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: 4.82). 02/2008; 98(2):282-8. DOI: 10.1038/sj.bjc.6604170
Source: PubMed

ABSTRACT 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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    ABSTRACT: Results conflict on the association between progesterone receptor gene (PRG) polymorphism PROGINS and ovarian cancer risk, despite wide-ranging investigations. We therefore performed a meta-analysis of 4,285 ovarian cancer cases and 6,257 controls from 11 published case-control studies. The strength of association between PROGINS polymorphism and ovarian cancer susceptibility was assessed using pooled odds ratios (ORs) with corresponding 95 % confidence intervals (CIs). The results suggest no significant associations exist between PROGINS polymorphisms and ovarian cancer risk in overall comparisons in all genetic models (T2T2 vs. T1T1: OR = 1.37, 95 % CI = 0.89-2.12, P = 0.15; T1T2 vs. T1T1:OR = 1.09, 95 % CI = 0.88-1.35, P = 0.41; T1T2 + T2T2 vs. T1T1:OR = 1.15, 95 % CI = 0.94-1.40, P = 0.17; T2T2 vs. T1 T1 + T1T2:OR = 1.34, 95 % CI = 0.87-2.07, P = 0.18). In conclusion, the results of this meta-analysis indicate that the PRG polymorphism PROGINS is not associated with ovarian cancer risk when multiple ethnic groups or regions were considered overall.
    Molecular Biology Reports 09/2013; 40(10). DOI:10.1007/s11033-013-2709-x · 1.96 Impact Factor
  • Gastroenterology 01/2011; 140(5). DOI:10.1016/S0016-5085(11)62347-0 · 13.93 Impact Factor
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    ABSTRACT: Background Ovarian malignancies are often diagnosed in advanced stage and at the same time resistance to treatment, both intrinsic and developed during treatment, is sometimes observed. These facts underscore the need for new markers of ovarian cancer risk, as well as markers of treatment effectiveness.Methods In this study we genotyped 225 ovarian cancer patients, 64 breast and ovarian cancer patients and 348 healthy controls. In total, 12 polymorphic variants and 2 deletions in PGR, ABCB1, ABCG2, GSTT1, GSTM1, GSTP1, ATM, TP53 and ATP7B genes were analyzed using ASA-PCR, RFLP-PCR, multiplex-PCR and sequencing.ResultsTen genetic polymorphisms were significantly associated with the risk of developing ovarian carcinoma in at least one of the groups under study. Impact of PGR gene polymorphisms on ovarian cancer risk was specific only for the group of the BRCA1 mutation carriers (in presence of p.Val660Leu variant- OR 2,82; p¿=¿0,010), which confirms the difference in modulation of ovarian cancer risk between sporadic and hereditary malignancies, including the breast-ovarian cancer group (as a cancer-prone group). The analyses showed also the importance of ATP7B gene in ovarian carcinogenesis, both studied variants of which significantly modulated the ovarian cancer risk in all groups excluding the group with BRCA1 mutation. Cumulative risk analysis revealed 3 unfavorable variants that increased significantly the risk of developing ovarian cancer (p.Ile1145¿=¿ABCB1+ p.Asp1853Asn ATM+ p.Ser406Ala ATP7B- OR 7,47; p¿=¿0,002) and significantly modified the progression free survival (PFS) of the patients, and also two favorable genotypes which protected against ovarian cancer (p.Arg952Lys ATP7B+ p.Arg72Pro TP53- OR 0,50; p¿=¿0,008). PFS analysis for carriers of favorable versus unfavorable genotypes emphasized the impact of the regulation of cell cycle (p.Asp1853Asn ATM) and active transport of xenobiotics (p.Ser894Ala/Thr ABCB1) on the risk of disease progression (HR 3,81; p¿=¿0,010) after paclitaxel/cisplatin chemotherapy.Conclusions The unfavorable genetic variants could facilitate carcinogenic process and once their carriers developed malignancy, their chances of survival were smaller. Our analyses also showed a strong gene-dosage effect with the decrease of progression-free survival for the carriers of two unfavorable genetic factors.
    Journal of Experimental & Clinical Cancer Research 01/2015; 34(1):2. DOI:10.1186/s13046-015-0124-y · 3.27 Impact Factor

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