Arginine Homozygotes Research Articles

Polymorphism at codon 31 of CDKN1A (p21) as a predictive factor for bevacizumab therapy in glioblastoma multiforme

Glioblastoma (GBM), a prevalent and malignant brain tumor, poses a challenge in surgical resection due to its invasive nature within the brain parenchyma. CDKN1A (p21, Waf-1), a cyclin-dependent kinase inhibitor, plays a pivotal role in regulating cell growth arrest, terminal differentiation, and apoptosis. The existence of natural variants of CDKN1A has been associated with specific cancer types. In this retrospective study, our objective was to identify polymorphic variants of CDKN1A, specifically c.93C > A (codon 31 Ser31Arg), and investigate its potential impact within the scope of bevacizumab therapy for glioblastoma multiforme. This study involved a cohort of 139 unrelated adult Chinese GBM patients in Taiwan. Genomic DNA extracted from tumor samples was utilized for genotyping using the polymerase chain reaction (PCR) restriction fragment length polymorphism method (PCR–RFLP analysis). Through unconditional logistic regression analysis, odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. Our findings unveiled that among these GBM patients, the distribution of codon 31 polymorphisms was as follows: 23.02% were Serine homozygotes (Ser/Ser), 27.34% were Arginine homozygotes (Arg/Arg), and 49.64% were Serine/Arginine heterozygotes (Ser/Arg). While CDKN1A c.93C > A polymorphisms did not exhibit a direct association with overall survival in GBM patients, noteworthy survival benefits emerged among individuals with Arg/Arg and Arg/Ser genotypes who received combined concurrent chemoradiotherapy (CCRT) and bevacizumab treatment compared to those who underwent CCRT alone. Our findings indicate a significant involvement of the CDKN1A c.93C > A polymorphism in the development and onset of GBM, offering potential implications for the early prognostication of bevacizumab therapy outcomes.

DNAR-15. POLYMORPHISM AT P21 CODON 31 PROVIDED A PREDICTION FOR BEVACIZUMAB THERAPY IN GLIOBLASTOMA MULTIFORME

Abstract Glioblastoma (GBM) is a common, malignant brain tumor. While it rarely metastasizes to distant organs, the diffuse invasion of glioma cells within the brain makes it difficult to resect. P21 (Waf-1) is a cyclin-dependent kinase inhibitor that plays an essential role in cell growth arrest, terminal differentiation, and apoptosis. Thus, the existence of natural variants of p21 could be linked to specific cancer. The purpose of this study was to identify the polymorphism variants of p21 codon 31 (Ser31Arg) and to explore its role in the therapy of glioblastoma multiforme. A total of unrelated 99 GBM subjects, were enrolled in the study, and genomic DNA was obtained from each tumor sample for genotyping. Genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism method (PCR-RFLP analysis. Odds ratios (Ors) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression analysis. We found that among these GBM patients, the distribution of codon 31 polymorphisms was 20.2% for Serine homozygotes (Ser/Ser), 32.3% for arginine homozygotes (Arg/Arg), and 47.5% for Serine/arginine heterozygotes (Ser/Arg). Although the polymorphisms of p21 codon 31 were not directly associated with the overall survival of GBM, both the Arg/Arg and Arg/Ser genotypes were associated with significant benefits in terms of overall survival in patients treated with CCRT plus bevacizumab compared to patients treated with CCRT alone. Our findings suggest that the p21 Ser31Arg polymorphism may play an important role in the pathogenesis and initiation of GBM. Moreover, the polymorphism seems to contribute to a significant prediction at early diagnosis for bevacizumab therapy.

Both p53 codon 72 Arg/Arg and pro/Arg genotypes in glioblastoma multiforme are associated with a better prognosis in bevacizumab treatment

