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The Codon 72 TP53 Polymorphism Contributes to TSC Tumorigenesis through the Notch-Nodal Axis.

ABSTRACT: We discovered that 90.3% of patients with angiomyolipomas, lymphangioleiomyomatosis (LAM), and tuberous sclerosis complex (TSC) carry the arginine variant of codon 72 (R72) of TP53 and that R72 increases the risk for angiomyolipoma. R72 transactivates NOTCH1 and NODAL better than the proline variant of codon 72 (P72); therefore, the expression of NOTCH1 and NODAL is increased in angiomyolipoma cells that carry R72. The loss of Tp53 and Tsc1 within nestin-expressing cells in mice resulted in the development of renal cell carcinomas (RCC) with high Notch1 and Nodal expression, suggesting that similar downstream mechanisms contribute to tumorigenesis as a result of p53 loss in mice and p53 polymorphism in humans. The loss of murine Tp53 or expression of human R72 contributes to tumorigenesis via enhancing epithelial-to-mesenchymal transition and motility of tumor cells through the Notch and Nodal pathways. IMPLICATIONS: This work revealed unexpected contributions of the p53 polymorphism to the pathogenesis of TSC and established signaling alterations caused by this polymorphism as a target for therapy. We found that the codon 72 TP53 polymorphism contributes to TSC-associated tumorigenesis via Notch and Nodal signaling.

SUBMITTER: Cho JH

PROVIDER: S-EPMC6677621 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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TP53 codon 72 polymorphism may predict early tumour progression in paediatric pilocytic astrocytoma.

Project description:Pilocytic astrocytoma and ganglioglioma may occur in inaccessible or surgically difficult areas. In case of incomplete resection, the availability of biological predictors of tumour progression could be particularly important. To this end, an analysis of p53 codon 72 polymorphism and assessment of its role as prognostic marker were performed.The status of the p53 Arg72Pro polymorphism was evaluated by pyrosequencing method in a multicenter cohort of 170 paediatric patients. Genotype/phenotype associations were investigated either by means of bivariate or multivariate analyses.In the partially resected pilocytic astrocytomas, the Arg/Arg variant predicts early tumour progression (median survival time: 23.1 months) and is associated with poor event-free survival (p value = 0.0009). This finding remains true also in case of adjuvant therapies, with a 5-year event-free survival of 30.6% for cases with Arg/Arg variant vs. 78.7% for those with other genotypes. There is no association between ganglioglioma and the polymorphism.The assessment of Arg/Arg variant could improve the management of pilocytic astrocytoma. TP53 codon 72 analysis could distinguish low-risk cases, in which surgery could be conservative, from high-risk cases needing an aggressive surgery plan.

| S-EPMC5216988 | biostudies-literature

TP53 Codon 72 Polymorphism and the Risk of Colorectal Cancer in an Azerbaijani Population.

Project description:BackgroundWe aimed to evaluate the association between the TP53 Arg72Pro gene polymorphism and risk of colorectal cancer in an Azerbaijani population.MethodsA total of 141 patients with colorectal cancer and 150 gender- and age-matched controls were involved in the study. The genotypes of the TP53 gene Arg72Pro polymorphism were detected by polymerase chain reaction-based restriction fragment length polymorphism analysis.ResultsWe found that the heterozygous genotypes Arg/Pro (odds ratio, 1.128; 95% CI, 0.657-1.937) and mutant Pro/Pro (odds ratio, 1.274; 95% CI, 0.648-2.504) were more frequent in colorectal cancer patients compared to healthy controls. The frequency of the mutant Pro allele (odds ratio, 1.122; 95% CI, 0.809-1.554) was revealed in 47.5% of colorectal cancer patients and in 44.7% of healthy controls. There was no association observed between TP53 Arg72Pro polymorphism and risk of colorectal cancer in an Azerbaijani population (P > .05).ConclusionOur findings indicate a lack of relationship between TP53 Arg72Pro polymorphism and risk of colorectal cancer. Furthermore, we have found no statistical differences in the frequency of genotype and allele by sex, age, histological grade, tumor stage, smoking status, and alcohol consumption in this study.

| S-EPMC9321240 | biostudies-literature

Codon 72 polymorphism (rs1042522) of TP53 is associated with changes in diastolic blood pressure over time.

