The genetic landscape of the childhood cancer medulloblastoma

D. Williams Parsons, Meng Li, Xiaosong Zhang, Siân Jones, Rebecca J. Leary, Jimmy Cheng Ho Lin, Simina M. Boca, Hannah Carter, Josue Samayoa, Chetan Bettegowda, Gary L Gallia, George Jallo, Zev A. Binder, Yuri Nikolsky, James Hartigan, Doug R. Smith, Daniela S. Gerhard, Daniel W. Fults, Scott VandenBerg, Mitchel S. Berger & 27 others Suely Kazue Nagahashi Marie, Sueli Mieko Oba Shinjo, Carlos Clara, Peter C. Phillips, Jane E. Minturn, Jaclyn A. Biegel, Alexander R. Judkins, Adam C. Resnick, Phillip B. Storm, Tom Curran, Yiping He, B. Ahmed Rasheed, Henry S. Friedman, Stephen T. Keir, Roger McLendon, Paul A. Northcott, Michael D. Taylor, Peter C. Burger, Gregory J Riggins, Rachel Karchin, Giovanni Parmigiani, Darell D. Bigner, Hai Yan, Nickolas Papadopoulos, Bert Vogelstein, Kenneth W Kinzler, Victor E Velculescu

Research output: Contribution to journalArticle

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

Original languageEnglish (US)
Pages (from-to)435-439
Number of pages5
JournalScience
Volume331
Issue number6016
DOIs
StatePublished - Jan 28 2011

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Medulloblastoma
Neoplasms
Histone-Lysine N-Methyltransferase
Genes
Wnt Signaling Pathway
Genetic Association Studies
MicroRNAs
Brain Neoplasms
Histones
Methylation
Carcinogenesis
Mutation
Proteins

ASJC Scopus subject areas

  • General

Cite this

Parsons, D. W., Li, M., Zhang, X., Jones, S., Leary, R. J., Lin, J. C. H., ... Velculescu, V. E. (2011). The genetic landscape of the childhood cancer medulloblastoma. Science, 331(6016), 435-439. https://doi.org/10.1126/science.1198056

The genetic landscape of the childhood cancer medulloblastoma. / Parsons, D. Williams; Li, Meng; Zhang, Xiaosong; Jones, Siân; Leary, Rebecca J.; Lin, Jimmy Cheng Ho; Boca, Simina M.; Carter, Hannah; Samayoa, Josue; Bettegowda, Chetan; Gallia, Gary L; Jallo, George; Binder, Zev A.; Nikolsky, Yuri; Hartigan, James; Smith, Doug R.; Gerhard, Daniela S.; Fults, Daniel W.; VandenBerg, Scott; Berger, Mitchel S.; Marie, Suely Kazue Nagahashi; Shinjo, Sueli Mieko Oba; Clara, Carlos; Phillips, Peter C.; Minturn, Jane E.; Biegel, Jaclyn A.; Judkins, Alexander R.; Resnick, Adam C.; Storm, Phillip B.; Curran, Tom; He, Yiping; Rasheed, B. Ahmed; Friedman, Henry S.; Keir, Stephen T.; McLendon, Roger; Northcott, Paul A.; Taylor, Michael D.; Burger, Peter C.; Riggins, Gregory J; Karchin, Rachel; Parmigiani, Giovanni; Bigner, Darell D.; Yan, Hai; Papadopoulos, Nickolas; Vogelstein, Bert; Kinzler, Kenneth W; Velculescu, Victor E.

In: Science, Vol. 331, No. 6016, 28.01.2011, p. 435-439.

