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TP53 codon 72 Gene Polymorphism Paradox in Associated with Various Carcinoma Incidences, Invasiveness and Chemotherapy Responses  [cached]
Hung-Yu Lin,Chun-Hsiung Huang,Wen-Jen Wu,Li-Ching Chang
International Journal of Biomedical Science , 2008,
Abstract: TP53 is the most common mutated gene in human cancers. Approximately half of all human malignancies exhibit TP53 mutations. The TP53 codon 72 polymorphism is a single-nucleotide polymorphism (SNP) in exon 4, resulting in the expression of either arginine (CGC) or proline (CCC) residues. In this article, we review literatures published in MEDLINE, and attempt to describe how these two polymorphic variants of TP53 are functionally distinct, and how they influence cancer vulnerability and response to chemotherapy. The Arg72 variant has been shown to be more likely to induce apoptosis than the Pro72 variant, due to its ability to localize itself to mitochondria and trigger the release of cytochrome c into the cytosol. However, but the influence of the PT53 codon 72 polymorphism on the risk of developing various cancers, and their progression remains inconclusive because there has been no sustained evidence supporting a crucial role for the codon 72 variant in cancer therapy till now. We hypothesize that TP53 might not only be involved in cell cycle control and the apoptosis induction response to DNA damage, but may also modulate individual cancer risk, and that this may correlate with the biofunctions of the two codon 72 variants. Additionally, latent factors might function synergistically with codon 72 variants to confer susceptibility to cancer development, progression, prognosis, and therapeutic responsiveness. Further etiological investigations are essential to reveal the association of and interaction between genetic and environmental factors in relation to carcinogenesis.
TP53 Codon 72 Polymorphism and P53 Protein Expression in Colorectal Cancer Specimens in Isfahan
Mehdi Nikbahkt Dastjerdi
Acta Medica Iranica , 2011,
Abstract: The TP53 tumor suppressor gene plays important roles in genomic stability. A common polymorphism at codon 72 of TP53 gene has been associated with increased risk for many human cancers. The p53 protein is expressed in colorectal cancer, but the reported prevalence of its expression varies widely. In the present study, the p53 protein expression in different genotypes of its codon 72 , was investigated. We undertook a case-control study on 250 controls and 250 paraffin block specimens of sporadic colorectal adenocarcinomas from the city of Isfahan. PCR amplification of TP53 codon 72 polymorphism: TP53 codon 72 genotypes were detected by PCR using specific primer pairs for amplifying the proline or the arginine Alleles. The PCR reaction was done separately for each of the two polymorphic variants. The amplified products were subjected to electrophoresis on 1% agarose gel in 1× TBE buffer and visualized on a transilluminator using ethidium bromide. Immunohistochemical Staining: We evaluated the expression patterns of p53 protein, as potential prognostic marker in colorectal cancer specimens by immunohistochemical staining. Statistical analyses: The χ2-test was used to assess the significance of any difference in the prevalence of TP53 codon 72 polymorphism between colorectal cancer patients and controls. The odds ratio and 95% CI (confidence intervals) was used as a measure of the strength of the association. Statistical significance level was set to P≤0.05. In control samples, the genotype distribution for TP53 polymorphism showed 30.4%, 45.2% and 24.4% for the arginine/arginine, arginine/proline and proline/proline genotypes, respectively. Allelic frequencies corresponded to 0.663 for the arginine allele and 0.338 for the proline allele. In the cancer group 38.8% of the cases were arginine/arginine, 40.4% were arginine/proline and 20.8% were proline/proline. The corresponding frequencies were 0.590 for the arginine allele and 0.410 for the proline allele. A significant difference between cases and controls was found for the arginine/arginine genotype compared with (grouped) arginine/proline and proline/proline genotypes (Odds Ratio = 1.451 (1.002-2.103), P=0.048). Overexpression of p53 was observed in 50.8 percent of cancer specimens which most of them were arginine/arginine genotype (P<0.001). TP53 polymorphism and arginine/arginine genotype may be correlated with overexpression of p53 and increased risk for colorectal cancer in city of Isfahan.