Project description:p53 is involved in stress response, metabolism and cardiovascular functioning. The C-allele of rs1042522 in the gene encoding for p53 is associated with longevity and cancer. In this study, we aimed to investigate the association of rs1042522 with changes in blood pressure, BMI and waist circumference using a longitudinal approach. Rs1042522 was analyzed in two longitudinal studies; the Doetinchem Cohort Study (DCS) and the Botnia Prospective Study (BPS). Changes in quantitative traits over time were investigated according to rs1042522 genotypes. An association between rs1042522 and changes in diastolic blood pressure (DBP) in the DCS over time was observed (P=0.004). Furthermore, a borderline significant association was detected with changes in waist circumference over time (P=0.03). These findings were also observed in the BPS (P=0.02 and P=0.05). The C/C-genotype (Pro/Pro) showed the most moderate time-related increase for the studied endpoints. Furthermore, data from the BPS suggested that the C/C-genotype protects against increases in glucose levels over time at 30 and 60?min during oral glucose tolerance test (P=0.01 and P=0.02). In conclusion, we found an association between the C/C-genotype of rs1042522 and changes in DBP and waist circumference over time. This might contribute to the longevity phenotype observed for the same genotype by others.

| S-EPMC3355249 | biostudies-literature

Association of TP53 codon 72 polymorphism and the outcome of adjuvant therapy in breast cancer patients.

Project description:Single-nucleotide polymorphisms (SNPs) in codon 72 of the TP53 (also known as p53) gene (rs1042522) and in the promoter region of the MDM2 gene (SNP309; rs2279744) have been suggested to play roles in many cancers. We investigated whether these SNPs were associated with patient outcome and the effect of adjuvant systemic therapy.The genotypes of TP53 codon 72 and MDM2 SNP309 were defined among 557 primary Japanese breast cancer patients (median follow-up, 61.7 months). The effects of several variables on survival were tested by Cox's proportional hazards regression analysis.We showed that the Pro/Pro genotype of TP53 codon 72 was associated with poorer disease-free survival (DFS) than other genotypes by Kaplan-Meier analysis (P = 0.049) and multivariate Cox's proportional hazards regression analysis (P = 0.047, risk ratio of recurrence = 1.67), whereas MDM2 SNP309 status was not associated with DFS. The association of the Pro/Pro TP53 genotype with poorer DFS was especially significant in patients who received adjuvant chemotherapy (P = 0.009). In contrast, among the patients who had received adjuvant hormonal therapy or no adjuvant systemic therapy, TP53 codon 72 genotype was not associated with DFS.The Pro/Pro genotype of TP53 codon 72 appears to be an independent prognostic marker in breast cancer patients.

| S-EPMC1929098 | biostudies-literature

Associations of TP53 codon 72 polymorphism with complications and comorbidities in patients with type 1 diabetes.

Project description:Wild-type TP53 plays an important role in the regulation of immune response and systemic inflammation. In type 1 diabetes (T1D), TP53 pathways are upregulated and an increased susceptibility to apoptosis is observed. We hypothesize that TP53 codon 72 polymorphism could be associated with complications and comorbidities in patients with T1D. We have investigated the associations of the TP53 codon 72 polymorphism with the T1D complications and comorbidities (retinopathy, nephropathy, hypertension, dyslipidemia, autoimmune thyroiditis, and celiac disease) in 350 patients. The key results of our approach are as follows: (1) In diabetic subjects, the Pro/Pro genotype is associated with an increased risk of microvascular complications, dyslipidemia, and celiac disease; (2) the Arg/Arg variant is associated with a decreased risk of autoimmune thyroiditis and celiac disease; (3) the Pro allele is associated with an increased risk of dyslipidemia, autoimmune thyroiditis, and celiac disease. Although further studies are required, our results for the first time indicate that the TP53 codon 72 polymorphism could be considered a genetic marker to predict the increased susceptibility to some T1D complications and comorbidities. KEY MESSAGES: We analyzed the TP53 codon 72 polymorphism in patients with T1D. Pro/Pro genotype is associated with an increased risk of microvascular complications, dyslipidemia, and celiac disease. The Arg/Arg variant is associated with a decreased risk of autoimmune thyroiditis and celiac disease. The Pro allele is associated with an increased risk of dyslipidemia, autoimmune thyroiditis, and celiac disease.

| S-EPMC8055568 | biostudies-literature

TP53 codon 72 Arg/Arg polymorphism is associated with a higher risk for inflammatory bowel disease development.

