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. 2020 Jul 29:8:680.
doi: 10.3389/fcell.2020.00680. eCollection 2020.

Characterization of BRCA1/2-Directed ceRNA Network Identifies a Novel Three-lncRNA Signature to Predict Prognosis and Chemo-Response in Ovarian Cancer Patients With Wild-Type BRCA1/2

Meiling Zhang  1 , Guangyou Wang  2 , Yuanyuan Zhu  3 , Di Wu  1
Affiliations

Characterization of BRCA1/2-Directed ceRNA Network Identifies a Novel Three-lncRNA Signature to Predict Prognosis and Chemo-Response in Ovarian Cancer Patients With Wild-Type BRCA1/2

Meiling Zhang et al. Front Cell Dev Biol. .

Abstract

Long non-coding RNAs (lncRNAs) have been reported to interact with BRCA1/2 to regulate homologous recombination (HR) by diverse mechanisms in ovarian cancers (OvCa). However, genome-wide screening of BRCA1/2-related lncRNAs and their clinical significance is still unexplored. In this study, we constructed a global BRCA1/2-directed lncRNA-associated ceRNA network by integrating paired lncRNA expression profiles, miRNA expression profiles, and BRCA1/2 expression profiles in BRCA1/2 wild-type patients and identified 111 BRCA1/2-related lncRNAs. Using the stepwise regression and Cox regression analysis, we developed a BRCA1/2-directed lncRNA signature (BRCALncSig), composing of three lncRNAs (LINC01619, DLX6-AS1, and AC004943.2) from the list of 111 BRCA1/2-related lncRNAs, which was an independent prognostic factor and was able to classify the patients into high- and low-risk groups with significantly different survival in the training dataset (HR = 2.73, 95 CI 1.65-4.51, p < 0.001). The prognostic performance of the BRCALncSig was further validated in the testing dataset (HR = 1.9, 95 CI 1.21-2.99, p = 0.005) and entire TCGA dataset (HR = 2.17, 95 CI 1.56-3.01, p < 0.001). Furthermore, the BRCALncSig is associated with chemo-response and was also capable of discriminating nonequivalent outcomes for patients achieving complete response (CR) (log-rank p = 0.003). Functional analyses suggested that mRNAs co-expressed with the BRCALncSig were enriched in cancer-related or cell proliferation-related biological processes and pathways. In summary, our study highlighted the clinical implication of BRCA1/2-directed lncRNAs in the prognosis and treatment response of BRCA1/2 wild-type patients.

Keywords: BRCA1/2; ceRNA; long non-coding RNAs; ovarian cancers; signature.

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Figures

FIGURE 1
FIGURE 1
A global view of BRCA1/2-directed ceRNA networks comprised of 119 nodes (including BRCA1/2, 111 lncRNAs, and six miRNAs) and 250 edges.
FIGURE 2
FIGURE 2
Identification of a BRCA1/2-directed lncRNA signature (BRCALncSig) in the training set. (A) Kaplan–Meier survival curves of overall survival between high-risk and low-risk patients. (B) Kaplan–Meier survival curves of disease-free survival between high-risk and low-risk patients. (C) Risk scores distribution and expression pattern of the BRCALncSig.
FIGURE 3
FIGURE 3
Validation of the BRCALncSig. Kaplan–Meier survival curves of overall survival between high-risk and low-risk patients in the testing set (A) and entire TCGA set (C). Kaplan–Meier survival curves of disease-free survival between high-risk and low-risk patients in the testing set (B) and entire TCGA set (D).
FIGURE 4
FIGURE 4
Prognostic differences among three group patients. (A) Kaplan–Meier survival curves of overall survival among BRCA1/2 mutation group, the BRCALncSig-related high-risk wild-type group and the BRCALncSig-related low-risk wild-type group. (B) Kaplan–Meier survival curves of overall survival between BRCA1/2 mutation group and BRCALncSig-related low-risk wild-type group. (C) Kaplan–Meier survival curves of overall survival between the BRCA1/2 mutation group and the BRCALncSig-related high-risk wild-type group.
FIGURE 5
FIGURE 5
Association between the BRCALncSig and chemo-response. (A) The relationship between the BRCALncSig and the likelihood of complete response. (B) Differences in complete response ratios between the high-risk group and low-risk group. (C) Kaplan–Meier survival curves of overall survival between high-risk and low-risk patients for patients with CR.
FIGURE 6
FIGURE 6
Functional enrichment analysis. (A) The functional map of enriched GO terms. (B) Enriched Go terms. (C) Enriched KEGG pathways.
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