PGR+331 A/G and Increased Risk of Epithelial Ovarian Cancer

Abstract

Childbearing and use of oral contraceptives are known to lower the risk of ovarian cancer, and it has been suggested that progesterone or progestin exposures play a role in these associations. The effects of progesterone may be mediated in part through the progesterone receptor, which exists in two functionally distinct protein isoforms, hPR-A and hPR-B. It is known that individuals carrying the A allele of the progesterone receptor gene (PGR) polymorphism, +331 A/G (rs10895068), have greater production of the hPR-B receptor isoform. We therefore examined the association between PGR +331 A/G genotype and risk of ovarian cancer in a population-based study of 490 cases and 534 controls in the state of Connecticut. Adjusted for various reproductive and other factors, a statistically significant increased risk was seen for carriage of the A allele compared with GG genotype [odds ratio (OR), 1.68; 95% confidence interval (95% CI), 1.09-2.59]. When subjects were considered separately according to menopausal status, no increased risk with the A allele was seen for premenopausal women (OR, 0.96; 95% CI, 0.46-2.02) but significantly increased risk was found for postmenopausal women (OR, 2.31; 95% CI, 1.31-4.06). Similar increased risks particularly among postmenopausal women were seen for all histologic tumor types. These findings have been observed before for breast and endometrial cancer, although not for ovary, but still suggest that an hPR-B mechanism may be involved in ovarian neoplasia. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1738 -41)

Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the ovarian cancer association consortium pooled analysis

“…This association was particularly strong among clear cell/ endometrioid subtypes. However, Risch et al (2006) observed an increased risk of ovarian cancer associated with this SNP.…”

“…The participating groups for this PGR study are the Australian Cancer Study, (Merritt et al, 2008) the Australian Ovarian Cancer Study (Merritt et al, 2008), the Connecticut Ovary Study (CONN) (Risch et al, 2006), the Family Registry for Ovarian Cancer Study (Auranen et al, 2005;Song et al, 2006), the Hormones and Ovarian Cancer Prediction Study, the Danish Malignant Ovarian Cancer Study (MALOVA) (Auranen et al, 2005;Song et al, 2006), the Mayo Clinic Ovarian Cancer Case -Control Study (Sellers et al, 2005), the North Carolina Ovarian Cancer Study (Berchuck et al, 2004), the New England-based Case -Control Study (NECC) (Terry et al, 2005), the Polish Ovarian Cancer Study (POCS) (García-Closas et al, 2007), the UK SEARCH Ovarian Cancer Study (SEARCH) (Auranen et al, 2005;Song et al, 2006) and the USC/Los Angeles County Case -Control Studies of Ovarian Cancer (USC) (Pearce et al, 2005). Details of these studies have been published previously (Gayther et al, 2007); Table 1 shows the basic information for each study.…”

“…All groups used the 5 0 nuclease Taqman allelic discrimination assay (Taqman; Applied Biosystems, Foster City, CA, USA) to genotype samples with the exception of the Australian Cancer Study and Australian Ovarian Cancer Study, which used the iPlex Sequenom MassArray system (Sequenom Inc., San Diego, CA, USA), CONN that used dot blotting (Risch et al, 2006), and Mayo Clinic Ovarian Cancer Case -Control Study that used Pyrosequencing for PROGINS and rs608995.…”

Impact of Two Functional Progesterone Receptor Polymorphisms (PRP): +331G/A and PROGINS on the Cancer Risks in Familial Breast/Ovarian Cancer

“…Some case-control studies have suggested that PROGINS is protective against BC [2] but a risk-factor for OC [14,15,17], whereas the +331A allele appeared to be a risk-factor both for BC [19] and for OC [15,21]. Other authors, however, did not find any association [13,17,[22][23][24][25][26]28].…”

“…In case of the +331G/A promoter polymorphism [13], the rare allele +331A (with a frequency of 0.06-0.08 among Caucasians) increases the relative PRB/PRA expression compared to +331G. Both polymorphisms have been shown to modify the risk for breast [2,[17][18][19] and OC [14,15,17,20,21] in several case-control studies. However these associations were not confirmed by other studies [13,17,[22][23][24][25][26].…”