Project description:To investigate the association between tumor protein 53 (TP53) codon 72 polymorphisms and the risk for inflammatory bowel disease (IBD) development.Numerous genetic and epigenetic drivers have been identified for IBD including the TP53 gene. Pathogenic mutations in TP53 gene have only been reported in 50% of colorectal cancer (CRC) patients. A single nucleotide polymorphism (SNP) in the TP53 gene resulting in the presence of either arginine (Arg) or proline (Pro) or both at codon 72 was shown to alter TP53 tumor-suppressor properties. This SNP has been investigated as a risk factor for numerous cancers, including CRC. In this study we analyzed TP53 codon 72 polymorphism distribution in 461 IBD, 181 primary sclerosing cholangitis patients and 62 healthy controls. Genotyping of TP53 was performed by sequencing and restriction fragment length polymorphism analysis of genomic DNA extracted from peripheral blood.The most frequent TP53 genotype in IBD patients was Arg/Arg occurring in 54%-64% of cases (and in only 32% of controls). Arg/Pro was the most prevalent genotype in controls (53%) and less common in patients (31%-40%). Pro/Pro frequency was not significantly different between controls and IBD patients.The data suggests that the TP53 codon 72 Arg/Arg genotype is associated with increased risk for IBD development.

| S-EPMC4579882 | biostudies-literature

Systematic evaluation of TP53 codon 72 polymorphism associated with onset and progression of oral potentially malignant disorders.

Project description:BackgroundRecently, a systematic review and meta-analysis demonstrated that overexpression of p53 immunoprotein was significantly associated with progression risk of oral potentially malignant disorders (OPMD). However, the results of investigations on TP53 genetic typing in OPMD were inconsistent and inconclusive.MethodsA systematic evaluation was conducted to identify all eligible case-control studies on the association of TP53 codon 72 polymorphism with both onset and progression of OPMD.ResultsA total of 768 OPMD patients and 1173 healthy individuals were identified from 12 eligible case-control studies on TP53 codon 72 polymorphism OPMD onset. In overall and subgroup analyses, no significantly risk of OPMD onset was observed in the cases for genetic models including allele C vs. G, homozygote CC vs. GG, heterozygote GC vs. GG, dominant GC + CC vs. GG, and recessive CC vs. GG + GC (all P-value of association test > 0.05). Further, a total of 465 OPMD patients and 775 oral squamous cell carcinoma (OSCC) ones were identified from 8 eligible case-control studies on this polymorphism in OPMD progression to OSCC. The analyses revealed that there was also no significantly risk of OPMD progression in the cases for the genetic models (all P-value of association test > 0.05).ConclusionOur data of a pooled-analysis indicates that TP53 codon 72 polymorphism may not act as genetic factor for the risk of OPMD onset and progression. Combined with the conclusion by a systematic review and meta-analysis, we put forward a new opinion that TP53 genetic typing cloud not influence p53 protein expression in OPMD.

| S-EPMC10496165 | biostudies-literature

TP53 codon 72 polymorphism is associated with FGFR3 and RAS mutation in non-muscle-invasive bladder cancer.

