PATHOME: an algorithm for accurately detecting differentially expressed subpathways

Abstract

The translation of high-throughput gene expression data into biologically meaningful information remains a bottleneck. We developed a novel computational algorithm, PATHOME, for detecting differentially expressed biological pathways. This algorithm employs straightforward statistical tests to evaluate the significance of differential expression patterns along subpathways. Applying it to gene expression data sets of gastric cancer (GC), we compared its performance with those of other leading programs. Based on a literature-driven reference set, PATHOME showed greater consistency in identifying known cancer-related pathways. For the WNT pathway uniquely identified by PATHOME, we validated its involvement in gastric carcinogenesis through experimental perturbation of both cell lines and animal models. We identified HNF4α-WNT5A regulation in the cross-talk between the AMPK metabolic pathway and the WNT signaling pathway, and further identified WNT5A as a potential therapeutic target for GC. We have demonstrated PATHOME to be a powerful tool, with improved sensitivity for identifying disease-related dysregulated pathways.

WNT5A Correlates with Clinicopathological Characteristics in Gastric Cancer: a Meta-Analysis

“…WNT5A targeting in GC cell lines and xenograft models demonstrated antitumor activity, supporting its value as a potential therapeutic target in GC [16]. Also, HNF4α (hepatic nuclear factor-4) is an upstream regulator of WNT5A transcription, and we have shown the HN4α-WNT5A axis to be inhibited by small molecular weight compounds, in vitro, and xenograft models [8].…”

“…Despite the many efforts to identify GC clinically relevant biomarkers, the lack of feasible specifying patient groups for stratification, potential targeted therapies continue to be sought. Consequently, , we herein performed a systematic review for GC clinical relevance through multiple publications, since WNT5A (a member of WNT signaling [15]) has been well-implicated in GC progression, and possible druggable signaling, in our previous studies [8,16].…”

Detecting Perturbed Subpathways towards Mouse Lung Regeneration Following H1N1 Influenza Infection

“…Subpathway-based tools, with their capacity to scan the entire pathway network and zoom into the specific subareas that are deregulated, can explore deeper the biological significance of disease-associated mutations identified by genome-wide association studies and full-genome sequencing. Hence, in the recent years several tools have been published under this perspective, offering new horizons in the Network Medicine field [9][10][11][12][13][14][15][16].…”

“…More recently, pathway analysis evolved to subpathway analysis, which searches for sub-areas on the topology to interpret the related biological phenomena and provides more targeted and context-specific molecular candidate signatures for disease etiology [9][10][11][12][13][14][15][16]. Subpathways are local subnetworks in the pathway topology which can be associated with small scale biological functions, within the boundaries of the pathway, and whose deregulation can give rise to a disease.…”

WDNfinder: A method for minimum driver node set detection and analysis in directed and weighted biological network

“…When applied to the directed and weighted biological network, it could¯nd smaller and more biologically meaningful MDS set, which suggests high con¯dence drug targets or driver genes. Thus, we suggest that biologists should use WDN¯nder, by following pathway detection algorithms such as PATHOME, 17 to analyze related biological networks in the¯rst place. The algorithms proposed are applicable to any directed and weighted network.…”