Bulk transcriptomic subtypes in high-grade serous ovarian carcinoma (HGSC) are readouts of tumor cellular composition

High-grade serous ovarian carcinoma (HGSC) is classified into four transcriptomic subtypes that are reproducible across cohorts but have not informed treatment. These subtypes are associated with stromal and immune content, yet they are assigned from bulk expression, from which composition is also estimated. We tested whether composition alone determines subtype. In tumors constructed from single cells with epithelial cells held constant, varying a single cell type within the range observed in primary tumors reassigned the subtype, and known composition distinguished all four subtypes. Varying epithelial cell identity at fixed composition displaced tumors approximately half as far in expression space. Across 2,161 primary tumors from ten cohorts, composition structured the leading axes of expression and predicted subtype in held-out cohorts (ROC-AUC 0.817 to 0.963). The consequence is prognostic. Adjustment for composition largely attenuated subtype associations with survival, whereas fibroblast content remained prognostic. Subtype-associated biology and prognosis therefore largely reflect the tumor microenvironment.