p53 codon 72 polymorphism and recurrent pregnancy loss: a meta-analysis

Background  

Arg72Pro polymorphism of the p53 tumour suppressor gene have been associated with recurrent pregnancy loss. However, results were inconsistent. We performed this metaanalysis to drive amore precise estimation of association between p53 codon 72 polymorphism and recurrent pregnancy loss.     

p53 codon 72 polymorphism and endometriosis: a meta-analysis

Background

p53 tumour suppressor gene Arg72Pro polymorphism has been associated with endometriosis. However, the current available data were inconsistent. We performed this meta-analysis to estimate the association between p53 Arg72Pro polymorphism and endometriosis.

Methods

Electronic screening of PubMed library was conducted to select studies. Studies containing available genotype frequencies of Arg72Pro were chosen, and pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association.

Results

Six published studies, including 749 endometriosis and 857 controls were identified. The overall results suggested that the variant genotypes were not associated with the endometriosis risk (Pro/Pro?+?Arg/Pro vs. Arg/Arg: OR?=?1.552, 95% CI 0.916–2.632, p?=?0.103). In the stratified analysis, individuals carried the Pro allele in a dominant model had increased risk of endometriosis (OR?=?2.595, 95% CI 1.005–6.702, p?=?0.049) in Asian subjects. The symmetric funnel plot, the Egger’s test (p?=?0.602), and the Begg’s test (p?=?0.167) were all suggestive of the lack of publication bias. However, the association was not significant between this polymorphism and endometriosis in Caucasian (OR?=?1.005, 95% CI 0.755–1.337, p?=?0.972).

Conclusion

This meta-analysis suggests that p53 codon 72 Pro/Pro?+?Arg/Pro genotypes are associated with increased risk of endometriosis in Asian. To validate the association between p53 codon 72 polymorphism and endometriosis, further studies with larger participants worldwide are needed.     

The relationship between p53 codon 72 genetic polymorphism and sperm parameters. A study of men with varicocele

PurposeRegulation of the apoptotic process has an important role in spermatogenesis. p53 has a prominent function in apoptosis and recent data suggest a relationship between varicocele and p53 codon 72 polymorphism and male infertility. This prompted us to study the relationship between this polymorphism and spermatic parameters.MethodsWe studied 134 subjects with varicocele admitted consecutively to the outpatients Department of Infertility at the University of Rome La Sapienza. We investigated in these subjects the effect of a strong apoptosis inducer, the p53 codon 72 *Arg/*Arg genotype, on spermatic parameters.The p53 codon 72 genotype was determined by DNA analysis.ResultsThe proportion of spermatozoa with abnormal (curvilinear) motility is higher in men with the *Arg/*Arg genotype than in men carrying the *Pro allele (p = 0.003). No statistical significant relationship has been observed with spermatozoa concentration and atypical spermatozoa.ConclusionsWe conclude: the p53 codon 72*Arg/*Arg genotype, with its strong apoptotic effects, negatively influences spermatozoa motility and male fertility.     

PROGINS receptor gene polymorphism is associated with endometriosis

OBJECTIVE: To investigate the association between the 306-base pair insertion polymorphism in intron G of the progesterone receptor (PROGINS) and endometriosis. DESIGN: Case-control study. SETTING: Tertiary care center. PATIENT(S): Ninety-five white women with surgically diagnosed and histologically confirmed endometriosis and 107 white women without endometriosis (controls). INTERVENTION(S): Determination of PROGINS was performed by polymerase chain reaction and gel electrophoresis. MAIN OUTCOIME MEASURE(S): Frequency and distribution of the PROGINS allele. RESULT(S): Frequencies of the mutant allele T2 was 0.17 among women with endometriosis and 0.08 among controls (odds ratio, 2.41 [CI, 1.31-4.53]). Homozygosity for allele T2 was present in 3.2% of women with endometriosis and 0.9% of controls. CONCLUSION(S): PROGINS appears to be associated with endometriosis in white persons.     

