Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the Ovarian Cancer Association Consortium pooled analysis

Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA.
British Journal of Cancer (Impact Factor: 4.84). 02/2008; 98(2):282-8. DOI: 10.1038/sj.bjc.6604170
Source: PubMed


There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.

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    • "Included in this report are data from 16 OCAC studies. Ten of these are from the USA: the Diseases of the Ovary and their Evaluation (DOVE), the Genetic Epidemiology of Ovarian Cancer Study (GEOCS; previously FROCS) (Auranen et al, 2005; Song et al, 2006), the Hawaii Ovarian Cancer Study (HAWAII) (Goodman et al, 2001b), the Hormones and Ovarian Cancer Prediction Study (HOPE) (Pearce et al, 2008a), the Mayo Clinic Ovarian Cancer Case – Control Study (MAYO) (Sellers et al, 2005), the North Carolina Ovarian Cancer Study (NCOCS) (Berchuck et al, 2004), the New England-based Case – Control Study (Terry et al, 2005), the Ovarian Contraceptive and Reproductive Experiences study (Holt et al, 2007), the Orange and San Diego Counties, California (UCI) study and the USC/Los Angeles County Case – Control Studies of Ovarian Cancer (USC) (Pearce et al, 2008b). There are data from three European studies: the Danish Malignant Ovarian Cancer Study (MALOVA) (Auranen et al, 2005; Song et al, 2006), the UK SEARCH Ovarian Cancer Study (SEARCH) (Auranen et al, 2005; Song et al, 2006), and the UK Ovarian Population Study (UKOPS) (Ramus et al, 2008). "
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    ABSTRACT: The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.
    Full-text · Article · Nov 2009 · British Journal of Cancer
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    • "For ovarian cancer three polymorphisms have been examined in a large multi-center case–control study as part of the Ovarian Cancer Association Consortium (OCAC) with more than 4700 cases and 7600 controls. The þ331C/T promoter polymorphism , one of the PROGINS polymorphisms and a polymorphism in the 3 0 UTR region of the gene have been examined (Pearce et al., 2008). In this analysis no strong association with ovarian cancer risk and these polymorphisms could be found. "
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    ABSTRACT: The value of identifying women with an inherited predisposition to epithelial ovarian cancer has become readily apparent with the identification of the BRCA1, and BRCA2 genes. Women who inherit a deleterious mutation in either of these genes have a very high lifetime risk of ovarian cancer (10-60%) and to some extent, increased risks of fallopian tube and peritoneal cancer. These highly lethal cancers are almost completely prevented by prophylactic salpingoophorectomy. BRCA1/2 mutation testing has become the accepted standard of care in families with a strong history of breast and/or ovarian cancer. This approach has the potential to reduce ovarian cancer mortality by about 10%. Although the ability to perform genetic testing for BRCA1 and 2 represents a significant clinical advance, the frequency of mutations in these high penetrance ovarian cancer susceptibility genes is low in most populations. There is evidence to suggest that ovarian cancer susceptibility might be affected by common low penetrance genetic polymorphisms like it was shown for several common disorders like diabetes or breast cancer. Although such polymorphisms would increase risk to a lesser degree, they could contribute to the development of a greater proportion of ovarian cancers by virtue of their higher frequencies in the population. It has been shown that the most powerful approach to studying low penetrance genes is an association study rather than a linkage study design. This review describes the efforts that have been made in this field by individual case-control studies and through multi-center collaborations as part of international consortia such as the Ovarian Cancer Association Consortium (OCAC).
    Preview · Article · May 2009 · Molecular oncology

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