5-hydroxymethylcytosine signatures of tissue as potential predictive markers for platinum resistance in epithelial ovarian cancer patients

Platinum-based systemic therapy is the cornerstone of treatment for epithelial ovarian cancer (EOC). Although most patients initially respond to platinum-based therapy, they eventually develop drug resistance after multiple relapses. Currently, there is no effective method to predict platinum resistance in EOC patients. We collected EOC tissues from 50 patients, including 15 drug-resistant (DR) and 35 drug-sensitive (unDR) individuals. Genomic DNA (gDNA) was extracted from the cancer tissues for 5-hydroxymethylcytosine (5hmC) sequencing. Concurrently, we performed 5hmC-Seal on the cisplatin-sensitive ovarian carcinoma cell line A2780 and its isogenic cisplatin-resistant derivative, A2780-DDP. Differentially hydroxymethylated regions (DhMRs) were identified separately, and the intersection of these differentially modified genes was used to construct platinum resistance and prognosis prediction models via logistic regression. We identified 27 upregulated and 19 downregulated differentially expressed intersection genes, totaling 46 differentially hydroxymethylated insection genes. Each patient group was divided into training and validation cohorts for model development and validation. In this predictive model, we selected 12 5hmC markers to distinguish platinum resistance in EOC patients and 10 5hmC markers to differentiate between patients with short overall survival (OS ≤ 36 months, n = 16) and long OS (OS > 36 months, n = 34). The area under the curve (AUC) values were 0.937 (95% CI 0.733–1.000) and 0.971 (95% CI 0.785–1.000), respectively. We used 5hmC-Seal to detect differential changes associated with platinum resistance and sensitivity in EOC on the tissue and cell line levels. These 5hmC signatures represented promising preliminary predictive markers for platinum resistance and clinical outcomes in patients with EOC.