Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci

Abstract

Background Genome wide association studies (GWAS) have identified multiple loci associated with epithelial ovarian cancer (EOC) susceptibility, but further progress requires integration of epidemiology and biology to illuminate true risk loci below genome-wide significance levels (P<5×10−8). Most risk SNPs lie within non-protein-encoding regions, and we hypothesize that long non-coding RNA (lncRNA) genes are enriched at EOC risk regions and represent biologically relevant functional targets. Methods Using imputed GWAS data from ~18,000 invasive EOC cases and 34,000 controls of European ancestry, the GENCODE (v19) lncRNA database was used to annotate SNPs from 13,442 lncRNAs for permutation-based enrichment analysis. Tumor expression quantitative trait locus (eQTL) analysis was performed for sub-genome-wide regions (1×10−5>P>5×10−8) overlapping lncRNAs. Results Of 5,294 EOC-associated SNPs (P<1.0×10−5), 1,464 (28%) mapped within 53 unique lncRNAs and an additional 3,484 (66%) SNPs were correlated (r2>0.2) with SNPs within 115 lncRNAs. EOC-associated SNPs comprised 130 independent regions, of which 72 (55%) overlapped with lncRNAs, representing a significant enrichment (P = 5.0×10−4) that was more pronounced among a subset of 5,401 lncRNAs with active epigenetic regulation in normal ovarian tissue. EOC-associated lncRNAs and their putative promoters and transcription factors were enriched for biologically relevant pathways and eQTL analysis identified five novel putative risk regions with allele-specific effects on lncRNA gene expression. Conclusion lncRNAs are significantly enriched at EOC risk regions suggesting a mechanistic role for lncRNAs in driving predisposition to EOC. Impact lncRNAs represent key candidates for integrative epidemiological and functional studies. Further research on their biological role in ovarian cancer is indicated.

An integrative functional genomics framework for effective identification of novel regulatory variants in genome–phenome studies

“…network) for follow-up validation. This strategy has been demonstrated as being effective in previous studies [ 75 , 76 ]. Taken together, regulatory analysis could prove an important addition to many upcoming PheWAS and GWAS, especially for the studies without large population sizes.…”

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations

“…Deregulation of some miRNAs, such as miR-509-3p and miR-211, through HR inhibition, has been implicated in platinum-sensitive (Pt-S) cancers [ 50 , 51 ]. Long noncoding RNAs (lncRNAs), which exhibit a wide range of physiological functions, such as transcription regulation and scaffolding within cells, have been linked to OC risk, carcinogenesis and prognosis [ 52 , 53 ]. For instance, PCAT -1 leads to HRD in prostate cancer by suppressing BRCA2 [ 54 ].…”

Non-Coding RNAs as Biomarkers of Tumor Progression and Metastatic Spread in Epithelial Ovarian Cancer

“…The variability in genes encoding lncRNAs also plays an important role in the function of these non-coding elements. GWAS of approximately 18,000 invasive OC and 34,000 control samples of European ancestry revealed that invasive OC behavior was associated with 5294 SNPs, of which 1464 SNPs were mapped to 53 lncRNA genes [ 120 ]. Among particular genetic variants, SNP rs17427875 (minor T allele) in lncRNA HOXA11-AS1 is associated with reduced tumor growth in an in vivo mouse xenograft model based on the OC C13 cell line [ 121 ].…”