Abstract 1497: A novel long non-coding RNA associated with poor prognosis in epithelial ovarian cancer

Abstract

Abstract Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in the Western world. In the US, there are ∼22,000 new diagnoses and ∼15,500 deaths from the disease each year. Identifying novel biomarkers associated with disease outcome, which may represent novel therapeutic targets, is critical to improve survival rates and reduce mortality from the disease. Research in this area has traditionally focused on protein-coding genes, and while this has yielded many insights into tumor biology, prognoses for women diagnosed with EOC have improved very little over the last four decades. However, protein-coding genes make up only ∼2% of the human genome. Recent studies show that the 98% non-coding ‘dark matter’ of the genome contains a myriad of RNA transcripts that are never translated, including long non-coding RNAs (lncRNAs). The existence and potential functional significance of lncRNAs is a relatively recent discovery, and the lncRNA transcriptome remains poorly characterized for most human diseases. In this study, we used RNA sequencing to profile lncRNAs in ovarian cancer and normal ovarian epithelial cells. We identified 294 significantly lncRNAs that were differentially expressed between the two cell types, the majority of which were novel antisense or intergenic RNAs. One of the most highly overexpressed lncRNAs in EOC was UCA1, which was expressed in cell lines representing the major subtypes of EOC (n=39) but not in normal ovarian or fallopian tube epithelial cells (n=10). We validated UCA1 overexpression in primary EOCs using data from 489 ovarian cancers analyzed by The Cancer Genome Atlas (TCGA) compared to expression in 8 normal fallopian tube tissue specimens (P=4.66x10-8). Overexpression or amplification of UCA1 was associated with a significantly worse prognosis, both overall survival (P=5.60x10-4) and disease-free survival (P=4.79x10-4). Using TCGA data, we also found that UCA1 amplification/overexpression occurred exclusively in patients without either germline or somatic BRCA1 mutations (P=6x10-4), suggesting functional redundancy between UCA1 and a failure in homologous recombination (HR) and defective double-stranded DNA break repair. This was supported by in silico analyses of HR and EOC associated susceptibility genes and the finding that, in contrast to UCA1, EOC patients with mutations in BRCA1 and BRCA2 have improved survival. Finally, functional knockdown of UCA1 in EOC cell lines caused a significant reduction in proliferation and migration in vitro, further suggesting that UCA1 plays and important role in EOC development. Citation Format: Kate Lawrenson, Tassja Spindler, Simon A. Gayther. A novel long non-coding RNA associated with poor prognosis in epithelial ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1497. doi:10.1158/1538-7445.AM2014-1497