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1
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Hatletvedt ND, Engebrethsen C, Geisler J, Geisler S, Aas T, Lønning PE, Gansmo LB, Knappskog S. The impact of functional MDM2-polymorphisms on neutrophil counts in breast cancer patients during neoadjuvant chemotherapy. BMC Cancer 2025; 25:308. [PMID: 39979836 PMCID: PMC11843751 DOI: 10.1186/s12885-025-13675-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 02/06/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Functional polymorphisms in the MDM2 promoters have been linked to cancer risk and several non-malignant conditions. Their potential role in bone marrow function during chemotherapy is largely unknown. METHODS We investigated the potential associations between genotypes of MDM2 SNP309 (rs2279744), SNP285 (rs117039649) and del1518 (rs3730485) and neutrophil counts in breast cancer patients receiving neoadjuvant sequential epirubicin and docetaxel, with additional G-CSF, in the DDP-trial (NCT00496795). We applied longitudinal ratios, post vs. pre-treatment, of neutrophil counts as our main measure. Differences by genotypes were tested by Jonckheere-Terpstra test for ranked alternatives, while dominant and recessive models were tested by Mann-Whitney U test, and additional sub-analyses were performed for genotype combinations. RESULTS The SNP309 reference T-allele was associated with a better sustained neutrophil count (p = 0.035). A similar association was observed for the alternative del-allele of the del1518 (p = 0.049). Additionally, in combined genotype-analyses, patients with the SNP309 TT genotype and at least one copy of the del1518 del-allele had particularly favorable sustained neutrophil counts during chemotherapy treatment (p = 0.005). CONCLUSIONS Our study provides evidence that MDM2 promoter polymorphisms may be associated with neutrophil counts and bone marrow recovery during chemotherapy treatment in breast cancer patients. TRIAL REGISTRATION The DDP-trial was registered at ClinicalTrials.gov (NCT00496795; registration date 2007-07-04).
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Affiliation(s)
- Nora D Hatletvedt
- Department of Clinical Science, University of Bergen, 5020, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Christina Engebrethsen
- Department of Clinical Science, University of Bergen, 5020, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Jürgen Geisler
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Stephanie Geisler
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
| | - Turid Aas
- Department of Surgery, Haukeland University Hospital, Bergen, Norway
| | - Per E Lønning
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Liv B Gansmo
- Department of Clinical Science, University of Bergen, 5020, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Stian Knappskog
- Department of Clinical Science, University of Bergen, 5020, Bergen, Norway.
- Department of Oncology, Haukeland University Hospital, Bergen, Norway.
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Dedousi D, Mavrogianni D, Papamentzelopoulou M, Stavros S, Raouasnte R, Loutradis D, Drakakis P. Association between TP53 Arg72Pro variant and recurrent pregnancy loss in the Greek population. Horm Mol Biol Clin Investig 2022; 43:421-426. [PMID: 35776848 DOI: 10.1515/hmbci-2021-0093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 06/11/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES The present case-control study investigates whether TP53 Arg72Pro variant (rs1042522) serves as a risk factor for recurrent pregnancy loss (RPL) in Greek women. METHODS The study group consisted of 100 patients with at least two miscarriages of unexplained etiology, before the 24th week of gestation. The control group included 106 women with no pregnancy loss history. DNA was extracted and genotyped using specific primers for PCR amplification of the Arg72 and Pro72 alleles. Sanger sequencing was used for the discrimination between heterozygotes and homozygotes for Arg72Pro variant. RESULTS This is the first study demonstrating the statistically significant higher frequency of TP53 Arg72Pro variant in Greek RPL women compared to controls (38% vs. 6.6%; OR=8.6682, 95% CI: 3.6446-20.6160; p<0.0001). GC genotype (Arg/Pro) and CC genotype (Pro/Pro) were statistically more common in RPL patients than in controls (16% vs. 1.9%; p=0.0027, and 22 vs. 4.7%; p=0.0008, respectively). C allele frequency was statistically significant higher in RPL group than in controls (30.0 vs. 5.7%; p<0.0001). According to the inheritance mode analysis, the model that best fit the data was the dominant model (OR=8.67, 95% CI=3.64-20.62; p<0.0001). CONCLUSIONS The is the first study disclosing strong evidence that TP53 rs1042522 is significantly associated with a higher risk for recurrent pregnancy loss in Greek women following a dominant model, thus, serving as a genetic marker for identifying women at increased risk of recurrent miscarriages.
