A large consortial GWAS effort recently identified several SNPs on 9p22 that are associated with ovarian cancer risk 
. The SNPs are located in the region of the BNC2
gene which is involved in ovarian development 
. Spurred by these independent prior findings on 9p22/BNC2
and ovarian biology we sought to leverage available TVU and genetic data to study the association between genetic variation and abnormal ovarian ultrasound findings. Our study is an example of an exploration of biological mechanisms following GWAS. Ovarian cancer screening using ultrasound and CA-125 testing is currently evaluated in two large randomized trials in the US and the UK. Previous analyses in PLCO have shown that the positive predictive value of TVU-based screening is low; almost all women with abnormal ultrasound findings do not have and do not develop ovarian cancer 
. Therefore, we do consider these TVU findings as surrogates for biological changes occurring in the ovary (with carcinogenic changes being one option), rather than surrogates for cancer.
In our study of women without ovarian cancer, we observed a significantly increased risk of abnormal suspicious TVU results for several SNPs on 9p22 that have been found to be associated with reduced ovarian cancer risk 
. We did not expect that SNPs associated with reduced ovarian cancer risk would correlate positively with abnormalities on ultrasound. Although the findings appear perplexing at first sight, it is conceivable that SNPs found to lower the risk of ovarian cancer may be associated with prevalent abnormal TVU findings.
We explored the association of 9p22 genotypes with morphologic characteristics recorded during TVU in women with abnormal TVU screening results. Although numbers were limited, we observed that women carrying minor 9p22 alleles had ultrasound features corresponding to complex ovarian cysts 
. In a previous analysis in PLCO, women with complex cysts were not found to share established risk factors for ovarian malignancy 
. In a more recent analysis in PLCO, the risk of ovarian cancer among women with prevalent cysts was slightly, but non-significantly lower compared to women with no cysts 
. Unfortunately, histology reports of benign outcomes in women treated for abnormal TVU results were not systematically collected in PLCO and could not be evaluated in relation to 9p22 genotypes.
Most importantly, our findings require independent confirmation, which is challenging, as there are only few resources that provide both TVU screening information and genetic data from a population-based study. If confirmed, our data suggest that some genes potentially protective against ovarian cancer actually are associated with suspicious TVU findings such as increased ovarian volume or complex cysts that gradually arise over decades and are detected at the first TVU screen.
The biology of ovarian cancer development is not well understood. It has been suggested that incessant ovulation, associated with repeated disruption and micro-traumas of the ovarian surface epithelium, may lead to initial transformation 
. Other theories suggest that hormonal stimulation of the epithelium, especially by estrogens and estrogen metabolites, may initiate carcinogenesis 
. There is now growing evidence that at least a subset of ovarian cancers may arise in the Fallopian tube and implant in the ovaries early on 
Ovarian abnormalities associated with SNPs at the 9p22 locus may protect against cancer development by interfering with these carcinogenic mechanisms, e.g. by reducing the number of lifetime ovulations or by modulating the exposure of ovarian tissue to endogenous or exogenous hormones. Ovarian cysts may impede implantation of early transformed cell clones derived from the Fallopian tube. Furthermore, although we did not see any evidence in PLCO, we cannot exclude that the reduced ovarian cancer risk associated with these SNPs is related to more frequent oophorectomies following suspicious TVU results, rather than to a direct biological mechanism.
If the 9p22 locus is associated with false positive ovarian cancer screening results, genotyping might have influence on the interpretation of TVU results.
A recent study demonstrated that cancer-related SNPs may influence prostate cancer risk estimates related to prostate specific antigen levels 
. In a study of breast cancer risk models, 10 common genetic variants associated with breast cancer risk had similar performance as the Gail model based on clinical at predicting breast cancer risk, but adding the SNPs to the clinical data only modestly improved risk prediction 
. Replication of our findings in other studies, evaluation of risk factors associated with the 9p22 locus and extension to ovarian cancer cases are necessary to understand the complex relationship between screening abnormalities and ovarian carcinogenesis and to evaluate whether this locus can influence the risk stratification of TVU screening. Moreover, detailed mapping of the region is needed to identify the actual ‘at risk’ and protective haplotypes.