ESR1 PvuII polymorphism: from risk factor to prognostic and predictive factor of the success of primary systemic therapy in advanced breast cancer

Background The ESR1 gene encodes Estrogen Receptor alpha (ERα), which plays a role in the tumourigenesis of breast cancer. A single nucleotide polymorphism (SNP) in intron 1 of this gene called ESR1 PvuII (rs2234693) has been reported to increase the risk of breast cancer. This study aimed to investigate the ESR1 PvuII polymorphism as a prognostic and predictive factor guiding the choice of therapy for advanced breast cancer. Methods This retrospective study was conducted in 104 advanced breast cancer patients at Dharmais Cancer Hospital from 2011 to 2018. The ESR1 PvuII polymorphism was analysed by Sanger sequencing of DNA from primary breast tumour samples. Results The percentages of patients with ESR1 PvuII genotypes TT, TC, and CC were 42.3, 39.4, and 18.3%, respectively. Looking at prognosis, patients with ESR1 PvuII TC + CC had shorter overall survival than those with the TT genotype [HR = 1.79; 95% CI 1.05–3.04; p = 0.032]. As a predictive marker, TC + CC was associated with shorter survival (p = 0.041), but TC + CC patients on primary hormonal therapy had a median overall survival longer than TC + CC patients on primary chemotherapy (1072 vs 599 days). Conclusion The ESR1 PvuII TC + CC genotypes confer poor prognosis in advanced breast cancer, but these genotypes could be regarded as a good predictor of the therapeutic effect of hormonal treatment.

Effect of interactions between APOE and ESR1 polymorphisms on cognitive functions in postmenopausal women

IntroductionDuring menopause the level of estrogens is decreased, which may lead to cognitive impairment or dementia. Some forms of genetic polymorphism were found to be related to cognitive functions, including APOE and ESR1 (PvuII and XbaI) polymorphisms. In the present study we aimed to analyze the impact of interactions between APOE and ESR1 polymorphisms on cognitive functions in the group of postmenopausal women.Material and methodsThe study group consisted of 266 postmenopausal women aged 50–65 years without symptoms of dementia. A computerized battery of the Central Nervous System Vital Signs (CNS VS) test was used to diagnose cognitive functions. APOE and ESR1 polymorphisms were genotyped using multiplex PCR and PCR-RFLP methods, respectively. Statistical analysis was performed using two-way analysis of variance in Statistica software.ResultsThe best memory, visual memory, processing and psychomotor speeds were found in women carrying the C allele of the PvuII polymorphism (TC + CC genotypes) in the presence of the APOE 2/3 genotype, while a lower outcome was noted in women with 3/3, and the lowest if they had the 4 allele. In the case of women with TT genotype of the PvuII polymorphism, cognitive functioning did not decrease in women with the 4 allele. A similar effect on cognitive functions was observed for AG + GG genotypes of the XbaI and APOE polymorphisms. Women who simultaneously carried CC PvuII and GG XbaI genotypes had the lowest cognitive functions.ConclusionsInteractions of polymorphic variants of APOE and ESR1 genes influenced cognitive functions in postmenopausal women.

PVUII POLYMORPHISM IN THE ESTROGEN RECEPTOR ΑLPHA GENE AS AN INDICATOR FOR SURGICAL TREATMENT IN PATIENTS WITH BENIGN MAMMARY DYSPLASIA

