Abstract
Dysregulated long noncoding RNAs (lncRNAs) are potential markers of several tumor prognoses. This study aimed to develop a lncRNA expression signature that can predict chemotherapeutic sensitivity for patients with advanced stage and high-grade serous ovarian cancer (HGS-OvCa) treated with platinum-based chemotherapy. The lncRNA expression profiles of 258 HGS-OvCa patients from The Cancer Genome Atlas were analyzed. Results revealed that an eight-lncRNA signature was significantly associated with chemosensitivity in the multivariate logistic regression model, which can accurately predict the chemosensitivity of patients [Area under curve (AUC) = 0.83]. The association of a chemosensitivity predictor with molecular subtypes indicated the excellent prognosis performance of this marker in differentiated, mesenchymal, and immunoreactive subtypes (AUC > 0.8). The significant correlation between ZFAS1 expression and chemosensitivity was confirmed in 233 HGS-OvCa patients from the Gene Expression Omnibus datasets (GSE9891, GSE63885, and GSE51373). In vitro experiments demonstrated that the ZFAS1 expression was upregulated by cisplatin in A2008, HeyA8, and HeyC2 cell lines. This finding suggested that ZFAS1 may participate in platinum resistance. Therefore, the evaluation of the eight-lncRNA signature may be clinically implicated in the selection of platinum-resistant HGS-OvCa patients. The role of ZFAS1 in platinum resistance should be further investigated.
Highlights
Ovarian cancer yields the highest mortality rate of all lethal gynecologic cancers and represents approximately 3% of all cancers diagnosed in women worldwide[1,2]
The the Cancer Genome Atlas (TCGA) dataset with 258 HGS-OvCa patients was used for the detection of long noncoding RNAs (lncRNAs) related with platinum chemotherapeutic sensitivity
By subjecting the lncRNA expression data to univariate and multivariate logistic regression models, we identified a set of eight lncRNAs that were significantly correlated with the patients’ chemotherapeutic sensitivity (p < 0.003 in the univariate model and p < 0.01 in the multivariate model; Table 1)
Summary
Ovarian cancer yields the highest mortality rate of all lethal gynecologic cancers and represents approximately 3% of all cancers diagnosed in women worldwide[1,2]. 70% of patient deaths are advanced stage and high-grade serous ovarian cancers (HGS-OvCa)[4]. Clinical biomarkers that accurately predict sensitivity to chemotherapy have yet to be developed[10,11] These factors should be understood to identify prognostic signatures, which can be utilized to develop effective treatment modalities for stratified patients who unlikely respond to platinum-based chemotherapy and can benefit from alternative strategies[10]. The prognostic significance of lncRNAs in the chemotherapeutic sensitivity of HGS-OvCa treated with platinum-based chemotherapy has yet to be investigated. The association between lncRNA expression profiles and platinum-based chemotherapy sensitivity for HGS-OvCa patients from the Cancer Genome Atlas (TCGA) Research Network was investigated to determine whether lncRNA expression profiling can be used as a prognostic predictive signature for chemotherapeutic sensitivity. Our findings were validated on the basis of independent datasets from Gene Expression Omnibus (GEO)
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