Project description:ObjectiveTP53, a well-known tumor-suppressor gene in bladder carcinogenesis, has a functional single-nucleotide polymorphism on codon 72. The aim of this study was to elucidate the association between TP53 codon 72 polymorphism and somatic mutations in bladder cancer.Material and methodsGermline TP53 codon 72 polymorphism and somatic mutations of 50 cancer-associated genes were analyzed in 103 bladder cancer patients (59 non-muscle-invasive and 44 muscle-invasive), using Taqman genotyping assay and target sequencing, respectively. The expression of FGF-FGFR signaling pathway genes was analyzed by RNA sequencing of frozen tissue.ResultsThe allele frequency of TP53 codon 72 in our cohort was 37, 42, and 21% for Arg/Arg, Arg/Pro, and Pro/Pro, respectively. Interestingly, the prevalence of FGFR3 mutation was higher in patients with the Arg allele, whereas that of the RAS mutation was higher in patients without the Arg allele. The same association was seen in non-muscle-invasive bladder cancer (NMIBC) patients and no differences were observed in muscle-invasive bladder cancer patients. In NMIBC, FGFR1 expression was higher in patients without the Arg allele and FGFR3 expression was higher in patients with the Arg allele.ConclusionThe germline TP53 codon 72 polymorphism was associated with mutations of FGFR3 or RAS and expression of FGFR1 and FGFR3 in NMIBC. These findings provide new insight into the molecular mechanisms underlying the influence of the genetic background on carcinogenesis in bladder cancer.

| S-EPMC6675066 | biostudies-literature

Meta-Analysis Results on the Association Between TP53 Codon 72 Polymorphism With the Susceptibility to Oral Cancer.

Project description:Objectives: TP53 is an important tumor suppressor gene to maintain genomic integrity, and its mutations increase the susceptibility to oral carcinoma. Previous published studies have reported the relation of TP53 codon 72 polymorphism with the risk of oral carcinoma, but the results remain controversial and inconclusive. Methods: We therefore utilized meta-analysis based on a comprehensive search in PubMed, EMBASE, and Google of Scholar databases up to August 19, 2017. Results: Total 3,525 cases and 3,712 controls from 21 case-control studies were selected. We found no significant association between TP53 codon 72 polymorphism and oral carcinoma susceptibility in all genetic contrast models, including subgroup analysis based on control source and ethnicity. Furthermore, TP53 codon 72 polymorphism was not significant associated with oral carcinoma susceptibility in tobacco or alcohol use, and HPV infection status. Our results were confirmed by sensitivity analysis and no publication bias was found. Conclusions: Taken together, our data indicate that TP53 codon 72 polymorphism is not associated with the susceptibility to oral carcinoma.

| S-EPMC6082947 | biostudies-other

The Role of TP53 Gene Codon 72 Polymorphism in Leukemia: A PRISMA-Compliant Systematic Review and Meta-Analysis.

Project description:The purpose of this meta-analysis was aimed to evaluate the association of tumor protein p53 (TP53) gene codon 72 polymorphism with leukemia susceptibility. We searched PubMed to identify relevant studies, and 16 case-control studies from 14 published articles were identified as eligible studies, including 2062 leukemia patients and 5826 controls. After extracting data, odds ratio (OR) with the corresponding 95% confidence interval (95%CI) was applied to assess the association between TP53 codon 72 polymorphism and leukemia susceptibility. The meta-analysis was performed with the Comprehensive Meta-Analysis software, version 2.2. Overall, no significant association between TP53 codon 72 polymorphism and leukemia susceptibility was found in this meta-analysis (Pro vs Arg: OR?=?1.05, 95%CI?=?0.90-1.21; Pro/Pro vs Arg/Arg: OR?=?1.13, 95%CI?=?0.84-1.52; Arg/Pro vs Arg/Arg: OR?=?0.94, 95%CI?=?0.76-1.15; [Pro/Pro?+?Arg/Pro] vs Arg/Arg: OR?=?0.99, 95%CI?=?0.80-1.21; Pro/Pro vs [Arg/Arg?+?Arg/Pro]: OR?=?1.19, 95%CI?=?0.93-1.51). Similar results were also found in subgroup analysis by ethnicity, source of controls, and types of leukemia (either acute myeloid leukemia or acute lymphocytic leukemia). Our meta-analysis demonstrates that TP53 codon 72 polymorphism may not be a risk factor for acute leukemia; however, due to the limitations of this study, it should be verified in future studies.

| S-EPMC4635761 | biostudies-literature

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