期刊
SCIENTIFIC REPORTS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep16066
关键词
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资金
- National Natural Science Foundation of China [81472537, 81130038, 81372189]
- State Key Laboratory of Oncogenes and Related Genes [91-14- 18, 91-15- 12]
- Shanghai Institutions of Higher Learning (Eastern Scholar)
- Chinese Ministry of Science and Technology [2012CB966800]
- Shanghai Health Bureau Key Discipline and Specialty Foundation
- KC Wong foundation
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.
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