TP53 codon 72 polymorphism as a risk factor for cardiovascular disease in a Brazilian population
Smith, M.A.C.;Silva, M.D.A.;Cendoroglo, M.S.;Ramos, L.R.;Araujo, L.M.Q.;Labio, R.W.;Burbano, R.R.;Chen, E.S.;Pay?o, S.L.M.;
Brazilian Journal of Medical and Biological Research , 2007, DOI: 10.1590/S0100-879X2006005000174
Abstract: tp53, a tumor suppressor gene, has a critical role in cell cycle, apoptosis and cell senescence and participates in many crucial physiological and pathological processes. identification of tp53 polymorphism in older people and age-related diseases may provide an understanding of its physiology and pathophysiological role as well as risk factors for complex diseases. tp53 codon 72 (tp53:72) polymorphism was investigated in 383 individuals aged 66 to 97 years in a cohort from a brazilian elderly longitudinal study. we investigated allele frequency, genotype distribution and allele association with morbidities such as cardiovascular disease, type ii diabetes, obesity, neoplasia, low cognitive level (dementia), and depression. we also determined the association of this polymorphism with serum lipid fractions and urea, creatinine, albumin, fasting glucose, and glycated hemoglobin levels. dna was isolated from blood cells, amplified by pcr using sense 5'-ttgccgtcccaagcaatggatga-3' and antisense 5'-tctgggaagggacagaagatgac-3' primers and digested with the bstui enzyme. this polymorphism is within exon 4 at nucleotide residue 347. descriptive statistics, logistic regression analysis and student t-test using the multiple comparison test were used. allele frequencies, r (arg) = 0.69 and p (pro) = 0.31, were similar to other populations. genotype distributions were within hardy-weinberg equilibrium. this polymorphism did not show significant association with any age-related disease or serum variables. however, r allele carriers showed lower hdl levels and a higher frequency of cardiovascular disease than p allele subjects. these findings may help to elucidate the physiopathological role of tp53:72 polymorphism in brazilian elderly people.
Analysis of TP53 Codon 72 Polymorphism in Mucinous and Non-Mucinous Colorectal Adenocarcinoma in Isfahan, Iran
Mehdi Nikbahkt Dastjerdi
Iranian Journal of Medical Sciences , 2010,
Abstract: Background: The tumor suppressor gene TP53 (alias p53)located on chromosome 17 is involved in various cancers.Case-control studies have shown that p53 codon 72 polymorphismmodulates the prognosis and susceptibility to variousmalignancies. We undertook the present study to explore apossible association between mucinous and non-mucinousadenocarcinomas with different genotypes or alleles at codon72 of TP53.Methods: The genotype distribution and allelic frequenciesfor p53 polymorphism was assessed in 46 and 134 specimensfrom patients with colorectal mucinous and non-mucinousadenocarcinomas, respectively, by using allele-specific PCR.Results: The PCR products were 177bp for proline allele and141bp for arginine allele. In the mucinous samples, the genotypedistribution for p53 polymorphism showed 63%, 23.9%,and 13.1% for the Arg/Arg, Arg/Pro, and Pro/Pro genotypes,respectively. In the non-mucinous specimens 32.1% of thecases were Arg/Arg, 48.5% Arg/Pro, and 19.4% pro/pro. A significantdifference between the two types of adenocarcinomasfor the Arg 72 Arg genotype compared with (grouped) Arg 72Arg and Pro 72 Pro genotypes was noted [OR=3.61 (1.76-7.27),P<0.001]. The arginine allele was found more often in patientswith mucinous adenocarcinoma [OR=1.85 (1.07-3.19), P<0.03].A higher portion of Dukes stage C was noted in the mucinousspecimens (P<0.02) and also mucinous specimens were seenmore often at advanced TNM stages (P=0.01).Conclusion: The Arg/Arg genotype at p53 codon 72 is moreprevalent in mucinous colorectal carcinoma and the arginineallele may contribute to mucinous carcinogenesis. The prolineallele was associated with higher Duke's staging in nonmucinousadenocarcinoma.