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Affiliation(s)
- Dimitra Dedousi
- Molecular Biology Unit, Division of Human Reproduction, 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Despoina Mavrogianni
- Molecular Biology Unit, Division of Human Reproduction, 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Myrto Papamentzelopoulou
- Molecular Biology Unit, Division of Human Reproduction, 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Sofoklis Stavros
- Molecular Biology Unit, Division of Human Reproduction, 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Rami Raouasnte
- Molecular Biology Unit, Division of Human Reproduction, 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitris Loutradis
- Molecular Biology Unit, Division of Human Reproduction, 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Peter Drakakis
- Molecular Biology Unit, Division of Human Reproduction, 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
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3
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Liu T, Yan M, Liu F, Ma Y, Fang Y. The role of
p53‐MDM2
signaling in missed abortion and possible pathogenesis. J Obstet Gynaecol Res 2022; 48:2686-2696. [DOI: 10.1111/jog.15385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 05/03/2022] [Accepted: 07/21/2022] [Indexed: 11/27/2022]
Affiliation(s)
- Ting Liu
- Department of Gynecology and Obstetrics Qilu Hospital of Shandong University Jinan Shandong PR China
| | - Min Yan
- Yidu Central Hospital of Weifang Shandong PR China
| | - Fen Liu
- Department of Gynecology and Obstetrics Qilu Hospital of Shandong University Jinan Shandong PR China
| | - Yuyan Ma
- Department of Gynecology and Obstetrics Qilu Hospital of Shandong University Jinan Shandong PR China
| | - Yan Fang
- Department of Gynecology and Obstetrics Qilu Hospital of Shandong University Jinan Shandong PR China
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4
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Subi TM, Krishnakumar V, Kataru CR, Panigrahi I, Kannan M. Association of VEGF and p53 Polymorphisms and Spiral Artery Remodeling in Recurrent Pregnancy Loss: A Systematic Review and Meta-Analysis. Thromb Haemost 2021; 122:363-376. [PMID: 34041737 DOI: 10.1055/a-1518-1756] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Many studies have reported the association of VEGF-1154G/A, VEGF 936C/T, and p53 Arg72Pro polymorphisms with recurrent pregnancy loss (RPL), but the outcomes are inconsistent. We have used a meta-analysis to associate these polymorphisms with RPL, having the spiral artery remodeling as a major risk factor. The studies were identified from three different reputed databases, namely ScienceDirect, PubMed/Medline, and Scopus. The eligible studies of VEGF-1154G/A, VEGF 936C/T, and p53Arg72Pro polymorphisms associated with the RPL were selected for the analysis. They were segregated into three different ethnic groups as Asians, Caucasians, and mixed population. For the analysis, the overall prevalence, odds ratio, risk ratio, relative risk ratio, and p-values were calculated. A total of 3,241 RPL cases and 3,205 healthy controls from 21 different case-control studies were analyzed. RPL was highly prevalent in the mixed population with VEGF-1154G/A and p53 Arg72Pro polymorphisms (70.04 and 66.46%, respectively) and in the Asian population with VEGF 936C/T polymorphism (53.58%). The homozygous recessive genotypes of VEGF and p53 exhibited significant association between the respective polymorphisms and RPL along with the increased risk of outcome. The current analysis conclusively reports the geographic distribution of the different genetic polymorphisms which shows high association with the progression of RPL. Understanding the spectrum of polymorphisms on different populations with the spiral artery remodeling as a risk factor encloses the importance of the vasculature during the pregnancy.
