Characterization of the Immunogenomic Landscape of Ovarian Cancer Uncovers a Distinct Subset of Endometroid Tumors Associated with High CST2 Expression and a Favorable Prognosis.

Ovarian cancers with similar histopathologic but diverse immunogenomic profiles may require different treatment regimens to achieve the best clinical outcomes. The development of optimal treatment regimens will thus require an understanding of the main ways in which ovarian cancers differ with respect to their immunogenomic profiles. We used a multimodal latent variable model to enable an integrated analysis of somatic mutation, mRNA expression, and multiplex immunofluorescence data to uncover the principal drivers of intertumor heterogeneity across 197 patients with ovarian cancer. We found that the majority of the immunogenomic intertumor heterogeneity was driven by gene expression and immune infiltration in the tumor core and invasive margin. Moreover, much of this heterogeneity could not be explained by histologic subtype; somatic mutation patterns explained much of the difference between high-grade serous and other subtypes. Clustering of samples according to their positions in the latent space revealed a distinct subgroup of endometrioid ovarian cancer tumors, characterized by increased CST2 expression and improved prognosis, among other immunogenomic features. We identified a group of collagen-related genes, for which expression in all subtypes was inversely correlated with the density of proliferating tumor cells in the tumor core and associated with increased levels of inflammatory fibroblasts, independent of tumor purity. In summary, our findings advocate for a paradigm shift in how we classify and approach the treatment of ovarian cancer. By moving beyond the constraints of histologic subtypes and delving into the molecular intricacies of patient-specific tumor microenvironments, we unveil a new opportunity for targeted immuno-oncological treatment of a subset of patients with ovarian cancer. SIGNIFICANCE: Our study employs a multimodal latent variable model across 197 patients to identify principal drivers of immunogenomic intertumor heterogeneity. We uncover a distinct subgroup of endometrioid ovarian cancer with a unique immunogenomic signature and better prognosis and a set of collagen-related genes associated with the tumor microenvironment. This work challenges the adequacy of existing histologic classifications in capturing the molecular diversity of ovarian cancer, potentially informing more personalized treatment strategies.