The Genetic Landscape of the Childhood Cancer Medulloblastoma

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.

National Cancer Institute, National Institutes of Health (NIH)[HHSN261200800001E]

Virginia and D. K. Ludwig Fund for Cancer Research

Alex`s Lemonade Stand Foundation

American Brain Tumor Association

Brain Tumor Research Fund at Johns Hopkins

Hoglund Foundation

Ready or Not Foundation

Children`s Brain Tumor Foundation

Pediatric Brain Tumor Foundation Institute

David and Barbara B. Hirschhorn Foundation

American Association for Cancer Research

Johns Hopkins Sommer Scholar Program

NIH[CA121113]

NIH[CA096832]

NIH[CA057345]

NIH[CA118822]

NIH[CA135877]

NIH[GM074906-01A1/B7BSCW]

NSF[DBI 0845275]

DOD NDSEG[32 CFR 168a]