Abstract
BackgroundRecent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different diseases including cancers such as breast, prostate and colorectal. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40% of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist.MethodsWe have taken a candidate approach to identifying moderate risk susceptibility alleles for ovarian cancer. To date, we have genotyped 340 SNPs from 94 candidate genes or regions, in up to 1,491 invasive epithelial ovarian cancer cases and 3,145 unaffected controls from three different population based studies from the UK, Denmark and USA.ResultsAfter adjusting for population stratification by genomic control, 18 SNPs (5.3%) were significant at the 5% level, and 5 SNPs (1.5%) were significant at the 1% level. The most significant association was for the SNP rs2107425, located on chromosome 11p15.5, which has previously been identified as a susceptibility allele for breast cancer from a genome wide association study (P-trend = 0.0012). When SNPs/genes were stratified into 7 different pathways or groups of validation SNPs, the breast cancer associated SNPs were the only group of SNPs that were significantly associated with ovarian cancer risk (P-heterogeneity = 0.0003; P-trend = 0.0028; adjusted (for population stratification) P-trend = 0.006). We did not find statistically significant associations when the combined data for all SNPs were analysed using an admixture maximum likelihood (AML) experiment-wise test for association (P-heterogeneity = 0.051; P-trend = 0.068).ConclusionThese data suggest that a proportion of the SNPs we evaluated were associated with ovarian cancer risk, but that the effect sizes were too small to detect associations with individual SNPs.
Highlights
One of the strongest risk factors for invasive epithelial ovarian cancer is a family history of the disease; a woman with a single firstdegree relative diagnosed with ovarian cancer has a 2–3 fold increased risk [1]
The results of this study showed that a proportion of single nucleotide polymorphisms (SNPs) in these candidate genes were associated with breast cancer risk, but that the effects of individual SNPs were likely to be small
The overall evidence for an excess of associations between common variants and ovarian cancer risk was evaluated with the admixture maximum likelihood (AML) method, which is described in detail in Tyrer et al [31]
Summary
One of the strongest risk factors for invasive epithelial ovarian cancer is a family history of the disease; a woman with a single firstdegree relative diagnosed with ovarian cancer has a 2–3 fold increased risk [1]. Other highly penetrant genes may exist, but these are likely to be rare and account for only a small fraction of the excess familial risk. 60% of this familial relative risk is not accounted for by the known high risk loci [7]. This remaining risk is likely to be caused by a combination of common low penetrance genes (the common variant: common disease hypothesis) and/or rare variants of moderate penetrance [8]. The known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40% of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist
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