BackgroundIt has previously been shown that bevacizumab, when added to chemotherapy, improved overall survival in several cancers. In glioblastoma multiforme (GBM), bevacizumab increased progression-free survival and it is widely used for tumor recurrence, though it has failed to improve overall survival (OS) in controlled trials. However, an effective biomarker for predicting the prognosis of bevacizumab treatment has yet to be identified. This study, therefore, aimed to retrospectively analyze the polymorphisms of p53 codon 72 and the clinical characteristics of GBM specimens from Taiwanese patients.MethodsThe polymorphisms of p53 codon 72 in 99 patients with GBM treated at Taichung Veterans General Hospital in Taiwan from 2007 to 2017 were analyzed using direct DNA sequencing and PCR-RFLP analysis.ResultsWe found that among these GBM patients, the distribution of codon 72 polymorphisms was 28.3% for proline homozygotes (Pro/Pro), 38.4% for arginine homozygotes (Arg/Arg), and 33.3% for proline/arginine heterozygotes (Pro/Arg). Although the polymorphisms of p53 codon 72 were not directly associated with the overall survival of GBM, both the Arg/Arg and Arg/Pro genotypes were associated with significant benefits in terms of overall survival in patients treated with CCRT plus bevacizumab compared to patients treated with CCRT alone.ConclusionsThis pilot study suggests that both the Arg/Arg and Arg/Pro genotypes of p53 codon 72 polymorphism may have value as independent prognostic or predictive parameters for bevacizumab treatment response and failure. Relatedly, the results of the study further demonstrate the utility of stratifying GBM patients according to bevacizumab sensitivity.

Genetic Variation in the TP53 Gene and Patient Outcomes Following Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of death and disability, with more than 5 million people in the United States living with long-term complications related to TBI. This study examined the relationship between TP53, the gene that codes for the protein p53, and outcome variability following severe TBI. The p53 protein impacts neuronal apoptosis following TBI, thus investigation into TP53 genetic variability as a prognosticator for TBI outcomes (mortality, Glasgow Outcome Scale [GOS], Neurobehavioral Rating Scale [NRS], and Disability Rating Scale [DRS]) is warranted. Participants (N = 429) with severe TBI (Glasgow Coma Scale score ≤8) were enrolled into a prospective study with outcomes assessed over 24 months following injury. The single-nucleotide polymorphism Arg72Pro (rs1042522), a functional missense polymorphism for which the CC homozygous genotype is most efficient at inducing apoptosis, was investigated. Individuals with the CC genotype (arginine homozygotes) were more likely to have poorer outcomes at 24 months following TBI compared to individuals with CG/GG genotypes (GOS: p = .048, DRS: p = .022). These findings add to preliminary evidence that p53 plays a role in recovery following TBI and, if further replicated, could support investigations into p53-based therapies for treating TBI.

Association of Codon 72 of P53 Gene Polymorphism with Chronic Hepatitis C Virus Infection: A Case Control Study

Single nucleotide polymorphism in codon 72 of p53 gene (Arg/Pro) changes p53 protein structure and affects its activities. Hepatitis C virus (HCV) is believed to induce hepatocellular carcinoma and P53 polymorphisms have been associated with human cancers. The aim of this study was to evaluate genetic variants of codon 72 of p53 gene polymorphism in HCV patients and its relationship with HCV infection. The study was conducted on 67 HCV patients, who were referred to medical centers of Mashhad city, Iran, and 73 healthy people from the same region. Genotyping of codon 72 of p53 gene was performed by PCR-RFLP method. The distributions of different alleles of p53 polymorphisms did not differ significantly between groups. The respective proportions of Proline homozygotes, heterozygotes, and Arginine homozygotes were 37.31%, 35.82%, 26.86% in patients and 39.72%, 27.39%, and 32.87% in the control group respectively. However, we found no significant differenece for the allelic or genotype distribution between cases and controls. Our results indicated no strong evidence of association of the p53 polymorphism with HCV infection; however, further investigation is needed in different ethnic groups to elucidate the role of this polymorphism in HCV infection.

Prevention of Atrial Fibrillation by Bucindolol Is Dependent on the Beta1389 Arg/Gly Adrenergic Receptor Polymorphism

