by ecancer reporter Clare Sansom

Ovarian carcinoma is a fairly common condition, causing about 160,000 deaths annually; its prognosis is relatively poor, largely because it is often diagnosed at a late stage.

Many types of the disease have been defined, and these differ in histology, genetic and other risk factors, prognosis and response to therapy.

High grade serous ovarian carcinoma (HGSOC) is the most common and most widely studied ovarian cancer histotype.

The large increase in ovarian cancer risk seen in women who inherit a mutated copy of one of the breast cancer susceptibility genes BRCA1 and BRCA2 applies to this type of ovarian cancer only, with the risk variants of these genes conferring little or no extra risk of developing other types of ovarian cancer.

About 3% of all primary ovarian carcinomas are classified as mucinous ovarian carcinomas (MOCs), which are characterised by large amounts of intracellular mucin in more than 90% of the tumour cells.

This characteristic is also seen in ovarian metastases from some gastro-intestinal tumours, which has historically led to an over-diagnosis of this tumour type.

The low overall prevalence of MOCs makes them challenging to study; it has been difficult to define the cell type that is transformed in these tumours as normal mucin-secreting cells are not present in the ovaries, and no genetic variants that confer an increase in HGSOC risk, including BRCA1 and BRCA2, have yet been associated with an increase in the risk of developing MOCs.

Furthermore, some research with small sample sizes has appeared to suggest that these tumours have more in common with colorectal tumours than with HGSOCs, which arise in the ovarian epithelium.

Research by an international multi-centre team set up through the Ovarian Cancer Association Consortium (OCAC) and led by Simon Gayther of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, USA has now identified some genetic susceptibility alleles for this type of cancer.

This genome-wide association study (GWAS) pooled data from over 40 international studies of women with ovarian cancer obtained from OCAC investigators in order to obtain a large enough number of MOC cases for a rigorous statistical analysis.

The consortium studied genome-wide genotypes obtained from a total of 16,038 cases of ovarian cancer and 30,816 controls; 1,003 of the ovarian cancer cases were confirmed as invasive MOC and a further 641 as MOC with low malignant potential.

These genotypes were imputed into a reference panel from the 1000 Genomes Project to provide observed or imputed genotypes at over 15 million variant positions.

The consortium identified single nucleotide polymorphisms (SNPs) that were significantly associated with MOC risk in three independent genomic regions: 2q13 (SNP rs752590); 2q31.1 (rs71111830) and 19q13.2 (rs688187).

Two of these regions, 2q13 and 19q13.2, have not previously been associated with the risk of any type of ovarian cancer; 2q31.1 has been associated with an increased risk of HGSOC.

The consortium identified and annotated all known SNPs in each of these regions with significant statistical odds of being the disease-associated variant, and found that most were located within non-coding, regulatory elements of the genome.

Most of the candidate SNPs at 2q13 spanned regulatory elements of the gene PAX8, which encodes a paired-box transcription factor involved in development.

The candidate SNPs at 19q13.2 spanned a region encoding the interferon genes IFNL3 and IFNL4, and the candidate SNPs at 2q31.1 spanned the homeobox gene HOXD3 and a non-coding RNA gene, HAGLR.

The consortium then used expression quantitative trait locus (eQTL) analysis to identify associations between candidate SNP variants and gene expression in ovarian (HGSOC) and colorectal tumours from the Cancer Genome Atlas.

The SNP rs6542127 at 2q13 was associated with MOC risk and also with PAX8 expression in colorectal tumours but not in HGSOCs.

At 2q31.3, the SNP that was most significantly associated with MOC risk was associated with the over-expression of another homeobox gene, HOXD9, in both HGSOC and colorectal tumours; this is a candidate susceptibility gene for HGSOC.

Chromosome conformation capture suggested that there was a physical interaction between DNA fragments containing risk-associated SNPs at 2q31.3 and the promoter region of the HOXD9 gene in MOC cells.

Furthermore, over-expression of this gene enhanced cell growth in a MOC cell line.

Taken together, these results suggest that the known HGSOC susceptibility gene HOXD9 is also a candidate susceptibility gene for MOC, and provide some new insights into the etiology of this subtype of ovarian carcinoma.

Reference

Kelemen, L.E., Lawrenson, K., Tyrer, J. and many others for the Ovarian Cancer Association Consortium (2015). Genome-wide significant risk associations for mucinous ovarian carcinoma. Nature Genetics, published online ahead of print 15 June 2015.