The paper presents the results of studying the relationship between the genetic characteristics of the individual and the phenotypic manifestations of benign mammary dysplasia. Data were provided on the role of PvuII polymorphism in the development of breast tissue proliferation through the mechanisms of EsRα overexpression; this can be used as a marker for surgical treatment necessity. The objective of the work was to develop criteria for the diagnosis of proliferative benign mammary dysplasia on the basis of immunohistochemical and molecular genetic studies to substantiate the indications for surgical treatment. Materials and methods: The study involved 84 patients: 66 (78.6%) subjects from Sumy and 18 (78.6%) subjects – from the Sumy region. The mean age of the subjects was (32.3 ± 1.1) years, with the range of 16–62 years. Among the subjects, 82 (97.6%) were women with BMD and 2 (2.4%) were men who suffered from nodular gynecomastia. The burdened history of breast cancer in close relatives was reported in 33 (39.3%) individuals. Apart from a profound assessment of history data, the clinical course of the disease and comorbidities were studied. Instrumental and laboratory tests were performed. The morphological and immunohistochemical features of dissected tissues, as well as genetic differences of patients, were studied. By age, the subjects were divided into three groups: the first group (under 21 years) included 15 (17.8%) individuals, the second group (22–39 years) – 43 individuals (51.2%), the third group (over 40 years) – 26 individuals (31.0%). Results: The frequency of allelic variants of the EsRα gene PvuII polymorphism in patients with a proliferative form of benign mammary dysplasia was distributed as follows: T/T genotype - 27.4%, T/C genotype – 51.2%, C/C genotype - 21.4%. The most significant clinical predictors in patients with proliferative benign mammary dysplasia were: mastodynia (χ2 = 11.444; P = 0.003), decreased BMI of up to (21.17 ± 1.06) kg/m2 (F = 5.020; P = 0.009), prolonged menstruation of up to (5.67 ± 0.30) days (F = 3.017; P = 0.055). A group of patients whose mammary cells do not have estrogen receptors was identified. Since prescription of antiestrogens as a means of prevention in patients of this group will not be effective, such patients should be offered surgery as an option for further atypia prevention. Conclusions: Additional studies of EsRα expression and the pathological C-allele of the EsRα gene PvuII polymorphism have been found to play an important role as criteria for the diagnosis of proliferative benign mammary dysplasia that substantiate indications for surgical treatment. The specificity of the histological structure of tissue, the features of the cell receptor apparatus, and genetic predictors are important indicators for understanding the causes and mechanisms of proliferation in BMD. The calculated results indicate that BMDs begin to develop against the background of retained menstrual cycle and reproductive function, which indicates a crucial role of local estradiol receptors status in breast tissue in the development of proliferation foci in BMD. Hormone imbalance contributes to morphofunctional changeover. The results of the study will serve as the basis for identifying patients prone to the development of BMD proliferative forms and their timely surgical treatment to prevent the development of malignancy. Keywords benign mammary dysplasia, PvuІІ polymorphism in the estrogen receptor α gene, tissue proliferation.

Associations of Estrogen Receptor Alpha Gene Polymorphisms with Type 2 Diabetes Mellitus and Metabolic Syndrome: A Systematic Review and Meta-Analysis

The associations between PvuII (T>C) and XbaI (A>G) polymorphisms of estrogen receptor alpha (ESR1) gene with type 2 diabetes mellitus (T2DM) or metabolic syndrome (MetS) are reported in many studies, but the results are inconsistent. This present work aims to assess the associations by performing a comprehensive meta-analysis. Relevant studies were searched through several databases. The pooled odd ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the associations of PvuII and XbaI polymorphisms with the risk of T2DM and MetS by using the STATA 14.0 software. Eight studies for T2DM and three articles about MetS were included in this meta-analysis. The overall results indicated that PvuII, rather than XbaI polymorphism, was associated with T2DM (regressive model: OR=0.673, 95% CI=0.550 to 0.823, praw<0.001, pFDR<0.003). The subgroup analysis based on race revealed an association of PvuII polymorphism with the decreased T2DM risk in Chinese population and a relationship between XbaI polymorphism and the reduced T2DM susceptibility in Caucasians. The difference of country may be one source of the heterogeneity for PvuII polymorphism and T2DM. However, neither PvuII nor XbaI polymorphism was related to the risk of MetS. The C allele of PvuII polymorphism presents a protective role in T2DM risk, especially in Chinese people. The G allele of XbaI polymorphism is related to a reduced risk for T2DM in Caucasian population. Nevertheless, neither of PvuII nor XbaI polymorphism is associated with MetS risk.