Polimorfismo Pro72Arg del gen TP53 se asocia a enfermedad coronaria en individuos Chilenos TP53 codon 72 polymorphism is associated with coronary artery disease in Chilean subjects  [cached]
José Caama?o L,Nicolás Saavedra,Priscilla C Jaramillo,Cecilia Lanas
Revista Chilena de Cardiología , 2009,
Abstract: Introducción: Diferentes genes han sido implicados en la etiología de la enfermedad arterial coronaria, entre ellos, el gen TP53. Recientemente, el polimorfismo en el codon 72 (Pro72Arg, rs1042522) del gen TP53 fue se alado como factor de riesgo para enfermedad arterial coronaria. Sin embargo, otros autores no han confirmado esta observación. Así, en el presente estudio investigamos la posible asociación entre esta variante genética y la presencia de enfermedad arterial coronaria en individuos chilenos. Métodos: Se analizaron 209 pacientes, no relacionados, con diagnóstico de enfermedad arterial coronaria confirmada por angiografía (estenosis > 70%), 33 - 74 a os y 216 individuos controles (30-68 a os). Las concentraciones séricas de glucosa, acido úrico, triglicéridos, colesterol total y colesterol HDL fueron determinados por métodos enzimático-colorimétricos. El polimorfismo Pro72Arg del gen TP53 fue identificado mediante la técnica de reacción en cadena de polimerasa seguida de restricción enzimática (PCR-RFLP). Resultados: La distribución de genotipos para la mutación Pro72Arg del gen TP53 en pacientes y controles fue significativamente diferente (P=0.003). Adicionalmente, la frecuencia relativa de alelos fue también diferente (P=0.003). La OR para enfermedad coronaria relacionada al alelo 72Arg fue 2.0 (I.C.95%=1.33-2.90), confirmando la presencia de asociación. Por otro lado, no encontramos asociación entre los factores de riesgo tradicionales para enfermedad coronaria y los diferentes genotipos del polimorfismo Pro72Arg. Conclusión: Nuestro estudio muestra una interesante asociación entre enfermedad coronaria y el polimorfismo Pro72Arg del gen TP53 en individuos chilenos, sugiriendo que esta mutación podría ser útil como marcador genético de esta patología. Sin embargo, esta observación necesita ser reconfirmada con un estudio poblacional. Background: Different genes have been implicated in the aetiology of coronary artery disease, among these, the TP53 gene. Recently, the codon 72 polymorphism (Pro72Arg, rs1042522) of TP53 gene was indicated as a risk factor for coronary artery disease (CAD). However, other authors do not confirm this observation. Thus, in the present study we investigated the possible association between this genetic variant and the presence of CAD in Chilean subjects. Methods: 209 unrelated patients with diagnosis of CAD confirmed by angiography (33-74 years old) and 216 healthy controls (30 - 68 years old) were included in this study. The Pro72Arg polymorphism of the TP53 gene was evaluated by PCR-RFLP. Results: The genotype
Polimorfismo del codón 72 de TP53 y riesgo de cáncer gástrico: estudio caso-control en individuos de la región centroccidental de Venezuela TP53 codon 72 polymorphism and gastric cancer risk: a case-control study in individuals from the central-western region of Venezuela
Miryan Ca?as,Yeinmy Morán,María Eugenia Camargo,María Belén Rivero
Investigación Clínica , 2009,
Abstract: El polimorfismo del codón 72 del gen TP53 ha sido asociado con un riesgo elevado para el desarrollo de cáncer. Este polimorfismo origina dos variantes de la proteína, una con un residuo de Arginina (CGC), y otra con Prolina (CCC). El objetivo del estudio fue analizar la asociación de este polimorfismo con el riesgo de desarrollar cáncer gástrico en individuos procedentes de la región centroccidental de Venezuela, considerada de alto riesgo para esta neoplasia maligna. El ADN fue extraído de biopsias de adenocarcinoma gástrico incluídas en parafina (n = 65) y biopsias endoscópicas de pacientes con gastritis crónica (n = 87). El polimorfismo del codón 72 de TP53 fue determinado por PCR-RFLP. Se observó un incremento significativo de la frecuencia del alelo Arg en los pacientes con cáncer gástrico (P = 0,037), originando un riesgo 4,6 veces mayor (95% IC 1,0-21,3) de desarrollar esta enfermedad. Se evidenció un incremento del genotipo Arg/Arg en adenocarcinoma gástrico poco diferenciado (OR: 3,1; 95% IC 1,0-9,2), y del genotipo Arg/Pro en adenocarcinoma de moderado/buen grado de diferenciación (OR: 3,5; 95% IC 1,1-11,0) al comparar con el grupo de cáncer gástrico, y este último también al contrastar con los individuos con gastritis crónica (OR: 2,4; 95% IC 1,1-5,2). Los resultados de este estudio sugieren que la condición de portador del alelo Arg podría estar asociado con el desarrollo de cáncer gástrico en esta región de Venezuela. Codon 72 polymorphism of the tumor suppressor gene TP53 has been associated with a higher risk in the development of several types of cancer. The polymorphism results in a variant