This study assessed the impact of bucindolol, a beta-blocker/sympatholytic agent, on the development of atrial fibrillation (AF) in advanced chronic heart failure with reduced left ventricular ejection fraction (HFREF) patients enrolled in the BEST (Beta-Blocker Evaluation of Survival Trial). β-blockers have modest efficacy for AF prevention in HFREF patients. Bucindolol's effects on HF and ventricular arrhythmic endpoints are genetically modulated by β₁- and α(2c)-adrenergic receptor (AR) polymorphisms that can be used to subdivide HFREF populations into those with bucindolol effectiveness levels that are enhanced, unchanged, or lost. BEST enrolled 2,708 New York Heart Association (NYHA) class III to IV HFREF patients. A substudy in which 1,040 patients' DNA was genotyped for the β₁-AR position 389 Arg/Gly and the α(2c)322-325 wild type (Wt)/deletion (Del) polymorphisms, and new-onset AF was assessed from adverse event case report forms or electrocardiograms at baseline and at 3 and 12 months. In the entire cohort, bucindolol reduced the rate of new-onset AF compared to placebo by 41% (hazard ratio [HR]: 0.59 [95% confidence interval (CI): 0.44 to 0.79], p = 0.0004). In the 493 β₁389 arginine homozygotes (Arg/Arg) in the DNA substudy, bucindolol reduced new-onset AF by 74% (HR: 0.26 [95% CI: 0.12 to 0.57]), with no effect in β₁389 Gly carriers (HR: 1.01 [95% CI: 0.56 to 1.84], interaction test = 0.008). When β₁389 Gly carriers were subdivided by α(2c) Wt homozygotes (n = 413, HR: 0.94 [95% CI: 0.48 to 1.82], p = 0.84) or Del variant carriers (n = 134, HR: 1.33 [95% CI: 0.32 to 5.64], p = 0.70), there was a positive interaction test (p = 0.016) when analyzed with β₁389 Arg homozygotes. Bucindolol prevented new-onset AF; β₁ and α(2c) polymorphisms predicted therapeutic response; and the 47% of patients who were β₁389 Arg homozygotes had an enhanced effect size of 74%. (Beta-Blocker Evaluation in Survival Trial [BEST]; NCT00000560)

TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies

Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer. Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy-Weinberg equilibrium, study quality, and the material used to determine TP53 genotype. The pooled estimates (OR) for invasive cervical cancer were 1.22 (95% CI 1.08-1.39) for arginine homozygotes compared with heterozygotes, and 1.13 (0.94-1.35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy-Weinberg equilibrium (1.71 [1.21-2.42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1.35 [1.15-1.58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1.39 [1.13-1.73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes). Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies. German Research Foundation (DFG).

Beta-2 adrenergic receptor polymorphisms and the forearm blood flow response to mental stress

Circulating epinephrine plays an important role in skeletal muscle vasodilation during mental stress. Normotensive adults homozygous for glycine (Gly) of the Arg16/Gly beta2-adrenergic receptor polymorphism have a greater forearm beta2-receptor mediated vasodilation and a higher cardiac output response to isometric handgrip than arginine (Arg) homozygotes. To test the hypothesis that the Arg16/Gly beta2-adrenergic receptor polymorphism affects the forearm blood flow (FBF) and hemodynamic response to mental stress, and whether venous catecholamine concentrations predicted these responses, we measured venous epinephrine, norepinephrine, heart rate (HR), arterial pressure (Finapres), and FBF during mental stress in healthy subjects homozygous for Gly16 (n = 30; mean age +/- SE: 30 +/- 1.2, 13 women) and Arg16 (n = 17, age 30 +/- 1.6, 11 women). Resting HR, blood pressure, and FBF responses to mental stress were similar between genotype groups. There were positive correlations between epinephrine and peak FBF (r = 0.694, P < 0.001), peak forearm vascular conductance (r = 0.677, P < 0.001) and the change in epinephrine to the change in HR (r = 0.456, P = 0.002) in all subjects. These correlations were not significantly different in the Gly16 and Arg16 groups. We conclude that venous epinephrine predicts the FBF response to mental stress, and the increase in epinephrine is also correlated with the increase in HR. Furthermore, the Arg16/Gly beta2-receptor polymorphism has no significant influence on the FBF or cardiovascular responses to mental stress.

Arg16/Gly β2-adrenergic receptor polymorphism alters the cardiac output response to isometric exercise

Normotensive adults homozygous for glycine (Gly) of the Arg16/Gly beta2-adrenergic-receptor polymorphism have 1) greater forearm beta2-receptor mediated vasodilation and 2) a higher heart rate (HR) response to isometric handgrip than arginine (Arg) homozygotes. To test the hypothesis that the higher HR response in Gly16 subjects serves to maintain the pressor response [increased cardiac output (CO)] in the setting of augmented peripheral vasodilation to endogenous catecholamines, we measured continuous HR (ECG), arterial pressure (Finapres), and CO (transthoracic echocardiography) during isometric, 40% submaximal handgrip to fatigue in healthy subjects homozygous for Gly (n = 30; mean age +/- SE: 30 +/- 1.2, 13 women) and Arg (n = 17, age 30 +/- 1.6, 11 women). Resting data were similar between groups. Handgrip produced similar increases in arterial pressure and venous norepinephrine and epinephrine concentrations; however, HR increased more in the Gly group (60.1 +/- 4.3% increase from baseline vs. 45.5 +/- 3.9%, P = 0.03), and this caused CO to be higher (Gly: 7.6 +/- 0.3 l/m vs. Arg: 6.5 +/- 0.3 l/m, P = 0.03), whereas the decrease in systemic vascular resistance in the Gly group did not reach significance (P = 0.09). We conclude that Gly16 homozygotes generate a higher CO to maintain the pressor response to handgrip. The influence of polymorphic variants in the beta2-adrenergic receptor gene on the cardiovascular response to sympathoexcitation may have important implications in the development of hypertension and heart failure.

