Abstract 3175: Discoveries from whole exome sequencing of medulloblastomas.
Authors: Sandgren Johanna , Pfeifer Susan , Nistér Monica , Diaz de Ståhl Teresita 
Published: August 2014

Abstract
Medulloblastoma is the most common malignant brain tumour in children and survivors suffer from serious long-term effects due to current treatment. More advanced molecular markers are desirable to aid in diagnosis/prognosis as well as to guide treatment. Moreover, identification of new targets for development of more efficient therapeutic agents is highly needed.
As part of a comprehensive program to detect candidate genes and signaling pathways disrupted in medulloblastoma and brain tumour stem cells (BTSC) we are performing whole exome sequencing on paired tumour and blood samples. So far samples from 21 patients have been analyzed and the results show that damaging somatic small scale mutations in the coding regions are relatively rare in medulloblastoma genomes, in average 12 per patient. Few genes are recurrently mutated in the data set but interestingly, despite the low number, several candidate genes have been found to converge in the same developmental and oncogenic pathways. WNT, SHH and Notch as well as mTOR and AKT are examples of affected pathways already known to be implicated in medulloblastoma. Furthermore, we find damaging mutations among components of the BMP/TGF-beta and RAC/Rho signaling cascades in different subset of tumours. These are important neuronal developmental, differentiation and motility pathways not yet well studied in this pediatric malignancy.
Significant findings are also a few mutations in DNA and histone methylation associated genes. The success of generating DNA copy number profiles from the sequencing data have further increased our understanding of the studied samples and several tumour suppressor genes have shown mutation of one allele and loss of the other, as PTEN, KDM6A and DULLARD.
The relatively few events per sample may add support to the proposal that medulloblastomas could arise from stem/progenitor cells that are present in normal neuronal development and importantly, already possess the capacity of self renewal and proliferation and therefore might need fewer hits for malignant transformation. Overall these results contain several interesting candidate genes as well as describe the heterogeneity of the disease but also the possibility of being able to pinpoint aberrant pathways in the tumors depending on the genetic status.
Additional analyses will be done, including integrating the mutation data with results from RNA-seq, Methyl-seq and ChIP-seq. Comparing genetic and epigenetic status of established BTSC with primary tumours and perform functional studies and evaluation of selected drugs on BTSC is also planned. As targeted therapies are being developed based on new genetic and biology knowledge it is likely that (epi)genomic/genetic analysis will be increasingly implemented in the clinic to aid in diagnosis and treatment choice. This personalized medicine approach should be of great benefit for children with brain tumours as increased survival and quality of life will follow.
Citation Format: Johanna Sandgren, Susan Pfeifer, Monica Nistér, Teresita Diaz de Ståhl. Discoveries from whole exome sequencing of medulloblastomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3175. doi:10.1158/1538-7445.AM2013-3175