This research utilizes single-cell whole-genome sequencing (scWGS) and a novel evolutionary timing method, doubleTime, to characterize the impact of Whole-Genome Doubling (WGD) in high-grade serous ovarian cancer (HGSOC) across 41 patients. The analysis confirmed WGD as a pervasive and ongoing mutational process that greatly increases cell-to-cell diversity and chromosomal instability within tumors. Critically, WGD status dictates the innate immune response and phenotypic state of the cancer cells and their microenvironment. Tumors classified as WGD-low show an active anti-cancer inflammatory response characterized by cGAS-STING pathway activation resulting from genomic errors. In stark contrast, WGD-high tumors display cell-cycle dysregulation and actively suppress immunity through STING1 repression, creating an immunosuppressive microenvironment. Ultimately, these findings underscore WGD as a primary driver of cancer evolvability and suggest its importance for future therapeutic stratification strategies in HGSOC.

References:

• McPherson A, Vázquez-García I, Myers M A, et al. Ongoing genome doubling shapes evolvability and immunity in ovarian cancer[J]. Nature, 2025, 644(8078): 1078-1087.