Abstract 6580: Impact of copy number variations on EV-miRNA profiles in ovarian cancer

Abstract [Objective] Ovarian cancer has poor prognosis due to its late diagnosis and the development of drug resistance, particularly in advanced stages. High-grade serous ovarian carcinoma (HGSOC), the most common subtype, is characterized by extensive genomic alterations, including TP53 mutations and copy number variations (CNVs). However, the functional impact of CNVs remains largely unclear. This study aimed to investigate how CNVs influence extracellular vesicle (EV)-associated microRNA (miRNA) profiles to identify potential diagnostic biomarkers and therapeutic targets. [Methods] Clinical and genomic data from 489 ovarian cancer patients in The Cancer Genome Atlas (TCGA) dataset were initially reviewed. From these, TP53-mutant cases (n=247) were selected and classified into CNV-high (n=21) and CNV-low (n=62) groups. Additionally, 23 TP53-mutant ovarian cancer cell lines were divided into CNV-high (n=17) and CNV-low (n=6) groups. miRNA expression profiles were compared to identify CNV-associated miRNAs. Selected miRNAs were further analyzed through prognostic assessments, tumor validation, and functional assays. Finally, in vitro assays were performed to confirm miRNA expression levels and cisplatin resistance. [Results] Compared to the CNV-low group, patients in the CNV-high group exhibited shorter OS within 30 months. In 23 cell lines, a comparative analysis of miRNA expression profiles revealed that 7 miRNAs were significantly upregulated, while 9 were downregulated in the CNV-high group (p < 0.05). Among the upregulated miRNAs, miR-203a showed the highest expression levels in CNV-high cell lines and was strongly correlated with poor prognosis. Tumor tissue analysis confirmed that miR-203a expression was significantly higher in ovarian cancer tissues compared to adjacent normal tissues (p < 0.01), and elevated miR-203a levels were also detected in the serum of ovarian cancer patients. Furthermore, EVs isolated from TP53-mutant CNV-high cell lines (CAOV3, OVCAR3, RMUGS) were found to secrete miR-203a in abundance. Functional assays demonstrated that overexpression of miR-203a in these cell lines led to increased resistance to cisplatin, as evidenced by a higher IC50, particularly in the CNV-high group. Knockdown of miR-203a in CNV-high cell lines resulted in enhanced sensitivity to cisplatin and reduced cell proliferation. [Conclusion] Elevated miR-203a expression was linked to poor prognosis and chemoresistance in ovarian cancer patients with high CNV levels. Detection of miR-203a in EVs indicates its potential as a non-invasive biomarker for early diagnosis. Targeting CNV-associated miR-203a may provide new therapeutic strategies to overcome platinum resistance in HGSOC, offering insights into molecular mechanisms and potential treatment approaches. Citation Format: Hajime Araki, Yokoi Akira, Kosuke Yoshida, Kazuhiro Suzuki, Hironori Suzuki, Masami Kitagawa, Eri Asano-Inami, Hiroaki Kajiyama. Impact of copy number variations on EV-miRNA profiles in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6580.