Cancer systems biology : functional insights and therapeutic strategies for medulloblastoma from omic data integration

Abstract

Medulloblastoma (MB) is a chiefly pediatric cancer of the cerebellum that has been studied extensively using genomic, epigenomic, and transcriptomic data. It comprises at least four molecularly distinct subgroups: WNT, SHH, Group 3, and Group 4. Despite the detailed characterization of MB, many disease-driving events remain to be elucidated and therapeutic targets to be nominated. In this thesis, we describe three studies that contribute to a better understanding of this devastating disease: First, we describe a study that aims to fully describe the genomic landscape in the largest medulloblastoma cohort to date, using 491 sequenced MB tumors and 1,256 epigenetically analyzed cases. This work describes subgroup-specific driver alterations including previously unappreciated actionable targets; and, based on epigenetic data, identifies further heterogeneity within Group 3 and Group 4 tumors. Second, we focus on the proteomes and phospho-proteomes of 45 medulloblastoma samples.

We identified distinct pathways associated with two subsets of SHH tumors that showed robustly distinct proteomes, but similar transcriptomes, and found post-translational modifications of MYC that are associated with poor outcomes in Group 3 tumors. We also found kinases associated with subtypes and showed that inhibiting PRKDC sensitizes MYC-driven cells to radiation. This study shows that proteomics enables a more comprehensive, functional readout, providing a foundation for future therapeutic strategies. Third, we characterize the metabolomic space of MB on largely the same 45 tumors as used in the proteome-focused study. Here, we present preliminary insights from derived from integrative network and other analyses. We find that MB consensus subgroups are preserved in metabolic space, and that certain classes of metabolites are elevated in MYC-activated MB.

We also show that, similar to other cancers, a previously described gain-of-function mutation in IDH1 may cause elevated 2-hydroxyglutarate levels in MB. The work described in this thesis significantly enhances previous knowledge of medulloblastoma and its subgroups, and provides insights that may aid in the development of medulloblastoma therapies in the near future.