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

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.