Analysis of p53 codon 72 polymorphism and its association with human papillomavirus 16 and 18 E6 in Chinese cervical lesions

The aim of this study was to analysis the relationship between p53 codon 72 polymorphism with human papillomavirus (HPV) 16 and 18 E6 in Chinese cervical cancer. A total of 81 cervical squamous cancer (specimens of G1, G2, and G3 are 13, 24, and 44, respectively; and of stage IB, IIA, IIB, and IIIA are 15, 37, 24, and 5, respectively), 18 cervical adenocarcinoma, 88 cervical intraepithelial neoplasm (CIN) (specimens of CIN II and III are 30 and 58), and 60 normal cervical specimens were included in this study. Polymerase chain reaction was used to examine p53 genotypes and HPV 16 and 18 E6. The frequencies of p53 Arg homozygosity in cervical squamous cancer, cervical adenocarcinoma, and CIN (II-III) were 58.02%, 55.55%, and 59.09%, respectively, that was much higher than that of p53 Arg/Pro heterozygosity (30.86%, 27.78%, and 21.59%) and of p53 Pro homozygosity (11.12%, 16.67%, and 19.32%) in each groups and higher than the frequency of p53 Arg homozygosity in normal samples (23.33%). There is no statistic difference in the normal samples for the frequency of p53 Arg homozygosity, p53 Arg/Pro heterozygosity, and p53 Pro homozygosity (23.33%, 40.00%, and 36.67%, respectively). The frequency of p53 Arg homozygosity in high risk (HR)-HPV E6-positive cervical squamous cancer samples (64.06%) is much higher than that in (HR)-HPV E6-negative cervical squamous cancer samples (35.29%) and in HR-HPV E6-positive normal samples (33.33%). No difference of p53 codon 72 polymorphism was found according to FIGO staging and grades. In conclusion, based on the findings of this study, it is suggested that p53 Arg homozygosity could act as a potential risk factor for the tumorigenesis of the cervix. p53 codon 72 polymorphism has no relation with the FIGO staging and grades of cervical cancer. p53 Arg homozygosity and HR-HPV E6 positive simultaneously can predict the fate of cervical lesions.     

Polymorphism at codon 72 of the p53 gene is not associated with endometriosis in a Japanese population

OBJECTIVE: Endometriosis is inherited as a complex trait, which means that multiple susceptibility genes interact with each other and the environment to produce the phenotype. Previous studies have implicated p53, a tumor suppressor gene, as a factor in the development of the disease. In a Japanese population, we investigated the frequency of the p53 polymorphism in women affected with endometriosis. METHODS: We compared the distribution of the p53 codon 72 polymorphism in endometriosis cases (n = 111) and population controls consisting of female neonates (n = 180) by using polymerase chain reaction restriction fragment-length polymorphism analysis in a Japanese population. RESULTS: The frequencies of the three p53 genotypes, Arginine (Arg)/Arg, Arg/Proline (Pro), and Pro/Pro in controls were 39.4%, 41.7%, and 18.9 %, respectively. The crude genotype frequencies in the endometriosis cases were similar to those of the controls (35.2%, 48.6%, and 16.2%, respectively). Using the Arg/Arg genotype as the reference, the odds ratios of the Arg/Pro and Pro/Pro genotypes were 1.30 (95% confidence interval [CI] 0.72-1.86, P =.33) and 0.96 (95% CI 0.47-1.94, P =.91), respectively. Thus, there were no significant differences in the frequency of the p53 codon 72 polymorphism between endometriosis cases and controls in this population. The endometriosis cases with severe disease only were also evaluated, but no significant difference was observed in the frequency of the polymorphism between this subgroup and the controls. CONCLUSION: Our findings suggest that the p53 codon 72 polymorphism is unlikely to be associated with endometriosis in Japanese women.     

Germline polymorphism of p53 codon 72 in gynecological cancer

OBJECTIVE: To investigate the biological significance of single nucleotide polymorphism at codon 72 of the p53 gene in the development of gynecological cancer. METHODS: p53 codon 72 polymorphism was examined in a total of 354 blood samples from 95 normal, 83 cervical, 108 endometrial and 68 ovarian cancer cases using polymerase chain reaction and restriction fragment length polymorphism techniques. RESULTS: When p53 codon 72 genotype was classified into two subgroups of Arg/Arg and Arg/Pro + Pro/Pro, the Arg/Arg genotype was associated with an increased risk for the development of endometrial cancer (OR = 1.86, 95% CI = 1.06 to 3.26) compared with the Arg/Pro + Pro/Pro genotype (P = 0.0301). The Arg allele also increased the risk of endometrial cancer (OR = 1.42, 95% CI = 0.93 to 1.52) compared with the Pro allele, but no statistical difference was found (P = 0.1031). There was no significant difference in the genotype or allele prevalence between control subjects and cervical or ovarian cancer patients. CONCLUSION: Homozygous Arg at codon 72 of the p53 gene may be a risk factor for developing endometrial cancer in a Japanese population.     