Research output: Contribution to journalArticle

Parsons, DW, Li, M, Zhang, X, Jones, S, Leary, RJ, Lin, JCH, Boca, SM, Carter, H, Samayoa, J, Bettegowda, C, Gallia, GL, Jallo, G, Binder, ZA, Nikolsky, Y, Hartigan, J, Smith, DR, Gerhard, DS, Fults, DW, VandenBerg, S, Berger, MS, Marie, SKN, Shinjo, SMO, Clara, C, Phillips, PC, Minturn, JE, Biegel, JA, Judkins, AR, Resnick, AC, Storm, PB, Curran, T, He, Y, Rasheed, BA, Friedman, HS, Keir, ST, McLendon, R, Northcott, PA, Taylor, MD, Burger, PC, Riggins, GJ, Karchin, R, Parmigiani, G, Bigner, DD, Yan, H, Papadopoulos, N, Vogelstein, B, Kinzler, KW & Velculescu, VE 2011, 'The genetic landscape of the childhood cancer medulloblastoma', Science, vol. 331, no. 6016, pp. 435-439. https://doi.org/10.1126/science.1198056
Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JCH et al. The genetic landscape of the childhood cancer medulloblastoma. Science. 2011 Jan 28;331(6016):435-439. https://doi.org/10.1126/science.1198056
Parsons, D. Williams ; Li, Meng ; Zhang, Xiaosong ; Jones, Siân ; Leary, Rebecca J. ; Lin, Jimmy Cheng Ho ; Boca, Simina M. ; Carter, Hannah ; Samayoa, Josue ; Bettegowda, Chetan ; Gallia, Gary L ; Jallo, George ; Binder, Zev A. ; Nikolsky, Yuri ; Hartigan, James ; Smith, Doug R. ; Gerhard, Daniela S. ; Fults, Daniel W. ; VandenBerg, Scott ; Berger, Mitchel S. ; Marie, Suely Kazue Nagahashi ; Shinjo, Sueli Mieko Oba ; Clara, Carlos ; Phillips, Peter C. ; Minturn, Jane E. ; Biegel, Jaclyn A. ; Judkins, Alexander R. ; Resnick, Adam C. ; Storm, Phillip B. ; Curran, Tom ; He, Yiping ; Rasheed, B. Ahmed ; Friedman, Henry S. ; Keir, Stephen T. ; McLendon, Roger ; Northcott, Paul A. ; Taylor, Michael D. ; Burger, Peter C. ; Riggins, Gregory J ; Karchin, Rachel ; Parmigiani, Giovanni ; Bigner, Darell D. ; Yan, Hai ; Papadopoulos, Nickolas ; Vogelstein, Bert ; Kinzler, Kenneth W ; Velculescu, Victor E. / The genetic landscape of the childhood cancer medulloblastoma. In: Science. 2011 ; Vol. 331, No. 6016. pp. 435-439.
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abstract = "Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16{\%} of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.",
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T1 - The genetic landscape of the childhood cancer medulloblastoma

AU - Parsons, D. Williams

AU - Li, Meng

AU - Zhang, Xiaosong

AU - Jones, Siân

AU - Leary, Rebecca J.

AU - Lin, Jimmy Cheng Ho

AU - Boca, Simina M.

AU - Carter, Hannah

AU - Samayoa, Josue

AU - Bettegowda, Chetan

AU - Gallia, Gary L

AU - Jallo, George

AU - Binder, Zev A.

AU - Nikolsky, Yuri

AU - Hartigan, James

AU - Smith, Doug R.

AU - Gerhard, Daniela S.

AU - Fults, Daniel W.

AU - VandenBerg, Scott

AU - Berger, Mitchel S.

AU - Marie, Suely Kazue Nagahashi

AU - Shinjo, Sueli Mieko Oba

AU - Clara, Carlos

AU - Phillips, Peter C.

AU - Minturn, Jane E.

AU - Biegel, Jaclyn A.

AU - Judkins, Alexander R.

AU - Resnick, Adam C.

AU - Storm, Phillip B.

AU - Curran, Tom

AU - He, Yiping

AU - Rasheed, B. Ahmed

AU - Friedman, Henry S.

AU - Keir, Stephen T.

AU - McLendon, Roger

AU - Northcott, Paul A.

AU - Taylor, Michael D.

AU - Burger, Peter C.

AU - Riggins, Gregory J

AU - Karchin, Rachel

AU - Parmigiani, Giovanni

AU - Bigner, Darell D.

AU - Yan, Hai

AU - Papadopoulos, Nickolas

AU - Vogelstein, Bert

AU - Kinzler, Kenneth W

AU - Velculescu, Victor E

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