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We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC) [odds ratio (OR)=1.2, 95% confidence interval (CI)=1.0-1.4, Ptrend=0.01] that showed a stronger association with the serous histological subtype (OR=1.3, 95% CI=1.1-1.5, Ptrend=0.003).
We sought to replicate this association in 12 other studies comprising 4,482 cases and 6,894 controls of white non-Hispanic ancestry in the Ovarian Cancer Association Consortium.
No evidence for an association with all cancers or serous cancers was observed in a combined analysis of data from the replication studies (all: OR=1.0, 95% CI=0.9-1.1, Ptrend=0.61; serous: OR=1.0, 95% CI=0.9-1.1, Ptrend=0.85) or from the combined analysis of discovery and replication studies (all: OR=1.0, 95% CI=1.0-1.1, Ptrend= 0.28; serous: OR=1.1, 95% CI=1.0-1.2, Ptrend=0.11). There was no evidence for statistical heterogeneity in ORs across the studies.
Although rs2660753 is a strong a prostate cancer susceptibility polymorphism, the association with another hormonally related cancer, invasive EOC, is not supported by this replication study.
Our findings, based on a larger sample size, emphasize the importance of replicating potentially promising genetic risk associations.
Invasive epithelial ovarian cancer (EOC) has a recognized genetic component, but known high penetrance genes, such as BRCA1 and BRCA2, explain <10% of EOC risk (1). The remaining unexplained risk is probably caused by a combination of multiple low to moderate penetrance genetic variants (2).
We previously reported an association between rs2660753 on chromosome 3p12 and invasive EOC [odds ratio (OR)=1.2, 95% confidence interval (CI)=1.0-1.4, Ptrend=0.01, 1,973 cases/3,419 controls] that showed a stronger association with the serous histological subtype (OR=1.3, 95% CI=1.1-1.5, Ptrend=0.003, 901 cases/3,303 controls) (3). rs2660753 is a prostate cancer susceptibility polymorphism identified from a genome wide association study of Europeans (4) and replicated in independent populations of European (5) and non-European (6) ancestry. The nearest genes (70-198 kb away) to rs2660753, VGLL3, CHMP2B and Pit-1/POU1F1, encode proteins with potential roles in tumorigenesis (3) and the 3p12.3-pcen region has been identified as a candidate tumor suppressor gene locus (7).
In this investigation, we sought to replicate the association between rs2660753 and invasive EOC in a larger sample of 12 additional studies from the international Ovarian Cancer Association Consortium (OCAC) comprising 4,482 cases and 6,894 controls.
Sixteen ovarian cancer case-control studies contributed data to this analysis. Four of the studies were included in our initial report (discovery set) (3) and 12 were included in follow up genotyping (replication set). Details of each of the studies have been published previously (8). Each study received ethics committee approval and all study subjects provided informed written consent. Pathologic and questionnaire data included tumor behavior, histology, age at diagnosis (or comparable date for controls), family history of ovarian cancer and ethnicity/race.
Genotyping was performed using the 5′ nuclease Taqman allelic discrimination assay (Applied Biosystems, Foster City, CA), except the Australian Ovarian Cancer Study and the Australian Cancer Study-Ovarian Cancer (AUS) that used the Sequenom iPLEX protocol (Sequenom Inc, San Diego, CA), and using similar conditions as the original study (3). Consistency across laboratories was assessed by genotyping a common set of 95 DNAs (90 CEPH trios and five duplicate samples) with >98% concordance in genotype calls. Details of OCAC's criteria for acceptable genotyping have been described previously (8).
Analyses were restricted to white non-Hispanic subjects. We excluded cases with non-epithelial ovarian cancer and borderline tumors. Genotypes of participants were used to estimate allele frequencies and departure from Hardy-Weinberg equilibrium (HWE) was assessed in controls using a chi-squared test. Single nucleotide polymorphism (SNP) associations were evaluated using unconditional logistic regression under ordinal and co-dominant genetic models to estimate ORs and 95% CIs. Statistical models were adjusted for age (<40, 40-49, 50-59, 60-69 and ≥70 years) in study-specific analyses and for age and study in combined analyses. Prior to pooling, tests of heterogeneity in ORs across studies were conducted using the likelihood ratio test comparing models with and without a product term for genotype and study. Statistical tests were implemented with SAS (SAS Institute, NC) software.