Study of p53 codon 72 polymorphism in patients with breast cancer

Breast cancer is a common disease in Western societies, with an incidence of 46.31/100,000 women/year in Brazil. The tumor suppressor gene TP53 is one of the most studied genes regarding the presence of mutations. Indeed, 50% of all tumors are known to exhibit changes in the TP53 nucleotide sequence due to carcinogenic processes. As to the presence of polymorphism, the TP53 gene is polymorphic at the nucleotide residue 347 (codon 72). In the current study, we examine if this polymorphism is associated with the clinicopathological parameters of breast cancer patients in a Brazilian population. One hundred and thirteen patients with breast cancer were included. The polymorphic region of the TP53 gene was PCR-amplified from genomic DNA obtained from buccal cells. Specific primers for the Pro and Arg allele were used. Correlations of polymorphism with age, staging, nuclear grade, lymph node status, estrogen receptor status and lymphatic and/or blood vessel invasion were evaluated. Statistical analysis was performed using the Fisher's exact test. The frequency of p53 Arg/Arg was 57% and of the heterozygous allele Arg/Pro it was 39%. There was no correlation between polymorphism and clinicopathological parameters. According to our results, the TP53 polymorphism, at the 347 residue, is not associated with any clinicopathological findings of patients with breast cancer.     

Association of TP53 codon 72 polymorphism with susceptibility to ovarian carcinomas in Serbian women

Objectives

Finding a potential genetic factor associated with a deadly disease, such as ovarian carcinoma, is of particular importance. The aim of this study was to examine the role of the TP53 codon 72 polymorphism in ovarian carcinoma development in Serbian women.

Study design

47 wild-type TP53 gene ovarian carcinoma samples and 70 cervical smears from gynecologically healthy women were analyzed. DNA was extracted by a salting-out procedure. Codon 72 polymorphism was assessed by PCR-RFLP method. χ², Fisher exact test and odds ratio were used for statistical analysis.

Results

The distribution of Arg/Arg, Arg/Pro and Pro/Pro genotypes of codon 72 of the TP53 gene was: 46.8%, 46.8% and 6.4%, respectively in the ovarian carcinomas and 64.3%, 31.4% and 4.3%, respectively in the control group. We observed an increased risk for the development of ovarian carcinoma for Pro homozygotes in relation to heterozygotes plus Arg homozygotes (OR = 1.52; 95% CI 0.29–7.89) and a higher one for Pro/Pro plus Arg/Pro genotype in relation to Arg homozygotes (OR = 2.04; 95% CI 0.96–4.34).

Conclusion

The results showed no association between codon 72 TP53 gene polymorphism and risk for development of ovarian carcinoma in Serbian women. However, this observation requires further analysis of a larger case–control study group.     

Association of p53 polymorphism with ICSI/IVF failure and recurrent pregnancy loss

Background: The p53 tumour suppressor gene is a well-known factor regulating apoptosis in a wide variety of cells. Alterations in the p53 gene are among the most common genetic changes in human cancers. Several polymorphisms of the p53 tumour suppressor gene have been associated with recurrent pregnancy loss (RPL).
Aims: To evaluate the association of polymorphisms p53 codon 72 with the response to in vitro fertilisation (IVF) treatment and occurrence of repeated miscarriages.
Methods: The homozygous and heterozygous genotypes and allelic frequencies of Arg and Pro p53 at codon 72 were identified by using polymerase chain reaction–restriction fragment length polymorphism technique in 70 infertile women with more than two IVF failures. Each comparison was made with 97 women experiencing RPL and 32 fertile women each with at least two healthy children as the control group.
Results: The frequency of homozygous Pro/Pro genotypes was found significantly higher among the women with RPL than the other two groups ( P  = 0.041). Whereas, Arg/Arg genotype was significantly different in the recurrent implantation failure (RIF) group ( P  = 0.005).
Conclusion: It is concluded that p53 codon 72 polymorphism may serve as a susceptible factor affecting the chances of RPL and RIF.     