P53 Codon 72 Alleles Influence the Response to Anticancer Drugs in Cells from Aged People by Regulating the Cell Cycle Inhibitor p21WAF1

A common polymorphism at codon 72 in p53 gene leads to an arginine to proline aminoacidic substitution which affects in an age-dependent manner the susceptibility of cells to undergo apoptosis after oxidative stress. Here we report that dermal fibroblasts from Proline allele carriers (Pro+) display a higher expression of p21WAF1 gene, in both basal conditions and after treatment with doxorubicin and camptothecin. This phenomenon is accompanied by a lower susceptibility of Pro+ cells to undergo apoptosis, a lower capability to over cross G1-S transition and an increased propensity to express markers of cell senescence, with respect to fibroblasts from Arginine homozygotes (Pro-). All these phenomena are particularly evident in cells from centenarians. We conclude that the functional difference between the two p53 codon 72 alleles exerts a broadimpact on the capability of cell from aged people to respond to stressors such as cytotoxic drugs.

Association of specific genotype and haplotype of p53 gene with cervical cancer in India

Background: The predictive value of codon 72 arginine homozygosity at the p53 gene for human papilloma virus associated cervical cancer risk remains inconclusive. It has also been proposed that the...

Analysis of the codon 72 polymorphism of the TP53 gene in patients with endometriosis.

Endometriosis is a benign gynaecologic disease that is associated with a certain risk for malignant degeneration. The disease has a genetic background, but the locations of possible genomic aberrations are still poorly clarified. In this context, the proline form of TP53 codon 72 polymorphism has been recently associated with the risk of developing endometriosis. In this case-control study, we aimed to investigate further the potential association between endometriosis and this polymorphism in order to evaluate whether this genetic variant may influence the susceptibility to the disease. Genomic DNA was obtained from a consecutive series of 303 Italian Caucasian women of reproductive age who underwent laparoscopy for benign gynaecological pathologies. Endometriosis was defined according to the criteria of Holt and Weiss [Holt V and Weiss NS (2000) Recommendations for the design of epidemiologic studies of endometriosis. Epidemiol 11,654-659] for the definite disease. Subjects of similar age without laparoscopic evidence of the disease served as control group. Molecular analysis of TP53 codon 72 polymorphism was performed by PCR amplification. Endometriosis was documented in 151 women. We found no statistically significant difference in the distribution of TP53 codon 72 polymorphism genotypes between patients with and without endometriosis. The respective proportions of arginine homozygotes, heterozygotes and proline homozygotes were 55.6, 39.7 and 4.6% in the group with endometriosis and 59.9, 30.9 and 9.2% in the control group. Moreover, no statistically significant association was demonstrated between TP53 codon 72 polymorphism and the various clinical manifestations of the disease, although a non-significant tendency towards an increased frequency of the proline allele was observed in association with specific manifestations of the disease reflecting a more severe form. Our results suggest that the TP53 codon 72 polymorphism does not confer genetic susceptibility to endometriosis in the Italian population. However, a possible susceptibility role of this polymorphism in endometriosis development towards very severe forms cannot be ruled out.

The proline form of p53 codon 72 polymorphism is associated with endometriosis

Objective: To evaluate the association between endometriosis and the p53 polymorphism. Design: Prospective study. Setting: Department of gynecology and genetics in a medical center. Patient(s): Women with and without endometriosis. Intervention(s): Women were categorized as having moderate or severe endometriosis (n = 118) or no endometriosis (n = 140). Main Outcome Measure(s): Polymerase chain reaction was used to detect p53 codon 72 polymorphisms (arginine homozygosity, heterozygosity, and proline homozygosity). Associations between endometriosis and p53 polymorphisms were evaluated. Result(s): The distributions of different p53 polymorphisms differed significantly between groups. The respective proportions of arginine homozygotes, heterozygotes, and proline homozygotes were 10.2%, 66.9%, and 22.9% in the group with endometriosis and 30.7%, 50%, and 19.3% in the group without endometriosis. Conclusion(s): Endometriosis is associated with p53 polymorphism. p53 arginine homozygotes have lower risk for endometriosis. Heterozygotes and proline homozygotes have higher risk for endometriosis.