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Affiliation(s)
- Tamil Mani Subi
- Division of Blood and Vascular Biology, Department of Life Sciences, School of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India
| | - Vinodhini Krishnakumar
- Division of Blood and Vascular Biology, Department of Life Sciences, School of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India
| | - Chandreswara Raju Kataru
- Division of Blood and Vascular Biology, Department of Life Sciences, School of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India
| | - Inusha Panigrahi
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Meganathan Kannan
- Division of Blood and Vascular Biology, Department of Life Sciences, School of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India
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5
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Liu T, Ma Y, Yin Q, Zhou H, Fang Y. Association of β-arrestin1 and p53-Mdm2 signaling in the development of missed abortion. J Obstet Gynaecol Res 2021; 47:1675-1685. [PMID: 33611816 DOI: 10.1111/jog.14643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/02/2020] [Accepted: 12/17/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Missed abortion is a peculiar form of spontaneous abortion before 20 weeks' gestation. The definite etiology and pathogenesis are not fully understood. Recent studies have demonstrated that p53/Mdm2-mediated ubiquitination of the IGF-1R may be closely related to G-protein-coupled receptor kinases (GRK)/β-arrestin1 system. Our previous studies have confirmed that the elevated expression of p53 and Mdm2 may be responsible for apoptosis during missed abortion. However, there was no information surrounding β-arrestin1 in missed abortion. METHODS The mRNA levels of β-arrestin1 in villous samples of 30 missed abortion patients and 31 healthy controls were determined by real-time quantitative polymerase chain reaction (PCR). Immunohistochemistry was used to explore the expression and location of β-arrestin1, p53, Mdm2, VEGF and HIF-lα in trophoblasts. Transwell assays were performed to examine the influences of β-arrestin1 expression on cell invasion. Furthermore, we tested the effect of β-arrestin1 on the expression of p53, Mdm2, ERK, AKT and NF-κB. RESULTS The expression of β-arrestin1 in the villous samples of missed abortion group was dramatically lower than control group by quantitative real-time-PCR and immunohistochemistry. Furthermore, the patients with missed abortion showed significantly higher levels of p53, Mdm2, HIF-lα and lower level of VEGF than healthy controls by immunohistochemistry. Functional studies showed that suppression of β-arrestin1 in HTR-8 cells inhibited cell invasion. The protein expressions of ERK and AKT in HTR-8 cells were significantly downregulated by reducing the expression of β-arrestin1, while the expressions of p53, Mdm2, NF-κB were enhanced. Overexpression of β-arrestin1 exhibited the adverse effect. CONCLUSION Our data indicated that β-arrestin1 play an important role in maintaining the maternal-fetal tolerance, the decreased expression of β-arrestin1 in the villous samples may be related with the development of missed abortion.
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Affiliation(s)
- Ting Liu
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yuyan Ma
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Qihui Yin
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Huanyu Zhou
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yan Fang
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, Shandong, China
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6
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Wang Y, Liu HZ, Liu Y, Wang HJ, Pang WW, Zhang JJ. Disordered p53-MALAT1 pathway is associated with recurrent miscarriage. Kaohsiung J Med Sci 2019; 35:87-94. [PMID: 30848022 DOI: 10.1002/kjm2.12013] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 11/22/2018] [Indexed: 01/04/2023] Open
Affiliation(s)
- Yan Wang
- Department of Obstetrics; Affiliated Hospital of Weifang Medical University; Weifang China
| | - Hui-Ze Liu
- Department of Obstetrics; Affiliated Hospital of Weifang Medical University; Weifang China
| | - Yang Liu
- Department of Obstetrics; Affiliated Hospital of Weifang Medical University; Weifang China
| | - Hui-Juan Wang
- Department of Obstetrics; Affiliated Hospital of Weifang Medical University; Weifang China
| | - Wen-Wen Pang
- Department of Obstetrics; Affiliated Hospital of Weifang Medical University; Weifang China
| | - Jian-Jun Zhang
- Department of Obstetrics; Affiliated Hospital of Weifang Medical University; Weifang China
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7
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Abstract
Tumor protein 53 (TP53) and its related family of p63 and p73 are tumor suppressor genes that regulate cellular activity to enhance longevity. p53 binds to specific response elements in DNA, modulating the transcription of genes that govern the major defenses against tumor growth. Additional members of the p53 family are involved with male and female germ cell survival. Although the majority of studies have focused on p53 as a tumor suppressor gene, little is known about its function in normal cellular processes. Polymorphisms of TP53 codon 72 that alter activity levels have been studied with respect to implantation in both the murine and human models. TP53 codon 72 (arginine) exhibits higher rates of apoptosis and leukemia inhibitory factor expression, whereas the C allele (proline) reduces leukemia inhibitory factor expression. Here, we review the role of p53 and the family of p53 proteins, along with the potential effect of p53 polymorphisms on reproduction.
