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According to Cancer Research UK (CRUK), ovarian cancer is the fourth most common cancer in UK women, after breast, bowel and lung cancer, accounting for around 6% of all female deaths from cancer. The survival rate in patients with ovarian cancer is poor, with about 70% of patients being diagnosed in the late stage and less than 40% of the patients surviving more than 5 year after the diagnosis. Reproductive, demographic and lifestyle factors all affect the risk of ovarian cancer, and a family history of the disease increases the relative risk by around 3-fold for a first-degree relative, suggesting a strong heritable component. Although a small minority of familial cases are caused by highly penetrant mutations, such as those in the BRCA1 and BRCA2 genes, the cause of most cases is unknown and likely to include multiple interacting genetic and environmental factors.

 

The first common susceptibility locus for ovarian cancer has now been identified in a three-stage, multinational genome-wide association study (GWAS) [Song H et al. (2009) Nat Genet doi:10.1038/ng.424]. In the first stage, over half a million single nucleotide polymorphisms (SNPs) were genotyped, and a further 2 million predicted, in 1,817 patients with epithelial ovarian cancer (the most common form) and 2,353 controls from the UK. In the second stage, the highest ranked SNPs from the first stage were genotyped in a further 4,274 cases and 4,809 controls from Europe, the USA and Australia. A combined analysis of the data from both stages led to the identification of 12 SNPs associated with epithelial ovarian cancer risk (p<10⁸), all located in the same region of chromosome 9 (9p22.2). In the third stage of the study, the most statistically significant SNP (rs3814113) was genotyped in a further 2,670 cases and 4,668 controls, confirming its association with a significant decrease in the risk of ovarian cancer in carriers of the minor allele (odds ratio = 0.82, 95% CI 0.79-0.86). This effect was even more pronounced in the most serious subtypes of the disease.

 

Like the majority of hits from GWAS (see previous news), this SNP is located in between genes, rather than in a coding region, making the mechanism underlying the association somewhat elusive. However, the closest gene to rs3814113 is BNC2, and eight of the 12 SNPs on 9p22.2 associated with ovarian cancer are located within its second intron. This gene encodes a putative transcription factor and is highly expressed in reproductive tissue. It is therefore plausible that changes in the expression level of this gene are associated with ovarian cancer, although resequencing of the region will be needed to identify the causal variant.

 

Comments: Although this study was largely confined to individuals of European descent, it is the first identification of a common genetic variant associated with ovarian cancer, and adds BNC2 to the growing list of cancer susceptibility genes. As well as in improving our understanding of the aetiology of the disease, ultimately this finding may have implications for individual genetic risk-profiling and the development of novel therapies. Perhaps more importantly for contemporary research in human genetics, whilst there are undoubtedly drawbacks to conducting such a large study, the three-stage GWAS design exemplified in this paper offers a robust and powerful method for yielding reproducible genetic associations with common diseases.