LncRNA expression at the different sites of high-grade serous ovarian carcinoma

Introduction: High-grades serous ovarian carcinoma (HGSC) is the most aggressive subtype of ovary cancer. The disease appears at three anatomic sites: solid tumor, solid metastasis and effusions. Little is known about the regulatory pathways involved in cancer progression. Long non-coding RNA (lncRNA) is non protein coding RNA with a size of >200bp. They play roles in numerous cellular activities and it has been shown that lncRNA expression depends on the cell type and changes significantly under disease conditions. Exosomes are 30-100nm endosomal-derived vesicles containing mRNA, miRNA, lncRNA, transcription factors, proteins and lipids. They are secreted from various cells and their substance and amount alter between healthy and diseases state. In this study, we profiled the expression of lncRNA at the different sites of HGSC and identified lncRNA effecting patient survival.

Methods: Custom made lncRNA microarray (composed off ̴17,000 lncRNAs and ̴22,000 mRNAs) followed by validation series of 180 specimens from three anatomic sites, including 77 effusions, 40 ovarian HGSC specimens, 21 solid metastases and exosomes from 42 effusion supernatants. 10 Selected lncRNA were subjected to clinicopathologic parameters and survival association analysis.

Results: Among a total of 17,696 ncRNAs included in the array, approximately two-thirds were expressed in HGSC. The expression of lncRNAs between ovary tumors and extra-ovarian sites was scientifically different. We identified several hundred transcripts with site-specific expression. Out of 11 lncRNA chosen for validation, 6 lncRNA- ESRG, Link-A, MEG3, GATS, PVT1 and LOC642852 - were differently expressed between the anatomic sites and exosomes (all p<0.01). In univariate survival analysis, higher ESRG levels were significantly related to longer overall survival (OS) in the entire cohort (p=0.023), higher Link-A levels in post-chemotherapy specimens was significantly associated with longer OS (p=0.015). MEG3 levels were significantly higher in pre-chemotherapy effusions tapped at diagnosis (n=40) compared to post-chemotherapy specimens (p=37; p=0.017). Higher GATS expression was seen in specimens from patients who were sub-optimally debulked (p=0.046). Moreover, H19 which did not change between the site was higher in effusions from patients whose tumors showed primary resistance to chemotherapy (PFS≤6 months).

Conclusion: lncRNA are differently express at different anatomic site and exosomes in HGSC and can provide new therapeutic targets. Furthermore, their level at effusion fluids can serve as a prognostic marker.