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8
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Chan Y, Zhu B, Zhang J, Luo Y, Tang W. Associations Between TP53 and MDM2 Polymorphisms and the Follicle-Stimulating Hormone/Luteinizing Hormone Ratio in Infertile Women. Genet Test Mol Biomarkers 2018; 22:405-412. [PMID: 29957069 DOI: 10.1089/gtmb.2017.0260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
AIMS This is a follow-up study based on the results of our previous article, to further explore the effect of the TP53 codon 72 (rs1042522) and MDM2 SNP309 (rs2279744) polymorphisms on basal follicle-stimulating hormone (FSH)/luteinizing hormone (LH) ratios in infertility women. MATERIALS AND METHODS The distribution of two genetic polymorphisms (rs1042522 and rs2279744) and basal FSH/LH ratios were tested and analyzed in 1051 in vitro fertilization (IVF) patients at a university-affiliated hospital. RESULTS The TP53 codon 72 polymorphism had a significant association with the FSH/LH ratio (group I: FSH/LH <2.3 and group II: FSH/LH ≥2.3) (C/C vs. G/G: odds ratio [OR] = 1.69, 95% confidence interval [CI]: 1.07-2.65, p = 0.02; G/C vs. G/G: OR = 1.86, 95% CI: 1.25-2.77, p = 0.002). In a stratification analysis, C allele carriers and the C/C genotype showed a strong association with positive clinical pregnancy outcomes after IVF compared with G allele carriers and the G/G genotype in the recessive, dominant, and allelic genetic models in group I (C/C vs. G/G: OR = 1.84, 95% CI: 1.25-2.69, p = 0.01; C/C vs. G carrier: OR = 1.52, 95% CI: 1.12-2.07, p = 0.01; C carrier vs. G/G: OR = 1.46, 95% CI: 1.07-2.01, p = 0.02; C allele vs. G allele: OR = 1.34, 95% CI: 1.11-1.62, p = 0.003), no significant associations by stratification were observed for group II. No associations were found between MDM2 SNP309 and either of two groups. CONCLUSION The TP53 codon 72 polymorphism is associated with FSH/LH ratios, suggesting that it is a potential predictive genetic marker of IVF outcome in patients younger than 35 years of age with baseline FSH levels below 10 IU/L and who have an FSH/LH ratio <2.3.
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Affiliation(s)
- Ying Chan
- 1 Department of Gynecology and Obstetrics, First People's Hospital of Yunnan Province , Kunming, China .,2 Lab of Molecular Genetics of Aging and Tumor, Faculty of Medicine, Kunming University of Science and Technology , Kunming, China .,3 Department of Reproductive Medicine, The Second Hospital Affiliated Kunming Medical University , Kunming, China
| | - Baosheng Zhu
- 1 Department of Gynecology and Obstetrics, First People's Hospital of Yunnan Province , Kunming, China
| | - Jinman Zhang
- 1 Department of Gynecology and Obstetrics, First People's Hospital of Yunnan Province , Kunming, China
| | - Ying Luo
- 2 Lab of Molecular Genetics of Aging and Tumor, Faculty of Medicine, Kunming University of Science and Technology , Kunming, China
| | - Wenru Tang
- 2 Lab of Molecular Genetics of Aging and Tumor, Faculty of Medicine, Kunming University of Science and Technology , Kunming, China
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9
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Salimi S, Mohammadpour-Gharehbagh A, Rezaei M, Sajadian M, Teimoori B, Yazdi A, Mokhtari M, Yaghmaei M. The MDM2 promoter T309G polymorphism was associated with preeclampsia susceptibility. J Assist Reprod Genet 2017; 34:951-956. [PMID: 28508227 DOI: 10.1007/s10815-017-0941-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 04/30/2017] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Preeclampsia (PE) is a hypertensive disorder of pregnancy in which abnormal proliferation and apoptosis of placenta trophoblast has a pivotal role in its pathophysiology. The aim of the current study was to examine the association between Mouse Double Minute 2 (MDM2) T309G and 40 bp insertion/deletion (I/D) polymorphisms and PE risk. METHODS A case-control study was conducted on 208 PE women and 164 healthy pregnant women matching age, sex, and ethnicity. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR methods were used for genotyping. RESULTS The MDM2 309GG genotype was associated with PE, and this genotype was found to be a risk factor for PE. There was no association between the MDM2 I/D polymorphism and PE. The haplotype-based association analysis revealed no association between MDM2 T309G and 40 bp I/D polymorphisms and PE. The frequency of TT-DD and GG-DD combined genotypes were significantly higher in PE women with marginal P values (P = 0.046). CONCLUSIONS The MDM2 309GG genotype was associated with higher risk of PE. The TT-DD and GG-DD combined genotypes were higher in PE women.