Genotype distributions for controls in all the studies were consistent with HWE (Table). No evidence for an association was observed at rs2667053 in the replication set (OR=1.0, 95% CI=0.9-1.1, Ptrend=0.61 for all 4,482 cancers and OR=1.0, 95% CI=0.9-1.1, Ptrend=0.85 for 2,515 serous cancers) or in the combined discovery and replication sets (OR=1.0, 95% CI=1.0-1.1, Ptrend=0.28 for all 6,450 cancers and OR=1.1, 95% CI=1.0-1.2, Ptrend=0.11 for 3,563 serous cancers) under the ordinal model (Figure). No statistically significant associations were observed under the co-dominant model (data not shown). There was no statistical heterogeneity in ORs for all ovarian cancers or serous cancers when the discovery and replication sets were combined (Pheterogeneity>0.10).
Analyses stratified by family history of breast or ovarian cancer in first-degree relatives did not show statistically significant associations for all cancers (OR=0.9, P=0.67, 481 cases with family history and OR=1.0, P=0.81, 1,576 cases without family history) or for serous cancers (OR= 1.1, P=0.70, 297 cases with family history and OR=1.0, P=0.93, 928 cases without family history).
Our findings, based on 12 studies participating in the international OCAC, do not support an association between rs2667053 and invasive EOC overall or for the serous histological type. We used a larger sample size and applied similar assays and stringent quality control criteria to genotype data as in the original study. In the current study, the power to detect an OR of 1.2, as previously reported (3), with minor allele frequency of 0.12 and Type 1 error of 0.01 was 87%. To detect smaller effects, as observed for serous cancers in the current study, a much larger sample is required. There was no evidence of statistical heterogeneity in ORs across studies or of effect modification by family history. Although variant rs2667053 is a strong candidate for prostate cancer susceptibility, it does not appear to be a candidate risk factor for ovarian cancer.
The Australian Ovarian Cancer Study (AOCS) Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green and P.M. Webb) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.aocstudy.org/). The Australian Cancer Study Management Group (A. Green, P. Parsons, N. Hayward, P.M. Webb, and D. Whiteman) thank all of the project staff, collaborating institutions and study participants. The German Ovarian Cancer Study (GER) acknowledges Ursula Eilber and Tanja Koehler for technical assistance with the study. The Polish Ovarian Cancer Study (POL) thanks Drs Louise Brinton, Mark Sherman, Stephen Chanock of the National Cancer Institute, Prof Neolina Szeszenia-Dabrowska and Dr Beata Peplonska of the Nofer Institute of Occupational Medicine (Lodz, Poland), Prof Witold Zatonski of the M Sklodowska-Curie Cancer Center and Institute of Oncology (Warsaw, Poland), and Pei Chao and Jane Wang (IMS, Silver Spring, MD) for their contribution. The United Kingdom Ovarian Cancer Population Study (UKO) is thankful to all members of the research team, including nurses, scientists, data entry personnel, and consultant gynaecological oncologists.
The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith. Funding for the individual participating studies was provided by: the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), the Cancer Council Tasmania and Cancer Foundation of Western Australia (AOCS study), and the National Health and Medical Research Council of Australia (199600) (ACS study); GC-T and PMW are supported by the NHMRC of Australia; U.S. NIH grants R01-CA-112523 and R01-CA-87538 (DOV); the German Federal Ministry of Education and Research, the Programme of Clinical Biomedical Research 01 GB 9401, the state of Baden-Württemberg through the Medical Faculty, University of Ulm P.685 and the German Cancer Research Center (GER); the U.S. National Institutes of Health (R01 CA 58598, N01-CN-55424, N01-PC-67001) (HAW); Mermaid 1, The Danish Cancer Society and the National Cancer Institute R01-CA-61107 (MAL); National Cancer Institute R01-CA-122443 and R01-CA-122443 (MAY); National Cancer Institute R01-CA-76016 (NCO): U.S. National Institutes of Health P01 CA87969 and R01 CA49449 (NHS); National Institutes of Health R01 CA54419 and P50 CA105009 (NEC); Intramural Funds from the U.S. National Cancer Institute, National Institutes of Health, Division of Cancer Epidemiology and Genetics (POL); U.S.
National Institutes of Health U01 CA71966, R01 CA16056, and U01 CA69417 for recruitment of controls by the Northern California Cancer Center (STA); Cancer Research UK (SEA); National Cancer Institute CA-58860 and CA-92044 and the Lon V Smith Foundation LVS-39420 (UCI); Cancer Research UK, the Eve Appeal, the OAK Foundation and the Department of Health's NIHR Biomedical Research Centre funding scheme (UKO); the California Cancer Research Program grants 00-01389V-20170 and 2110200, U.S. Public Health Service grants CA14089, CA17054, CA61132, CA63464, N01-PC-67010 and R03-CA113148, and California Department of Health Services sub-contract 050-E8709 (USC). EKA is supported by a fellowship from the Alberta Heritage Foundation for Medical Research. LEK is supported by Alberta Cancer Research Institute and the Canadian Institutes of Health Research Investigator award.