protein with either an arginine (CGC) or a proline residue (CCC). The aim of this study was to analyze the association of the TP53 codon 72 polymorphism with the risk of developing gastric cancer in a high-risk population from the central-western region of Venezuela. DNA was extracted from paraffin-embedded gastric adenocarcinoma biopsies (n = 65) and endoscopic biopsies from chronic gastritis patients (n = 87). TP53 codon 72 polymorphism was determined by PCR-RFLP from all samples. Patients with gastric cancer had a significantly higher frequency (P = 0.037) of the Arg allele than those with chronic gastritis. A logistic regression analysis suggested that Arg carrier individuals had a 4.6-fold higher risk (95% CI 1.0-21.3) of developing gastric cancer. An increment of the Arg/Arg genotype was observed in poor-differentiated gastric adenocarcinoma (OR: 3.1; 95% CI 1.0-9.2), and of the Arg/Pro genotype in well/ moderate-differentiated adenocarcinoma s
Analysis of Tp53 Codon 72 Polymorphisms, Tp53 Mutations, and HPV Infection in Cutaneous Squamous Cell Carcinomas  [PDF]
Keith R. Loeb, Maryam M. Asgari, Stephen E. Hawes, Qinghua Feng, Joshua E. Stern, Mingjun Jiang, Zsolt B. Argenyi, Ethel-Michele de Villiers, Nancy B. Kiviat
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034422
Abstract: Background Non-melanoma skin cancers are one of the most common human malignancies accounting for 2–3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV infection and Tp53 polymorphisms and mutations in lesional specimens with squamous cell carcinomas. Methods We studied 55 cases of histologically confirmed cutaneous squamous cell carcinoma and 41 controls for the presence of HPV infection and Tp53 genotype (mutations and polymorphism). Results We found an increased number of Tp53 mutations in the squamous cell carcinoma samples compared with perilesional or control samples. There was increased frequency of homozygous Tp53-72R polymorphism in cases with squamous cell carcinomas, while the Tp53-72P allele (Tp53-72R/P and Tp53-72P/P) was more frequent in normal control samples. Carcinoma samples positive for HPV showed a decreased frequency of Tp53 mutations compared to those without HPV infection. In addition, carcinoma samples with a Tp53-72P allele showed an increased incidence of Tp53 mutations in comparison carcinomas samples homozygous for Tp53-72R. Conclusions These studies suggest there are two separate pathways (HPV infection and Tp53 mutation) leading to cutaneous squamous cell carcinomas stratified by the Tp53 codon-72 polymorphism. The presence of a Tp53-72P allele is protective against cutaneous squamous cell carcinoma, and carcinoma specimens with Tp53-72P are more likely to have Tp53 mutations. In contrast Tp53-72R is a significant risk factor for cutaneous squamous cell carcinoma and is frequently associated with HPV infection instead of Tp53 mutations. Heterozygosity for Tp53-72R/P is protective against squamous cell carcinomas, possibly reflecting a requirement for both HPV infection and Tp53 mutations.
Association of DRD4 uVNTR and TP53 codon 72 polymorphisms with schizophrenia: a case-control study
For-Wey Lung, Bih-Ching Shu, Wei-Tsung Kao, C Nathan Chen, Yu-Chi Ku, Dong-Sheng Tzeng
BMC Medical Genetics , 2009, DOI: 10.1186/1471-2350-10-147
Abstract: We recruited 934 patients with schizophrenia and 433 healthy individuals, and genotyped the locus of the TP53 codon 72 and DRD4 uVNTR polymorphisms by combining the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) with direct sequencing.No significant differences were found in the frequency of the genotype of the TP53 codon72 polymorphism between patients with schizophrenia and their controls. However, the long form alleles (≥ 5 repeats) of the DRD4 uVNTR polymorphism were more frequent in patients with schizophrenia than in controls (p = 0.001). Hence, this class of alleles might be a risk factor for enhanced vulnerability to schizophrenia (odds ratio = 3.189, 95% confidence interval = 1.535-6.622). In the logistic regression analysis, the long form variants of the DRD4 polymorphism did predict schizophrenia after the contributions of the age and gender of the subjects were included (p = 0.036, OR = 2.319), but the CC and GG genotypes of the codon 72 polymorphism of TP53 did not.The long form variants of the uVNTR polymorphism in DRD4 were associated with schizophrenia, in a manner that was independent of the TP53 codon 72 polymorphism. In addition, given that the genetic effect of the TP53 codon 72 polymorphism on the risk of developing schizophrenia was very small, this polymorphism is unlikely to be associated with schizophrenia. The roles that other single nucleotide polymorphisms (SNPs) in the TP53 gene or in other apoptosis-related genes play in the synaptic dysfunction involved in the pathogenesis of schizophrenia should be investigated.The results of neuropsychological and neuroimaging studies suggest that abnormal connections between various cortical and subcortical regions of the brain play an important role in the pathogenesis of schizophrenia [1,2]. During the last two decades, remarkable progress has been made in identifying changes in the brain that are related to the pathophysiology of schizophrenia. Although the a
