Ovarian Cancer Risk Variants Are Enriched in Histotype-Specific Enhancers and Disrupt Transcription Factor Binding Sites

Abstract

Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this study we first estimated the heritability explained by known common low penetrance risk alleles for EOC. The narrow sense heritability (h 2 g ) of EOC overall and high-grade serous ovarian cancer (HGSOCs) were estimated to be 5%-6%. Partitioned SNP heritability across broad functional categories indicated a significant contribution of regulatory elements to EOC heritability. We collated epigenomic profiling data for 77 cell and tissue types from Roadmap Epigenomics and ENCODE, and from H3K27Ac ChIP-seq data generated in 26 ovarian cancer and precursor-related cell and tissue types. We identified significant enrichment of risk single-nucleotide polymorphisms (SNPs) in active regulatory elements marked by H3K27Ac in HGSOCs. To further investigate how risk SNPs in active regulatory elements influence predisposition to ovarian cancer, we used motifbreakR to predict the disruption of transcription factor binding sites. We identified 469 candidate causal risk variants in H3K27Ac peaks that are predicted to significantly break transcription factor (TF) motifs. The most frequently broken motif was REST (p value ¼ 0.0028), which has been reported as both a tumor suppressor and an oncogene. Overall, these systematic functional annotations with epigenomic data improve interpretation of EOC risk variants and shed light on likely cells of origin.

Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases

“…This gave 286 T2D- and 366 CAD-associated super enhancer SNPs, part of which was annotated as being involved the regulation of chromatin structure and in the effects on TF binding [ 112 , 113 ]. Similarly, the own ChIP-seq data for the histone modifications marking the active regulatory elements of the genome were used for analyzing the GWAS SNPs associated with risk of epithelial ovarian cancer [ 115 ]. H3K27Ac ChIP-seq were generated for 26 ovarian cancer and precursor-related cell and tissue types and in combination with motifbreakR tool allowed for the discovery of 469 candidate causal risk variants in H3K27Ac peaks that were predicted to significantly break TF binding motifs [ 115 ].…”

Leveraging Genomics, Transcriptomics, and Epigenomics to Understand the Biology and Chemoresistance of Ovarian Cancer

“…Enhancers in OC have been found to contain single nucleotide polymorphisms (SNPs) that disrupt TF binding and are associated with OC risk variants [94]. Other studies have focused on the contribution of alterations in enhancers to chemoresistance in OC.…”

Overexpression of NPTX2 Promotes Malignant Phenotype of Epithelial Ovarian Carcinoma via IL6-JAK2/STAT3 Signaling Pathway Under Hypoxia

“…Ovarian cancer is one of the most common malignant tumors in females with the worst prognosis, accounting for 3.4% of all the female malignant tumors and 4.4% of female cancer deaths ( 1 ). Mostly, epithelial ovarian cancer (EOC) is the main subtype of ovarian cancer and shows a more aggressive phenotype than nonepithelial cancers ( 2 ). Although surgery combined with chemotherapy has achieved a certain effect, the patients’ long-term prognosis is not ideal.…”