Association of p53 mutations and a codon 72 single nucleotide polymorphism with lower overall survival and responsiveness to adjuvant radiotherapy in endometrioid endometrial carcinomas

p53 Genetic alterations are associated with advanced stage and aggressive tumors in a variety of human malignancies. The aim of this study was to examine p53 for genetic alterations and to evaluate the association of these alterations with clinical outcome and response to adjuvant radiotherapy in endometrioid endometrial carcinomas. p53 mutations in exons 2-11 were assessed in 59 endometrioid carcinomas by polymerase chain reaction-single-strand conformational polymorphism and sequence analysis. Twelve mutations (20.3%) and nine polymorphisms were identified. Seven of the nine polymorphisms were codon 72 single nucleotide polymorphisms (SNP) with an Arg/Pro allelotype. Women harboring either a mutation or an Arg/Pro allelotype at codon 72 had a lower overall survival rate than women whose tumors lacked alterations in the p53 gene (P= 0.0029). Women were stratified based on p53 genetic alterations (p53 mutation or p53 codon 72 SNP) and whether or not they received adjuvant radiation therapy. Women with p53 genetic alterations who did not receive adjuvant radiotherapy had the lowest survival rate (P= 0.0005). Treated women with p53 genetic alterations and untreated women with no p53 alteration had similar rates of survival. Among women with p53 alterations, adjuvant radiotherapy substantially increased survival (P= 0.035). In multivariate analyses, the group of women with p53 genetic alterations who did not receive adjuvant radiation therapy had a 5.9-fold increased risk of death (95% confidence interval: 1.5-22.7) compared to women whose tumors lacked p53 alterations and did not receive adjuvant radiation therapy.     

Role of p53 codon 72 polymorphism in recurrent pregnancy loss

Recurrent pregnancy loss (RPL) has been associated with low expression of apoptosis-and angiogenesis-related genes. The p53 tumour suppressor gene has been shown to induce apoptosis and angiogenesis. Recently, a low increased frequency of a p53 codon 72 polymorphism has been reported among women experiencing RPL. This study investigated the prevalence of p53 codon 72 polymorphism among women with a history of RPL, to determine whether this polymorphism may serve as a risk factor for miscarriage. Buccal swabs were obtained from 205 women with a history of two or more consecutive spontaneous abortions and 25 women with at least two live births and not more than one elective abortion. DNA was extracted from the buccal swabs and PCR amplification of p53 arginine(Arg)72 and proline(Pro)72 variants was performed. The frequency of homozygous Arg and Pro or heterozygous Arg/Pro genotypes among RPL patients and controls were not significantly different. No significant differences in allelic frequencies of p53 were observed. In addition, the allelic frequencies between controls and those previously reported were the same. It is concluded that p53 codon 72 polymorphisms do not serve as a susceptibility factor affecting the chances of miscarriage in an unselected population.     

Negative effect of P72 polymorphism on p53 gene in IVF outcome in patients with repeated implantation failure and pregnancy loss

Purpose

Investigate whether R72P on p53 gene polymorphism has a higher prevalence among women with a history of recurrent implantation failure (RIF) and pregnancy loss (RPL) and its influence in their IVF cycle outcome.

Material and methods

p53 polymorphism R72P has been studied in 181 women. The control group included 83 oocyte donors. In the study group 98 women were included: 44 with RIF and 54 with RPL. From the study group, 76 patients underwent IVF-cycles (55 RPL and 21 RIF).

Results

The frequency of PP genotypes on p53 among RIF was 11.4 % compared with 18.5 % for RPL and 6 % in controls (p < 0.01). There were no significant differences with respect to patient characteristics. Significant differences were reported in pregnancy rate (69.4 % for RR/RP and 33.3 % for PP; p < 0.05), embryo implantation rate (33.3 % for RR/RP and 7.3 % for PP; p < 0.05) and ongoing pregnancy rate (53.1 % for RR/RP and 14.3 % for PP; p < 0.05) among RIF and RPL.

Conclusions

This investigation reveals that in RIF and RPL patients R72P on p53 gene is more prevalent than fertile population. Moreover, patients carrying a PP genotype on p53 codon 72 will have less chance to achieve an ongoing pregnancy. This information together with some additional markers will allow development of diagnostic tests for detects risk for RIF and RPL before infertility treatment is initiated.