Molecular differential analysis of uterine leiomyomas and leiomyosarcomas through weighted gene network and pathway tracing approaches.

Uterine smooth muscular neoplastic growths like benign leiomyomas (UL) and metastatic leiomyosarcomas (ULMS) share similar clinical symptoms, radiological and histological appearances making their clinical distinction a difficult task. Therefore, the objective of this study is to identify key genes and pathways involved in transformation of UL to ULMS through molecular differential analysis. Global gene expression profiles of 25 ULMS, 25 UL, and 29 myometrium (Myo) tissues generated on Affymetrix U133A 2.0 human genome microarrays were analyzed by deploying robust statistical, molecular interaction network, and pathway enrichment methods. The comparison of expression signals across Myo vs UL, Myo vs ULMS, and UL vs ULMS groups identified 249, 1037, and 716 significantly expressed genes, respectively (p ≤ 0.05). The analysis of 249 DEGs from Myo vs UL confirms multistage dysregulation of various key pathways in extracellular matrix, collagen, cell contact inhibition, and cytokine receptors transform normal myometrial cells to benign leiomyomas (p value ≤ 0.01). The 716 DEGs between UL vs ULMS were found to affect cell cycle, cell division related Rho GTPases and PI3K signaling pathways triggering uncontrolled growth and metastasis of tumor cells (p value ≤ 0.01). Integration of gene networking data, with additional parameters like estimation of mutation burden of tumors and cancer driver gene identification, has led to the finding of 4 hubs (JUN, VCAN, TOP2A, and COL1A1) and 8 bottleneck genes (PIK3R1, MYH11, KDR, ESR1, WT1, CCND1, EZH2, and CDKN2A), which showed a clear distinction in their distribution pattern among leiomyomas and leiomyosarcomas. This study provides vital clues for molecular distinction of UL and ULMS which could further assist in identification of specific diagnostic markers and therapeutic targets. UL: Uterine Leiomyomas; ULMS: Uterine Leiomyosarcoma; Myo: Myometrium; DEGs: Differential Expressed Genes; RMA: Robust Multiarray Average; DC: Degree of Centrality; BC: Betweenness of Centrality; CGC: Cancer Gene Census; FDR: False Discovery Rate; TCGA: Cancer Genome Atlas; BP: Biological Process; CC: Cellular Components; MF: Molecular Function; PPI: Protein-Protein Interaction.