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Affiliation(s)
- Saeedeh Salimi
- Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.,Department of Clinical Biochemistry, School of Medicine and Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Abbas Mohammadpour-Gharehbagh
- Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran. .,Department of Clinical Biochemistry, School of Medicine and Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Mahnaz Rezaei
- Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.,Department of Clinical Biochemistry, School of Medicine and Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mojtaba Sajadian
- Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.,Department of Clinical Biochemistry, School of Medicine and Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Batool Teimoori
- Department of Obstetrics and Gynecology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Atefeh Yazdi
- Department of Obstetrics and Gynecology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mojgan Mokhtari
- Department of Obstetrics and Gynecology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Minoo Yaghmaei
- Department of Obstetrics and Gynecology, School of Medicine, Shahid Beheshty University of Medical Sciences, Tehran, Iran
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10
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Influence of TP53 Codon 72 Polymorphism Alone or in Combination with HDM2 SNP309 on Human Infertility and IVF Outcome. PLoS One 2016; 11:e0167147. [PMID: 27898708 PMCID: PMC5127557 DOI: 10.1371/journal.pone.0167147] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2016] [Accepted: 11/09/2016] [Indexed: 11/19/2022] Open
Abstract
To evaluate the association of the TP53 codon 72 (rs 1042522) alone or in combination with HDM2 SNP309 (rs 2279744) polymorphisms with human infertility and IVF outcome, we collected 1450 infertility women undergoing their first controlled ovarian stimulation for IVF treatment and 250 fertile controls in the case-control study. Frequencies, distribution, interaction of genes, and correlation with infertility and IVF outcome of clinical pregnancy were analyzed. We found a statistically significant association between TP53 codon 72 polymorphism and IVF outcome (52.10% vs. 47.40%, OR = 0.83, 95%CI:0.71–0.96, p = 0.01). No significant difference was shown between TP53 codon 72, HDM2 SNP309 polymorphisms, human infertility, and between the combination of two genes polymorphisms and the clinical pregnancy outcome of IVF. The data support C allele as a protective factor for IVF pregnancy outcome. Further researches should be focused on the mechanism of these associations.
