INTERNATIONAL CONGRESS OF
CancerGenetics
An Exploratory Transcriptomic Analysis of Granulosa Cells in Normal-Weight PCOS Women Suggests Altered DNA Repair and Signaling Pathways Linked to Cancer Risk
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Melika Emarati,1 Hossein Azizi,2,* Nima Ghasemi,3
1. Department of Applied Biotechnology and System Biology, College of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran
2. Department of Stem Cells and Cancer, College of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran
3. Department of Applied Biotechnology and System Biology, College of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran
- Introduction: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder often associated with infertility, even in normal-weight women. Beyond reproductive dysfunction, PCOS may influence susceptibility to hormone-related malignancies, such as endometrial cancer, through alterations in granulosa cell (GC) function. GCs are essential for oocyte development and hormonal signaling, and molecular dysregulation in these cells can impact not only fertility but also genomic stability and metabolic homeostasis, processes relevant to oncogenesis. Despite the known role of obesity in exacerbating PCOS pathology, the molecular changes in GCs from normal-weight PCOS patients remain underexplored. This study aimed to identify key molecular pathways and functional networks affected in GCs of normal-weight PCOS women and evaluate potential links to cancer-relevant mechanisms.
- Methods: We analyzed granulosa cell gene expression data from normal-weight PCOS and non-PCOS women undergoing IVF or ICSI (dataset GSE80432). Four normal-weight non-PCOS and four normal-weight PCOS samples were selected for differential gene expression analysis using GEO2R (p < 0.05). Identified differentially expressed genes (DEGs) were used to construct a protein–protein interaction (PPI) network via STRING, visualized with Cytoscape and Gephi. Functional clustering and enrichment analysis using Enrichr revealed five clusters with significant pathway involvement.
- Results: Granulosa cells from normal-weight PCOS patients exhibited multifaceted molecular alterations across five functional clusters. Cluster 1, enriched for GPCR signaling and the PI3K-AKT pathway, included key genes such as PIK3CA, STAT3, SMAD4, and FGFR1, highlighting disruptions in hormonal and metabolic signaling that are frequently dysregulated in cancer. Cluster 2 contained genes involved in lipid and cholesterol metabolism, including MTTP, COASY, ACLY, LPL, and MVK, suggesting metabolic reprogramming that supports steroidogenesis. Cluster 3 encompassed RNA metabolism and translation genes, such as DCP1A, AP2A2, PRPF19, VAMP2, and EPS15, indicating post-transcriptional dysregulation that could affect the expression of tumor suppressor and oncogenes. Cluster 4 was enriched for DNA repair and cell cycle pathways, with key genes HDAC2, BLM, TP53BP1, UBE2I, BRD3, and CCNA1, reflecting potential vulnerabilities in genomic stability relevant to cancer susceptibility. Finally, Cluster 5 involved extracellular matrix organization and immune signaling, including MMP1, TGFB2, ITGA2, COL5A2, IL18, and IDO1, suggesting altered tissue architecture and inflammation that are also critical in tumor progression.
- Conclusion: In summary, this hypothesis-generating study suggests granulosa cells from normal-weight PCOS patients exhibit multifaceted molecular alterations, including dysregulated signaling, metabolic reprogramming, genomic instability, and altered cell–matrix interactions. Many of these pathways intersect with mechanisms implicated in endometrial and hormone-driven cancers, suggesting that PCOS may not only affect fertility but also modulate susceptibility to malignancy. These insights provide a framework for exploring therapeutic interventions that address both reproductive dysfunction and long-term cancer risk in PCOS.
- Keywords: Polycystic Ovary Syndrome (PCOS), Granulosa Cells, Bioinformatics, Endometrial Cancer
