Progesterone receptor PROGINS and +331G/A polymorphisms confer susceptibility to ovarian cancer: a meta-analysis based on 17 studies

Abstract

Progesterone and its receptor, progesterone receptor (PGR), have been widely studied for their roles in the onset and development of ovarian cancer. Although numerous epidemiological studies have focused on the association of PGR PROGINS and +331G/A polymorphisms with ovarian cancer susceptibility, presently, available results remain controversial, in part due to low sample sizes. Thus, a meta-analysis is required to evaluate this association. A literature search of PubMed, Embase, Web of Science, CNKI, and CBM databases was performed to retrieve eligible studies published before August 15, 2013. Summary odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of this association. All analyses were done using STATA 12.0 software (Stata Corp., College Station, TX, USA). Seventeen case-control studies with a total of 6,365 cases and 9,998 controls were identified. While no statistically significant association between the PROGINS allele and ovarian cancer risk was found in an overall analysis, a stratified analysis revealed that for Caucasians, never-oral contraceptive (OC) users, and serous tumor patients, there were statistically significant ORs for ovarian cancer risk associated with the mutated PROGINS allele. No significant association, however, between the +331G/A polymorphism and ovarian cancer susceptibility was observed in the overall analyses and subgroup analyses based on ethnicity and histological type. This meta-analysis provides evidence that the PROGINS allele occurs more frequently in ovarian cancer patients and especially in non-OC users and serous cancer patients, indicating that PROGINS may be a risk modifier. No significant association between the +331G/A polymorphism and ovarian cancer was found, even in stratified analyses by ethnicity and histological type. More detailed and well-designed studies are still needed to confirm the role of the PROGINS allele in ovarian cancer development.

Progesterone and Breast Cancer: an NCI Workshop Report

“…PR mutations in both the PR-B promoter and PR primary sequence have been described in the literature primarily for reproductive cancers. For example, PGR gene polymorphisms (namely +331G/A and V660L SNP or PROGINS) that alter PR isoform expression or activity are associated with increased endometrial and ovarian cancers, while effects on breast cancer risk appear modest (17)(18)(19)(20). It should be noted that results reported in the greater literature are relatively inconsistent, suggesting that more study is needed, especially in light of newer deep-sequencing technologies.…”

Natural Selection Has Differentiated the Progesterone Receptor among Human Populations

“…Among many variants identified in PGR, the PROGINs alleles are the most extensively studied, characterized by one missense mutation, V660L (rs1042838, exon 4), one synonymous mutation, H770H (rs1042839, exon 5), and one 320-bp Alu insertion between exon 7 and 8. 47,48 Specifically, for the missense variant (rs1042838), its minor allele (A) has been associated with ovarian cancer 49,50 and preterm birth. 51 This risk allele reduces the responsiveness of PGR to progesterone, 52 consistent with the predicted deleteriousness of this missense mutation at the top 1% of the human genome by CADD.…”

“…56 We further investigated the sequence of the high-coverage Denisovan genome, 57 an extinct archaic human who lived 72,000 years ago, 45 but did not observe the risk allele from Denisovans, confirming its specific Neanderthal origin. Given its biochemical effect on progesterone responsiveness 52 and its phenotypic consequences on preterm birth 51 and ovarian cancer, 49,50 introgression of this archaic Neanderthal allele in modern humans likely contributes to phenotypic variances underlying these conditions.…”

The Neandertal Progesterone Receptor

“…2015 ; Li et al. 2018 ), ovarian and endometrial cancer ( Liu et al. 2014 ), migraine ( Palmirotta et al.…”