Multi-Omics Characterization of ctDNA Release Mechanisms in Ovarian Cancer

Abstract Circulating tumor DNA (ctDNA) is a powerful biomarker capable to predict tumor dynamics and treatment response. Despite its importance, the biological mechanisms behind ctDNA release have remained unclear. The variability among patients is affected by cancer burden, histology and stage, but these factors cover only a part of the detected variability. Herein, we characterized molecular drivers of baseline ctDNA variability in a real-world cohort of 118 patients with ovarian high-grade serous carcinoma (HGSC). Genomic and transcriptomic analyses revealed a strong positive correlation between ctDNA levels and cellular proliferation, and an inverse relationship with immune activity. Particularly, low ctDNA tumors exhibited higher bulk expression of mucins and CIITA, suggesting that intrinsic immune responses and immune landscape are linked to ctDNA release. The low and high ctDNA levels were significantly associated with poor prognosis compared to medium level in unresectable HGSC patients treated with neoadjuvant chemotherapy. In summary, our results suggest that ctDNA release is modulated by cancer cell proliferation and tumor microenvironment. Competing Interest Statement The authors have declared no competing interest. List of abbreviations - HGSC - High-grade serous carcinoma - cfDNA - cell-free DNA - ctDNA - circulating tumor DNA - WGS - Whole-genome sequencing - sWGS - shallow whole-genome sequencing - CNV - Copy number variations - PDS - Primary debulking surgery - NACT - Neoadjuvant chemotherapy - IDS - Interval debulking surgery - FIGO - International Federation of Gynecology and Obstetrics - EOC - Epithelial ovarian cells - DEG - Differently expressed gene - ORA - Overall representation analysis - HRD - Homologous recombination deficiency - HRP - Homologous recombination proficiency - PoN - Panel of normals - NSCLC - Non-small cell lung cancer