Abstract 6541: Geometry of gene expression network reveals potential novel indicator in Ewing sarcoma
Authors: Elkin Rena , Oh Jung Hun , Dela Cruz Filemon , Norton Larry , Deasy Joseph O. , Kung Andrew L. , Tannenbaum Allen R. 
Published: April 2023

Oncogenic driver mutations in different pediatric sarcoma subtypes have been identified but may not be druggable. In general, identifying novel therapeutic targets and biomarkers for response remains a major challenge. We hypothesize that considering the structure of the interaction network in which the genes operate as a system is crucial for understanding a gene's role. We propose to use the protein interaction network geometry to characterize the shape of network architecture and identify key aspects of direct and indirect cooperation pertaining to the cancer network and prognosis using geometrical methods.

We model gene networks as weighted graphs where edges indicate protein-level interactions and edge weights estimate the strength of the interaction. The Human Protein Reference Database was used to define the gene network topology. RNA-Seq data from pediatric sarcoma tissues extracted from patients treated at MSK (n=12 Ewing sarcoma; n=29 osteosarcoma; n=20 desmoplastic small round cell tumor) was employed to prescribe correlation-based weights to create pediatric sarcoma subtype-specific weighted graphs. The geometry of the weighted gene networks was computed via a discrete notion of Ricci curvature.

Intuitively, the curvature provides a measure of feedback (triangles) in the network. Positive curvature reflects robust communication and ease of information transfer, while negative curvature reflects bridge-like architecture or bottlenecks of information flow. We utilized a dynamic (multi-scale) notion of curvature to quantify the functional associations between genes, computed as a function of scale between diffusion processes initially localized on each node (i.e., gene). The curvature becomes more positive on edges between communal genes and more negative on bridge-like edges between communities, until reaching the critical scale. Curvature therefore, as we demonstrate, partitions the cancer networks into functionally associated communities.

Community detection by removing bridge-edges, determined as edges with negative curvature at the critical scale, revealed sarcoma subtype-specific preferential gene associations. In particular, we agnostically found the EWSR1-FLI1 association in a cluster that was unique to the Ewing sarcoma network. Interestingly, we found ETV6 in the same community as the characteristic Ewing sarcoma EWSR1-FLI1 feature, suggesting a novel implication of ETV6 in Ewing sarcoma. These results suggest that persisting communities found by leveraging the cancer network geometry may identify potential mechanisms of drug resistance and actionable therapeutic targets.

Citation Format: Rena Elkin, Jung Hun Oh, Filemon Dela Cruz, Larry Norton, Joseph O. Deasy, Andrew L. Kung, Allen R. Tannenbaum. Geometry of gene expression network reveals potential novel indicator in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6541.