Polymorphisms of TP53 codon 72 with breast carcinoma risk: evidence from 12226 cases and 10782 controls
Wenlei Zhuo, Yunsong Zhang, Zhaolan Xiang, Lei Cai, Zhengtang Chen
Journal of Experimental & Clinical Cancer Research , 2009, DOI: 10.1186/1756-9966-28-115
Abstract: We conducted a search in the Medline, EMBASE, OVID, Sciencedirect, and Chinese National Knowledge Infrastructure (CNKI) without a language limitation, covering all papers published up to Jan 2009. The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications.A total of seventeen case-control studies, including 12226 cases and 10782 controls, met the included criteria and thus were selected. Ultimately, the relevant data were extracted and further analyzed using systematic meta-analyses. Overall, no associations of TP53 codon 72 polymorphisms with breast carcinoma were observed (for Arg/Arg vs Pro/Pro: OR = 1.20; 95%CI = 0.96–1.50; for dominant model: OR = 1.12; 95%CI = 0.96–1.32; for recessive model: OR = 1.13; 95%CI = 0.98–1.31). In the subgroup analysis by ethnicity, statistically similar results were obtained when the data were stratified as Asians, Caucasians and Africans.Collectively, the results of the present study suggest that TP53 codon 72 polymorphisms might not be a low-penetrant risk factor for developing breast carcinoma.Breast cancer is the second leading cause of cancer death in women, exceeded only by lung cancer in the world [1]. It is believed that some epidemic factors such as Oral contraceptive use [2]; obesity [3] and hyperinsulinemia [4] are probable factors increasing risks of developing breast carcinoma. Although many individuals exposed to these risk factors, breast cancer develops only in a small group of exposed people, implying that genetic factors might contribute to the carcinogenic mechanisms and complex interactions between many genetic and environmental factors might be the major cause of breast cancer.Previously, a number of studies indicate that family history is a risk factor for breast cancer [5], indicating the possible roles for genetic variations on the increased susceptibility to breast cancer. Recent published meta-analyses suggest that polymorph
Validation of dot blot hybridization and denaturing high performance liquid chromatography as reliable methods for TP53 codon 72 genotyping in molecular epidemiologic studies
Tatiana Rabachini, Helen Trottier, Eduardo L Franco, Luisa L Villa
BMC Genetics , 2010, DOI: 10.1186/1471-2156-11-44
Abstract: We developed two new genotyping methods for TP53 codon 72 polymorphism detection: Denaturing High Performance Liquid Chromatography (DHPLC) and Dot Blot hybridization. These methods were compared with Restriction Fragment Length Polymorphism (RFLP) using two different restriction enzymes. We observed high agreement among all methodologies assayed. Dot-blot hybridization and DHPLC results were more highly concordant with each other than when either of these methods was compared with RFLP.Although variations may occur, our results indicate that DHPLC and Dot Blot hybridization can be used as reliable screening methods for TP53 codon 72 polymorphism detection, especially in molecular epidemiologic studies, where high throughput methodologies are required.The tumour suppressor protein p53 is a key transcription factor that participates in numerous homeostatic functions such as cell cycle checkpoint control, repair of DNA damage and apoptosis induction [1]. Tumour-associated mutations in TP53, typically single nucleotide substitutions in the coding sequence, are a hallmark of most human cancers and cause dramatic defects in p53 function [2]. By contrast, only a small fraction of the naturally occurring sequence variations (single nucleotide polymorphisms, SNP) of TP53 in human populations are expected to cause measurable perturbation of p53 function [3]. The best studied TP53 SNP is on codon 72. In human populations, codon 72 of TP53 has either the sequence CCC, which encodes proline, or CGC, which encodes arginine. TP53 codon 72 polymorphism alters the ability of the p53 protein to induce apoptosis, influences the behaviour of mutant p53 and decreases DNA repair capacity [4-6] .The role of this polymorphism in carcinogenesis has been well studied but is a matter of controversy. A decade ago, a dramatic effect of the TP53 codon 72 polymorphism on the risk of cervical cancer was reported. This effect was explained by the finding that the E6 oncoprotein from high-risk muco
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