3D spatial organization and network-guided comparison of mutation profiles in Glioblastoma reveals similarities across patients

Abstract

Mutation profiles of Glioblastoma (GBM) tumors are very heterogeneous which is the main challenge in the interpretation of the effects of mutations in disease. Additionally, the impact of the mutations is not uniform across the proteins and protein-protein interactions. The pathway level representation of the mutations is very limited. In this work, we approach these challenges through a systems level perspective in which we analyze how the mutations in GBM tumors are distributed in protein structures/interfaces and how they are organized at the network level. Our results show that out of 14644 mutations, 4392 have structural information and ~13% of them form spatial patches. Despite a small portion of all mutations, 3D patches partially decrease the heterogeneity across the patients. Hub proteins adapt multiple patches of mutations usually with a very large one and connects mutations in multiple binding sites through the core of the protein. We reconstructed patient specific networks for 290 GBM tumors. Network-guided analysis of mutations completes the interaction components that mutated proteins potentially affect, and groups the patients according to the reconstructed networks. As a result, we found 4 tumor clusters that overcome the heterogeneity in mutation profiles, and reveal predominant pathways in each group. Additionally, the network-based similarity analysis shows that each group of patients carries a set of signature 3D mutation patches. We believe that this study provides another perspective to the analysis of mutation effects and a good training towards the network-guided precision medicine. Author Summary Glioblastoma (GBM) is the most aggressive brain tumor type with a 15 months of survival on average. The mutation distribution of the GBM patients is very heterogeneous and standard treatments fail to consider the inter-tumor heterogeneity. In our study, we follow a systems level approach that integrates mutation profiles with protein-protein interaction networks. We hypothesized that although the mutations are heterogeneous, the mutations that are close in 3D of the same protein may affect the protein function similarly and this information can be used to get meaningful relation between disease state and mutations. Therefore, we spatially grouped these mutations as “patches” and reconstructed patient specific protein interaction networks. When we cluster these networks based on their pathway similarities, we found four patient groups in GBM. Then, the comparison of groups revealed overrepresentation of 3D patches. This finding can be used for patient specific therapy.