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International Consortium Links Dozen Loci to Ovarian Cancer Susceptibility

NEW YORK (GenomeWeb) – An international consortium of researchers has linked 12 new loci to ovarian cancer risk.

OncoArray Consortium investigators conducted genetic association studies of epithelial ovarian cancer using more than 25,500 cases and nearly 41,000 controls to home in on six loci associated with serous ovarian cancer, two with mucinous ovarian cancer, and one with endometrioid ovarian cancer. A meta-analysis of high-grade serous ovarian cancer uncovered an additional three susceptibility loci.

As the consortium reported today in Nature Genetics, their analyses also revealed a new candidate susceptibility gene, OBFC1, for low-grade and borderline serous epithelial ovarian cancer.

"Ovarian cancer is clearly a very complex disease — even the 30 risk variants that we now know increase risk of developing the disease account for just a small fraction of the inherited component," co-first author Catherine Phelan from the Moffitt Cancer Center said in a statement. "We believe that there will likely be many more genetic variants involved, each with extremely small effects."

Researchers from the OncoArray Consortium, which consisted of 418 researchers from the US, UK, Australia, and elsewhere, used a customized Illumina genotyping array to analyze some 533,000 variants and genotype 25,509 ovarian cancer cases and 40,941 controls. For this, the investigators drew on datasets from the Ovarian Cancer Association Consortium (OCAC) and the BRCA1 and BRCA2 mutation carriers of the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) study, as well as the Collaborative Oncological Gene-environment Study (COGS) study and three epithelial ovarian cancer GWAS.

Through this, they uncovered six new loci associated with serous epithelial ovarian cancer, five of which were also associated with borderline serous and four of which were also associated with low-grade serous ovarian cancer. Two loci were also associated with mucinous and one with endometrioid ovarian cancer.

A meta-analysis of the OCAC and CIMBA datasets uncovered a further three serous ovarian cancer risk loci.

These 12 loci harbor 571 SNPs that the researchers considered potentially causal. As most of these fell within non-coding regions, the consortium investigators reasoned that they might affect the expression of a nearby gene.

They mapped these SNPs to regulatory features in a variety of cell types. At six serous risk loci, the researchers noted an extensive overlap between the SNPs and biofeatures. For instance, they found that the 10q24.33 risk locus — associated with low-grade serous ovarian cancer and borderline serous ovarian cancer — had an enrichment of H3K27ac in normal fallopian cells, high-grade serous ovarian cancer cells, and mucinous serous ovarian cancer cells.

At the same time, to identify candidate susceptibility gene targets at these 12 loci, the researchers examined differences in copy number alterations and conducted eQTL and mQTL analyses.

In both high-grade serous ovarian cancer datasets, they reported that the most significant eQTL association was between the candidate causal risk SNPs at the 10q24.33 risk locus and OBFC1 expression. They noted that the risk allele was linked to decreased expression of OBFC1. This and other analyses suggested to the researchers that OBFC1 is a candidate susceptibility gene for low-grade and borderline serous ovarian cancer.

"In some ways, the hard work starts now," added Cedars-Sinai Medical Center's Simon Gayther, a co-senior author of the paper. "We really have little idea of the functional effect these variants have at the molecular or cellular level and so there are few clues as to how they might affect risk. If we can understand how they work, we will be in a better position to treat — and possibly prevent — ovarian cancer."