Abstract
High-grade serous ovarian carcinoma (HGS-OvCa) has the lowest survival rate among all gynecologic cancers and is hallmarked by a high degree of heterogeneity. The Cancer Genome Atlas network has described a gene expression-based molecular classification of HGS-OvCa into Differentiated, Mesenchymal, Immunoreactive and Proliferative subtypes. However, the biological underpinnings and regulatory mechanisms underlying the distinct molecular subtypes are largely unknown. Here we showed that tumor-infiltrating stromal cells significantly contributed to the assignments of Mesenchymal and Immunoreactive clusters. Using reverse engineering and an unbiased interrogation of subtype regulatory networks, we identified the transcriptional modules containing master regulators that drive gene expression of Mesenchymal and Immunoreactive HGS-OvCa. Mesenchymal master regulators were associated with poor prognosis, while Immunoreactive master regulators positively correlated with overall survival. Meta-analysis of 749 HGS-OvCa expression profiles confirmed that master regulators as a prognostic signature were able to predict patient outcome. Our data unraveled master regulatory programs of HGS-OvCa subtypes with prognostic and potentially therapeutic relevance, and suggested that the unique transcriptional and clinical characteristics of ovarian Mesenchymal and Immunoreactive subtypes could be, at least partially, ascribed to tumor microenvironment.
Highlights
To complement conventional histopathology, major efforts have recently been focused on the molecular classifications enabled by large-scale global gene expression profiling studies
The the Cancer Genome Atlas (TCGA) subtypes are not associated with patient prognosis
We presented a detailed analysis of the four molecular subtypes based on TCGA HGS-OvCa expression data
Summary
Major efforts have recently been focused on the molecular classifications enabled by large-scale global gene expression profiling studies. Tan et al presented a meta-analysis of epithelial ovarian cancer and identified five distinct subgroups, which exhibited significantly different patient outcome[9] These classification schemes have not yet achieved widespread application, partly due to the lack of imperative understanding of biologic rationale that determines the transcriptional and clinical characteristics of diverse subtypes. A statistically significant difference in patient survival was observed in the Mayo Clinic cohort, i.e. the Immunoreactive subtype had the longest survival time, while the Mesenchymal subtype had the shortest. These inconsistent findings necessitate further prudent investigations before employing the TCGA subtyping in patient stratification. We designed an analytical approach to delineate the cellular and molecular underpinnings of HGS-OvCa subtypes, with a specific focus on the involvement of tumor stromal constituents
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