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11
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Fraga LR, Dutra CG, Boquett JA, Vianna FSL, Gonçalves RO, Paskulin DD, Costa OL, Ashton-Prolla P, Sanseverino MTV, Schuler-Faccini L. p53 signaling pathway polymorphisms associated to recurrent pregnancy loss. Mol Biol Rep 2014; 41:1871-7. [PMID: 24435975 DOI: 10.1007/s11033-014-3036-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 01/04/2014] [Indexed: 01/24/2023]
Abstract
The p53 protein is known for performing essential functions in the maintenance of genomic stability in somatic cells and prevention of tumor formation. Studies of the p53 signaling pathway have suggested associations between some polymorphisms and infertility, post-in vitro fertilization implantation failure and recurrent abortions. The TP53 Pro72Arg polymorphism has been implicated as a risk factor for recurrent pregnancy loss (RPL); however, the association is controversial. In this study, our objective was to evaluate selected polymorphisms in genes of the p53 signalling pathway [TP53 c.215G>C (Pro72Arg), MDM2 c.14+309T>G (SNP309) and LIF c.1414T>G in the region 3' UTR] and determine their effect as risk factors for RPL. In a case-control study, we investigated 120 women with two or more pregnancy losses and 143 fertile control women reporting at least two live births and no history of pregnancy loss. When analyzed separately, the allele and genotype distributions of the polymorphisms in the two groups were not different. However, in a multivariate analysis adjusted for alcohol consumption, smoking, ethnicity, and number of pregnancies, the interaction between the genotypes TP53 Arg/Arg (rs1042522) and MDM2 TT (rs2279744) showed to be associated to RPL, increasing the risk for this condition (OR = 2.58, 95% CI: 1.31-5.07, p = 0.006). In conclusion, our study indicates that the combination of TP53 Arg/Arg (rs1042522) and MDM2 TT (rs2279744) genotypes may be a risk factor for RPL.
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Affiliation(s)
- L R Fraga
- Post-Graduation Program in Genetics and Molecular Biology, Departament of Genetics, Biosciences Institute, Universidade Federal do Rio Grande do Sul (UFRGS), Caixa Postal 15031 - Agencia Campus UFRGS, Porto Alegre, RS, 91501-970, Brazil,
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12
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Wei D, Wu Q, Shi H. Apoptosis and p53 expression in the placental villi of females with unexplained recurrent spontaneous abortion. Exp Ther Med 2013; 7:191-194. [PMID: 24348788 PMCID: PMC3861175 DOI: 10.3892/etm.2013.1399] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 10/28/2013] [Indexed: 01/17/2023] Open
Abstract
The aim of this study was to explore the level of apoptosis and p53 expression in the placental villi of patients with unexplained recurrent spontaneous abortion (URSA). Fifty-three pregnant females with URSA and 32 pregnant females who required an induced abortion were selected as the subjects of this study. Placental villus tissues were collected from June 2010 to June 2012 and quantitative polymerase chain reaction (qPCR) and immunohistochemical analysis were performed to determine the mRNA and protein levels of p53 in the placental villus tissues. The level of apoptosis in the tissues was studied using terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assay. The mRNA and protein expression levels of p53 in the URSA group were significantly higher than those in the control group (P<0.05). Furthermore, the levels of apoptosis were increased markedly in the URSA group compared with the control group (P<0.05). In conclusion, the placental villi of patients with URSA express a high level of p53, which may result in cell apoptosis and lead to recurrent spontaneous abortion.
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Affiliation(s)
- Dehua Wei
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China ; Department of Gynecology and Obstetrics, Puyang People's Hospital, Puyang, Henan 457000, P.R. China
| | - Qinghua Wu
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China
| | - Huirong Shi
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China
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13
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Abstract
MDM2 plays a key role to physiological processes like growth arrest, senescence and apoptosis. It binds to and inhibits key proteins like p53 and the RB protein, and MDM2 amplification as well as protein overexpression without amplification is seen in many solid tumors. An MDM2 promoter polymorphism (SNP309T>G) has been found associated with enhanced Sp1 transcription factor binding and elevated MDM2 transcription. While 309G has been found associated with elevated cancer risk and young age at diagnosis of different cancers, results in Caucasians have been at variance. Recently, we reported a second polymorphism (SNP285G>C) located on the 309G allele. The 285C/309G haplotype accounts for about 12% of all 309G alleles among Norwegians, Dutch and British habitants. Assessing Sp1 binding to the MDM2 promoter using surface plasmon resonance technology, we found SNP309G to enhance Sp1 binding by 22% while SNP285C reduced Sp1 binding by 51%. SNP285C reduced the risk of breast cancer and ovarian cancer among 309TG/309GG carriers by 21 and 26%, respectively, but in particular the risk of ovarian cancer among 309TG heterozygotes (reduction by 37%). The fact that the 285C/309G haplotype accounted for only 1.9% of all 309G alleles among Finns and was absent in Chinese indicate 285C to be a young polymorphism.
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