mutations initiate or progress cancer. To test this, we generated mice that express a conditional allele of the Pik3caE545K mutation. Mice harboring Pik3caE545K or Pik3caE545K and Tp53flx/flx were bred with Blbp-Cre that drives efficient recombination in LRLPs5. Blbp-Cre ; Pik3caE545K mice, with or without Tp53flx/flx, survived tumour free for a median of 212 days with no evidence of aberrant LRLP migration (Figure 4a and data not shown). In stark contrast, 100% (n=11/11) of Blbp-Cre ; Ctnnb1+/lox(Ex3) ; Tp53+/flx ; Pik3caE545K mice developed WNT-subgroup medulloblastomas by 3 months of age: only 4% (n=2/54) of Blbp-Cre ; Ctnnb1+/lox(Ex3) ; Tp53+/flx mice develop WNT-medulloblastoma by 11 months (Figure 4a,b). Pik3ca wild-type and mutant mouse medulloblastomas displayed similar ‘classic’ histologies and nuclear Ctnnb1+, but Pik3caE545K mutant tumors contained greater AKT pathway activity as measured by pS6 and p4EBP1 immunostaining. Thus mutations in PIK3CA likely activate the AKT pathway to progress, rather than initiate, WNT-medulloblastoma.


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)

Pik3caE545K accelerates but does not initiate WNT-subgroup medulloblastomaTumour free survival of mice of the indicated genotype. All mice carry the Blbp-cre allele. Log Rank P<0.0001. (b) Hematoxylin and eosin and immunohistochemical stains of indicated tumors. Scale=50 μm.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Pik3caE545K accelerates but does not initiate WNT-subgroup medulloblastomaTumour free survival of mice of the indicated genotype. All mice carry the Blbp-cre allele. Log Rank P<0.0001. (b) Hematoxylin and eosin and immunohistochemical stains of indicated tumors. Scale=50 μm.
Mentions: Cancer-associated, activating mutations in PIK3CA were detected in a single case each of WNT (PIK3CAQ546K), SHH (PIK3CAH1047R) and subgroup-4 (PIK3CAN345K) medulloblastoma (Figure 1; Supplementary Figure 23). Although PIK3CA mutations are common in adult cancers40 and reported in medulloblastoma41, their role in tumourigenesis remains controversial. In particular it is not known if these mutations initiate or progress cancer. To test this, we generated mice that express a conditional allele of the Pik3caE545K mutation. Mice harboring Pik3caE545K or Pik3caE545K and Tp53flx/flx were bred with Blbp-Cre that drives efficient recombination in LRLPs5. Blbp-Cre ; Pik3caE545K mice, with or without Tp53flx/flx, survived tumour free for a median of 212 days with no evidence of aberrant LRLP migration (Figure 4a and data not shown). In stark contrast, 100% (n=11/11) of Blbp-Cre ; Ctnnb1+/lox(Ex3) ; Tp53+/flx ; Pik3caE545K mice developed WNT-subgroup medulloblastomas by 3 months of age: only 4% (n=2/54) of Blbp-Cre ; Ctnnb1+/lox(Ex3) ; Tp53+/flx mice develop WNT-medulloblastoma by 11 months (Figure 4a,b). Pik3ca wild-type and mutant mouse medulloblastomas displayed similar ‘classic’ histologies and nuclear Ctnnb1+, but Pik3caE545K mutant tumors contained greater AKT pathway activity as measured by pS6 and p4EBP1 immunostaining. Thus mutations in PIK3CA likely activate the AKT pathway to progress, rather than initiate, WNT-medulloblastoma.

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