Premium
Meta‐analysis of transcriptome reveals let‐7b as an unfavorable prognostic biomarker and predicts molecular and clinical subclasses in high‐grade serous ovarian carcinoma
Author(s) -
Tang Zhiqun,
Ow Ghim Siong,
Thiery Jean Paul,
Ivshina Anna V.,
Kuznetsov Vladimir A.
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28371
Subject(s) - ovarian carcinoma , serous carcinoma , serous fluid , ovarian cancer , microrna , oncology , transcriptome , biomarker , biology , microarray , medicine , phenotype , survival analysis , gene , bioinformatics , cancer research , cancer , gene expression , genetics
High‐grade serous ovarian carcinoma (HG‐SOC) is a heterogeneous, poorly classified, lethal disease that frequently exhibits altered expressions of microRNAs. Let‐7 family members are often reported as tumor suppressors; nonetheless, clinicopathological functions and prognostic values of individual let‐7 family members have not been addressed in HG‐SOC. In our work, we performed an integrative study to investigate the potential roles, clinicopathological functions and prognostic values of let‐7 miRNA family in HG‐SOC. Using microarray and clinical data of 1,170 HG‐SOC patients, we developed novel survival prediction and system biology methods to analyze prognostic values and functional associations of let‐7 miRNAs with global transcriptome and clinicopathological factors. We demonstrated that individual let‐7 members exhibit diverse evolutionary history and distinct regulatory characteristics. Statistical tests and network analysis suggest that let‐7b could act as a global synergistic interactor and master regulator controlling hundreds of protein‐coding genes. The elevated expression of let‐7b is associated with poor survival rates, which suggests an unfavorable role of let‐7b in treatment response for HG‐SOC patients. A novel let‐7b‐defined 36‐gene prognostic survival signature outperforms many clinicopathological parameters, and stratifies HG‐SOC patients into three high‐confidence, reproducible, clinical subclasses: low‐, intermediate‐ and high‐risk, with 5‐year overall survival rates of 56–71%, 12–29% and 0–10%, respectively. Furthermore, the high‐risk and low‐risk subclasses exhibit strong mesenchymal and proliferative tumor phenotypes concordant with resistance and sensitivity to primary chemotherapy. Our results have led to identification of promising prognostic markers of HG‐SOC, which could provide a rationale for genetic‐based stratification of patients and optimization of treatment regimes.