The genetic landscape of the childhood cancer medulloblastoma

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.

Fig. 1. Number of genetic alterations detected through sequencing and copy number analyses in each of the 22 cancers

NS, non-silent mutations (including non-synonymous alterations, insertions, duplications, deletions, and splice site changes); S, silent mutations; Deletions, gene-containing regions absent in tumor samples; Amplifications, gene-containing regions focally amplified at levels > 10 copies per nucleus (21).

Fig. 2. Somatic mutations in MLL2 and MLL3 genes

Nonsense mutations and out of frame insertions and deletions are indicated as red arrows, while missense mutations are indicated as black arrows. Domains indicated include PHD, plant homeo domain finger, HMG, high mobility group box, FYRN, FY-rich N-terminal domain, FYRC, FY-rich C-terminal domain, SET, Su (var)3–9 Enhancer-of-zeste Trithorax methyltransferase domain.