Genome doubling as a dynamic driver of ovarian cancer evolution: insights from single-cell sequencing

Whole-genome doubling (WGD) is a macro-evolutionary event that is both prevalent and prognostically significant in human cancers, particularly in high-grade serous ovarian carcinoma (HGSOC). Historically, WGD has been viewed as a consequence of widespread genomic instability, but recent advancements in single-cell sequencing (sc-seq) have reframed its role as a central, dynamic driver of tumor evolution. This review summarizes cutting-edge findings, demonstrating how WGD acts as a catalyst for a distinct evolutionary trajectory characterized by the rapid accumulation of chromosomal losses and the selection of highly adaptable clones. A key finding is the resolution of a biological paradox: WGD-driven chromosomal instability, which should provoke an immune response, is instead correlated with a profoundly immunosuppressive phenotype via the repression of key innate immune pathways. Finally, this review discusses the clinical implications of these discoveries, highlighting WGD's potential as a predictive biomarker and a source of unique therapeutic vulnerabilities, paving the way for targeted strategies in advanced HGSOC.