ASSOCIATION OF THE ESR1 GENE WITH REPRODUCTIVE TRAITS OF SOWS OF LARGE WHITE AND MIRGOROD BREEDS

The speciality of the modern methodology in breeding is using the molecular information, received during genome analysis. This methodology can significantly accelerate the improvement of productivity traits and it is particularly useful in relation to the traits with low coefficient of inheritance while classic methods are not effective enough. The reproductive traits are one of the most important in pig farming, estrogen receptor 1 gene (ESR1) is involved in their control. Meanwhile, the use of ESR1 locus polymorphism in the marker-assisted selection needs to determine the extent of its association with the reproductive traits of animals in those populations where it is planned to conduct such selection. Implementation of marker-assisted selection in Large White and Mirgorod breeds for improving the reproductive traits is an actual task, but a necessary step in this work is the associative analysis. The purpose of the work is to research the association of polymorphisms of ESR1 locus with some reproductive traits of sows of Large White breed (ULW-1 and ULW-3 lines) and sows of Mirgorod breed. Materials and methods of research. Experimental groups: 1) the sows of Large White breed, ULW-3 line, bred in "Bahmutskiy Agrarian Union" farm, Donetsk region; 2) the sows of Large White breed, ULW-1 line, bred in “Stepne” farm, Poltava region; 3) the sows of Mirgorod breed, bred in «Named after Dekabristy» farm, Poltava region. All the experimental animals were previously genotyped on RYR1 gene and had RYR1CC genotype. The animals were genotyped on estrogen receptor 1 locus with aid of PCR-RFLP analysis on PvuII-polymorphic restriction site in the third intron of the gene – DNA marker for estrogen receptor 1 gene. Associations between genotypes and the studied traits were calculated using ANOVA in Excel 2007. Results. ULW-3 sows with ESR1BB genotype turned out to have 1.36 more piglets in a litter (analysing data from 2nd-4th farrows) comparing to animals with ESR1AA genotype. There is a tendency for bigger amount of newborn piglets in the heterozygotes animals than in sows with homozygous ESR1AA. A similar pattern appears in the 1st farrowing, the sows with ESR1BB and ESR1AB genotypes had the advantage in the total number of piglets at birth. In the experimental group of ULW-1 sows statistically proven patterns were not found, there was only a tendency to slight predominance of sows with ESR1BB and ESR1AB genotypes comparing to individuals with ESR1AA genotype. In the experimental group of Mirgorod sows there was a tendency to have most part of individuals with heterozygous genotype. Analysis of prolificacy of ULW-3 sows due to their genotype for the estrogen receptor 1 gene confirmed the superiority of ESR1BB and ESR1AB genotypes comparing to ESR1AA sows. According to 2nd-4th farrows, sows with ESR1BB and ESR1AB genotypes had the advantage in prolificacy comparing to ESR1AA sows by 1.15 and 0.53 piglets, respectively. According to the 1st farrowing difference between genotypes was absent. ESR1/PvuII-polymorphism do es not influence on prolificacy of ULW-1 sows. According to the 1st farrowing the trend towards a higher level of prolificacy of Mirgorod sows with ESR1AA genotype was found, while difference in 2nd-4th farrows between the groups was absent. It was found that ESR1/PvuII-polymorphism impact on the total number of piglets at birth and prolificacy for ULW-3 sows is characterized by predominance of additive component with a little contribution of the dominant component, the similar trend is observed for ULW-1 sows. There is a complex nature of the impact of ESR1/PvuII-polymorphism on the reproductive traits of Mirgorod sows in the predominance of the dominant component. Conclusions. The impact of polymorphism in estrogen receptor 1 gene on the total number of piglets in the litter after the birth and prolificacy in ULW-3 sows was detected. ULW-3 sows with ESR1BB genotype have 1.36 more piglets in a litter (analysing data from 2nd-4th farrows) and 1.15 more comparing to animals with ESR1AA genotype. ESR1/PvuII-polymorphism was not associated with total number of piglets in a litter and prolificacy in ULW-1 sows and Mirgorod sows. The counted parameters of additive-dominant model indicate that ESR1/PvuII polymorphism impact on the total number of piglets at birth and prolificacy for ULW-3 sows is characterized by predominance of additive component with a little contribution of the dominant component.

Association between Estrogen Receptor-αGene XbaI and PvuII Polymorphisms and Periodontitis Susceptibility: A Meta-Analysis

Background. Certain studies have previously explored the association between the estrogen receptor-α(ER-α) gene polymorphisms and periodontitis susceptibility, although the current results are controversial. The present study, using meta-analysis, aimed to investigate the nature of the genetic susceptibility of the ER-αfor developing periodontitis.Methods. A comprehensive literature search of PubMed, Embase, CNKI, and Wanfang databases was conducted up to January 8, 2015. Statistical manipulation was performed using Stata version 13.0 software. Odds ratios (ORs) and corresponding 95% confident intervals (CIs) were calculated to estimate the association in five genetic models.Results. A total of 17 eligible case-control studies from seven identified publications consisting of nine studies for the XbaI polymorphism and eight studies for the PvuII polymorphism were included in the meta-analysis. We found elevated risk of periodontitis in XbaI XX genotype carriers. Moreover, subgroup analyses demonstrated increased risk for chronic periodontitis of XbaI XX genotype carriers, specifically in the Chinese Han female population. No significant association was observed between PvuII polymorphism and periodontitis.Conclusion. Current evidence indicated that the homozygote (XX) genotype of ER-αgene XbaI polymorphism, but not PvuII mutation, may increase the risk of chronic periodontitis, specifically in the Chinese Han female population.