143 - Investigating differential gene expression in clear cell sarcoma of the kidney uncovers potential therapeutic targets

Publication Number: 2137.143

Robert L. Vickerman, University of Central Florida College of Medicine, Orlando, FL, United States; Sarah Voskamp, University of Central Florida College of Medicine, Orlando, FL, United States; Jacob Givoni, University of Central Florida College of Medicine, Orlando, FL, United States; Andrew O. Adeyiga, University of Central Florida College of Medicine, Chicago, IL, United States; Erlyn Smith, Nemours Children's Hospital, Orlando, FL, United States; Spencer C. Hiller, Advent Health Orlando, Orlando, FL, United States; Jennifer Nelson, Nemours Children's Hospital, Orlando, FL, United States

Background: Following Wilms tumor - accounting for up to 90% of pediatric renal tumors, clear cell sarcoma of the kidney (CCSK) is the second most common pediatric renal tumor - constituting approximately 5%. Due to both CCSK's rarity and similar presentation to Wilms tumor, it is easily misdiagnosed, resulting in poorer outcomes for CCSK pediatric patients who require a different treatment regimen. Treatment options continue to improve prognosis, up to 86% survival at 5 years; however, relapse remains a significant possibility, even years later. Several key genetic variations have been identified in CCSK - most notably BCOR internal tandem duplication and YWHAE-NUTM2 gene fusion. While the occurrence of these genetic variations are well documented, less is known about the underlying tumorigenesis of CCSK and remains an area needing further study.

Objective: To examine up- and down-regulated genes, characterize the canonical pathways of the aberrantly expressed genes, and predict what upstream regulators, diseases, and toxicity functions are involved in CCSK in order to identify therapeutic targets for further research.

Design/Methods: CCSK tumor samples along with healthy kidney control samples were obtained from publicly available datasets in NCBI's Gene Expression Omnibus (GEO) repository. Search, Tag, Analyze Resource for GEO (STARGEO) was used to identify differentially expressed genes in CCSK; CCSK genes with an absolute experimental log ratio greater than 0.5 compared to normal were logged as significant. Ingenuity Pathway Analysis (IPA) was used to interpret the statistically significant genes to both identify what diseases, upstream regulators, and canonical pathways are involved in CCSK and provide biological context for the results.

Results: Of the 22,260 genes included in the STARGEO meta-analysis, 3,641 were statistically significant. Canonical pathway analysis in CCSK revealed enrichment in adipogenesis, pulmonary fibrosis idiopathic signaling, and Sertoli cell-Sertoli cell junction signaling. IPA upstream regulator analysis predicted activation of KAT6A, TSC1, and NRIP1, along with inhibition of HNF1A, PKD1, and SMARCAL1. Disease and biofunction analysis indicated associations with activation of urination disorder, neural cell differentiation, and neural development.

Conclusion(s): Our findings are consistent with known genetic variations in CCSK and additionally provide insights into lesser-studied genes, including EGFR, which may represent promising therapeutic targets. These results also offer further understanding of the underlying pathogenesis of CCSK.

Top 10 up- and down-regulated genes in CCSK
Top 10 unregulated and top 10 downregulated genes in CCSK versus healthy kidney. Experimental log ratio indicates the magnitude and direction of differential expression on a logarithmic scale.

Predicted pathway of the upstream regulator TSC1
IPA generated pathway that predicts how the over-activation of TSC1 can lead to the differential gene expression of several of the genes included in the top 10 most aberrantly changed.

Pathway of the adipogenesis pathway - the top associated canonical pathway with CCSK
IPA generated pathway detailing the adipogenesis pathway - mesenchymal cells differentiating into mature adipocytes. IPA predicted this as the most associated pathway due to overlap between the genes involved in the canonical adipogenesis pathway and CCSK's gene expression profile, suggesting dysregulation of many of these genes contribute to the tumorigenesis of CCSK.