25IN - The molecular dissection of medulloblastoma

Date 29 September 2012
Event ESMO Congress 2012
Session Molecular neuro-oncology: New avenues in diagnosis and treatment
Topics Central Nervous System Malignancies
Pathology/Molecular Biology
Basic Scientific Principles
Presenter Stefan Pfister
Authors S.M. Pfister
  • German Cancer Research Center Heidelberg, 69120 - Heidelberg/DE


Medulloblastoma is the most common malignant brain tumor in childhood, displaying tremendous biological and clinical heterogeneity. Four biological subgroups are consistently revealed in various studies based on gene expression profiling, but details of the genetic events driving each of these subgroups remain elusive. We have performed an integrative deep-sequencing analysis to identify genetic alterations in 200 tumor-normal pairs. Strikingly, tetraploidy was found to be a common early event in clinically challenging Group 3 & 4 tumours. For SHH tumors in contrast, we have identified a subgroup of tumors in older children that show striking patterns of chromothripsis, all of which have underlying TP53 mutations, either early somatic or germline. SHH tumors in adults, which are the predominant subgroup in this age group, in turn show a largely different mutation spectrum from their pediatric counterparts. Overall, beside known alterations (CTNNB1, PTCH1, MLL2, SMARCA4), several genes not previously implicated in medulloblastoma (DDX3X, CTDNEP1, KDM6A) were recurrently mutated, often in subgroup-specific patterns and many of them involved in chromatin-remodelling. These findings provide a detailed insight into medulloblastoma tumorigenesis, and disclose novel targets for therapeutic approaches, especially for Group 3 and 4 patients in children, and SHH tumors in adults.


The author has declared no conflicts of interest.