Genome-wide significant risk associations for mucinous ovarian carcinoma

Abstract

Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

“…Growing literature demonstrates genetic associations between rs368234815 or its linked variants with other clinical phenotypes, such as relapse on DAA treatment of HCV (12), liver fibrosis (13, 14), hepatic metallothionein expression (15), post-partum immune activation (16, 17), risk of mucinous ovarian cancer (18), etc. Although other, invariantly expressed type-III IFNs might be also important for these phenotypes, only IFN-λ4 is directly and most dramatically affected by the associated variant, rs368234815, that either creates or eliminates IFN-λ4.…”

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

“…Analyses were based on four pooled GWAS totaling 46,213 subjects of European ancestry (15,397 invasive EOC cases, 30,816 controls) from 43 independent studies in the international Ovarian Cancer Association Consortium (OCAC)(14, 35). A meta-analysis was performed to combine results across studies.…”

“…That the known genetic risk factors account for <50 percent of the heritable risk of EOC suggests that additional risk alleles await discovery(5). The advent of genome wide association studies (GWAS) has enabled the international Ovarian Cancer Association Consortium (OCAC) to discover approximately 22 single nucleotide polymorphisms (SNPs) with mild effects(6–14). Since OCAC includes virtually every large case-control study of EOC in the world, which precludes a substantial increase in sample size, innovative approaches are needed to evaluate the thousands of risk SNPs at sub genome-wide levels of statistical significance (1×10 −5 >P>5×10 −8 ).…”

Mucinous ovarian cancer: A therapeutic review

“…Kelemen et al [57] evaluated 1644 patients with mEOC vs. 21693 controls and identified 3 new single nucleotide polymorphism (SNP) which were associated with mEOC risk at independent genomic loci. This consortium also used expression quantitative trait locus (eQTL) analysis to identify associations between candidate SNP variants and gene expression in both HGSOC and CRC tumours from the Cancer Genome Atlas.…”

“…One of the susceptibility genes for mEOC, HOXD9, is an established high grade HGSOC susceptibility gene, indicating a possible shared role for this gene in oncogenesis of both distinct types of EOC. Another SNP identified was associated with mEOC risk and PAX8 expression in colorectal cancers but not HGSOC [57].…”