P53 codon 72 polymorphism in vulval cancer and vulval intraepithelial neoplasia.

p53 codon 72 polymorphism was analysed in UK women with human papillomavirus (HPV)-associated vulval intraepithelial neoplasia and vulval squamous cell carcinoma. Arginine homozygotes were significantly less common in either group compared with controls. We conclude that the arginine polymorphism may confer protection against the development of HPV-associated vulval neoplasia. © 2000 Cancer Research Campaign

Polymorphism at Codon 72 of p53 Is Not Associated with Cervical Cancer Risk

P53 allelic polymorphism at codon 72 has been studied as a possible predisposing factor for cervical carcinogenesis with inconsistent results. Storey and colleagues recently published the interesting finding of a 7-fold increased risk for cervical cancer in women homozygous for the arginine allele at codon 72. This stimulated a number of independent investigations, the majority of which found no association of cervical cancer and arginine homozygosity.With the use of a modified Storey method for determining codon 72 allelotypes, DNA was examined from 431 microdissected, formalin-fixed, archival cervical conization specimens ranging from low-grade squamous lesions to invasive cancer. An alternative independent method using restriction fragment length polymorphism analysis was performed on all arginine homozygotes and all indeterminate cases for confirmation and final allelotype assignment.With the use of Storey's method alone, logistic regression suggested an association (odds ratio, 1.42) between arginine homozygosity and invasive disease. However, with the use of the combined method for accurate allelotyping, this trend disappeared (odds ratio, 1.00), the discordance was clearly resolvable as being due to methodologic variables.With the use of two separate methods for codon 72 allelotyping and accounting for a number of the issues raised in previously published reports, there is no increased risk for invasive cervical cancer associated with arginine homozygosity at codon 72 of p53.

No association between P53 codon 72 polymorphism and risk of squamous cell carcinoma of the head and neck.

An initial report suggested that patients homozygous for the arginine allele at codon 72 ofP53were at increased risk for human papillomavirus (HPV)-related cervical cancer, but other groups have not confirmed this finding. Since approximately 18–36% of head and neck cancers are HPV-related, we examined the genotypic frequencies at that locus in 163 cases with squamous cell carcinoma of the head and neck (SCCHN) and 163 ethnically matched controls. We found no significant excess of arginine homozygotes in cases compared to controls (P= 0.50). No significant differences in allele frequencies were observed when the data were stratified by tobacco exposure or by cancer site. These findings suggest a limited role, if any, for thisP53polymorphism in SCCHN.© 2000 Cancer Research Campaign

Human papillomavirus type 16 E6 variants in cervical carcinoma: relationship to host genetic factors and clinical parameters.

Infection with human papillomavirus type 16 (HPV-16) confers a high risk for the development of cervical neoplasia. Variants of this virus may interact differentially with host genetic factors, possibly altering the disease course. Thus, HPV-16 E6 variants may differ in their ability to degrade p53 whereas the polymorphic p53 alleles may provide more or less susceptible substrates for the viral oncogene product. Also, E6 variants may differ in immunogenicity by generating different peptides for presentation by polymorphic HLA molecules to specific T cells. This study examines HPV-16 E6 sequence variation in cervical carcinomas from the UK and its relationship to polymorphism of HLA and p53 and to clinical parameters. Sequence analysis of the HPV-16 E6 ORF from 77 tumour biopsies detected the viral prototype sequence in 38% of cases. The most common variation detected was a T to G transition at base pair 350, resulting in an amino acid change from a leucine to a valine. Overall, the frequencies of 350T and 350G sequences were similar (49. 4% and 50.6% respectively). Other mutations of lower frequencies were detected together with and independently of 350G. HPV-16 E6 sequence variation at base pair 350 did not correlate with HLA genotype or clinical outcome. There was no difference in the distribution of p53 proline and arginine alleles between HPV-16-positive cervical carcinoma patients and local controls, and no influence on clinical outcome; however, there was a trend for an increased frequency of p53 arginine homozygotes among the 350T carcinoma patients.

Codon 72 polymorphism of p53 and its association with cervical cancer

Swedish and Italian women with HPV 16-positive cervical disease were checked for codon 72 polymorphisms of p53. In both groups, arginine homozygotes were enriched in cancer compared with controls and precursor lesions.