Comprehensive Analysis of Long Non-Coding RNAs in Ovarian Cancer Reveals Global Patterns and Targeted DNA Amplification

Abstract

Long non-coding RNAs (lncRNAs) are emerging as potent regulators of cell physiology, and recent studies highlight their role in tumor development. However, while established protein-coding oncogenes and tumor suppressors often display striking patterns of focal DNA copy-number alteration in tumors, similar evidence is largely lacking for lncRNAs. Here, we report on a genomic analysis of GENCODE lncRNAs in high-grade serous ovarian adenocarcinoma, based on The Cancer Genome Atlas (TCGA) molecular profiles. Using genomic copy-number data and deep coverage transcriptome sequencing, we derived dual copy-number and expression data for 10,419 lncRNAs across 407 primary tumors. We describe global correlations between lncRNA copy-number and expression, and associate established expression subtypes with distinct lncRNA signatures. By examining regions of focal copy-number change that lack protein-coding targets, we identified an intergenic lncRNA on chromosome 1, OVAL, that shows narrow focal genomic amplification in a subset of tumors. While weakly expressed in most tumors, focal amplification coincided with strong OVAL transcriptional activation. Screening of 16 other cancer types revealed similar patterns in serous endometrial carcinomas. This shows that intergenic lncRNAs can be specifically targeted by somatic copy-number amplification, suggestive of functional involvement in tumor initiation or progression. Our analysis provides testable hypotheses and paves the way for further study of lncRNAs based on TCGA and other large-scale cancer genomics datasets.

The Role of Long Non-Coding RNAs in Ovarian Cancer

“…It shows narrow focal genomic amplification in a subset of tumors including high grade SOC and uterine corpus endometroid carcinoma; however, no obvious focal signal has been detected in other cancers [10] . Interestingly, endometrial tumors of the serous subtype were more likely to carry OVAL focal amplification compared to non-serous tumors.…”

“…Interestingly, endometrial tumors of the serous subtype were more likely to carry OVAL focal amplification compared to non-serous tumors. Consequently, OVAL amplification is detected specifically in serous tumors regardless of tumor site [10] .…”

“…Among 4,956 lncRNAs being analyzed in a microarray study, 583 and 578 were up-regulated and down-regulated in highly metastatic cells, compared with the parental cells, respectively, which shows a possible role for lncRNAs in epithelial ovarian cancer metastasis [9] . One study conducted in high-grade serous ovarian cancer (SOC) has identified 455 lncRNAs that were induced or repressed specifically in one of the four previously described subtypes (immunoreactive, differentiated, proliferative, and mesenchymal) relative to remaining samples [10] . Furthermore, a recent study has demonstrated that 115 lncRNAs have considerable changes in estrogen-treated ovarian cancer cells compared with untreated controls; most of them were predicted to contribute in cancer progression.…”

“…Considerably, it is among those lncRNAs that are being repressed in the proliferative subtype of highgrade SOC [10] . NEAT1 levels secreted by adiposederived stem cells (ADSC) from morbidly obese patients have been significantly higher than those from normal ADSC.…”

“…It is among lncRNAs with differential expression in ovarian cancer cells with varying metastatic potentials [9] . In addition, it has been claimed to be repressed in the proliferative subtype of highgrade SOC [10] . An investigation has shown the elevated expression of UCA1 in ovarian cancer tissues and revealed that the expression of UCA1 RNA in SKOV-3 cells could increase the cell migration, invasion, and cisplatin resistance of these cells.…”