Blood Based Biomarkers of DNA Methylation Associated with Platinum Resistance in High Grade Serous Ovarian Cancer

作者：Elnaz Abbasi Farid, Shu Zhang, Horacio Cárdenas, Zhen Fu, Adam Vieth, Collin M. Coon, Jian-Jun Wei, Daniel Matei, Kenneth P. Nephew · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.04.23.720362 · 研究领域：Epigenetics and DNA Methylation、Ferroptosis and cancer prognosis、Ovarian cancer diagnosis and treatment

Abstract Background High grade serous ovarian cancer (HGSC) is initially a responsive tumor to platinum (Pt)-based therapy. Pt resistance in HGSC is associated with epigenetic modifications and hypomethylating agents (HMAs) have been studied as carboplatin resensitizing agents. As DNA methylation is detectable in cancer cells and in blood, here we aimed to develop a blood-based methylation signature associated with cancer and cancer recurrence in HGSC. Results We evaluated genome-wide DNA methylation in de-identified peripheral blood mononuclear cells (PBMCs) from women 1) without cancer (controls, n=20); 2) newly diagnosed HGSC (prior to treatment, Pt-naive, n=60) 3) Pt-resistant recurrent HGSC before and after treatment with the novel HMA/DNA methyltransferase inhibitor (DNMTI) guadecitabine (Pt-resistant, n=30). The Pt-resistant patients were enrolled in NCT02901899 clinical trial testing guadecitabine and the PD-1 inhibitor pembrolizumab. DNA extracted from PBMCs was analyzed by using Infinium MethylationEPIC BeadChips. There were 30,369 differentially methylated loci (DMLs) in Pt-naïve patients vs. controls (adj. p < 0.05, β >10%), with most loci being demethylated. Enriched pathways in PBMCs from cancer patients included mechanisms of cancer, neutrophil degranulation, and cancer-related signaling pathways (PI3K/AKT, STAT3, HGF, interleukins) . The number of DMLs was greater (880 DMLs; adj. p<0.05, β>10%) in Pt-resistant vs. Pt-naïve patients, and top enriche...