p53基因第72密码子多态性与中国人肝细胞癌遗传易感性的相关性

目的探讨在有无慢性乙型肝炎的不同背景下郦基因第72密码子多态性（R72P）与中国人肝细胞癌（hepatocellular carcinoma，HCC）遗传易感性的关系。方法采用聚合酶链反应-限制性片段长度多态方法，检测469例HCC（HBsAg阴性110例、HBsAg阳性359例）与567名对照（HBsAg阴性430例、HBsAg阳性137例）的郦R72P基因型分布及差异。结果全样本以及HBsAg阳性样本的HCC与对照问的基因型分布差异均无统计学意义。但在HBsAg阴性人群中，72P是HCC发生的危险因素（OR=1，69，95％CI=1，25～2．27）。与R／R基因型相比，R／P的HCC风险增加至1．73倍（95％CI=0．96～3．11），P／P的HCC风险显著增加至3．29倍（95％CI=1．58～6．86）。携带72P的男性个体、HCC家族史阳性个体的HCC风险分别进一步增加至9．39倍（95％CI=3，08～28．62）和11，14倍（95％CI=1，62～76．67）。结论皿形72P增加HBsAg阴性中国人的HCC风险，并与男性、HCC家族史在增加HCC风险中有协同作用。     

p53基因第72位密码子多态与食管癌风险

目的 研究p53基因第７２位密码子Ａrg/Pro多态与食管癌遗传易感性的关系。方法 采用聚合酶链反应－－限制性片段长度多态性方法检测了９１例食管癌患者与２０４名正常对照组的p53 Arg/Pro基因型分布及差异。结果 正常对照组p53 Pro等位基因频率（０.588）与病例组（０.480）比较差异无显著性（Ｐ＝０.11）。但３种p53基因型频率在病例组和对照组的分布差异有显著性，病例组的Ｐro/Pro基因型频率（３９.6％）显著高于对照组（２１.1%）。携带Ｐro/Pro纯合变异基因型者患食管癌的风险比携带Ａrg/Arg纯合野生基因型者高２倍[校正比值比（odds ratio,OR）为２.18,95%可信区间（confidemce interval,CI）为１.10-4.35。杂合子基因型（Ａrg/Pro）与食管癌的遗传易感性无关（校正ＯＲ＝０.84％，９５％ＣＩ＝０.42－１.68）。吸烟增加食管癌风险（ＯＲ＝２.30,95%CI=1.30-4.12)，但与Ｐro/Pro基因型无协同作用。结论 p53基因第７２位密码子纯合突变是中国人的食管癌易感因素。     

TP53 codon 72 polymorphism and risk for cervical cancer in Portugal

High-risk human papillomavirus are essential for the development of cervical cancer; however, TP53 is the most frequently altered tumor suppressor gene among tumors and is described as a cofactor for cervical carcinogenesis. TP53 has two common polymorphic forms encoding either proline or arginine, at position 72, and the presence of homozygous arginine has been reported as a risk factor for cervical cancer in many populations. We evaluated the effect of this TP53 polymorphism in a northern Portuguese population. We analyzed blood samples of 385 women; 20 with low-grade squamous intraepithelial lesion (SIL), 56 with high-grade SIL, 164 with invasive cervical cancer, and 145 healthy controls, using allele specific-polymerase chain reaction methodology. We observed an increased frequency of the Arg/Arg genotype in the cancer group, but no statistical significance was found between cases and controls (P>0.05). Our results indicate that there is no association between the presence of the Arg allele in codon 72 of TP53 polymorphism and risk of cervical cancer in our population.     

P53 codon 72Arg polymorphism is not a risk factor for carcinogenesis in the chinese.

The potential association of distinct polymorphism of the tumor suppressor gene p53, with an increased susceptibility to malignant transformation has been reported for various cancers. A polymorphism at codon 72 of p53 results in translation to either arginine (p53Arg) or proline (p53Pro), and recent study showed that Caucasian women with arginine form of p53 are more susceptible to HPV-associated carcinoma of the cervix. To examine whether arginine 72 could be a significant risk factor for tumor development, we used a PCR-based assay to analyze p53 genotypes of patients for several types of carcinoma. No significant difference in the frequency of p53Arg was found between normal and cancer patients, the results showed that the individuals homozygous for arginine variant were not at increased risk for cancer.     

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.     

Polymorphism of TP53 codon 72 showed no association with breast cancer in Iranian women

Breast cancer is the most common female malignancy worldwide. Despite the high incidence of sporadic cases, the rate of familial breast cancer is low. The tumor suppressor gene TP53 (alias p53), located on chromosome 17, has been involved in various malignancies. Mutations in codon 72 of TP53 have been studied in breast cancer and most solid tumors. For study of polymorphisms and allele frequency, 221 female patients with sporadic breast cancer and 205 healthy blood donors as control group were recruited. DNA from peripheral blood mononuclear cells was extracted and amplified using allele-specific polymerase chain reaction. Frequency of homozygotic arginine at codon 72 was 37.6% in patients and 36.6% in controls, for homozygotic proline it was 13.1 and 19.5%, and for heterozygotic Arg/Pro it was 49.3 and 43.9%, respectively. No significant difference was found between patients and controls regarding allele frequencies. Mutation in codon 72 of TP53 gene was not associated with breast cancer in Iranian patients.     

Polymorphisms of the TP53 codon 72 and WRN codon 1367 in individuals from Northern Brazil with gastric adenocarcinoma

Abstract Gastric cancer is the second most frequent type of neoplasia and also the second most common cause of death in the world. TP53 codon 72, which produces variant proteins with an arginine (Arg) or proline (Pro), has been reported to be associated with cancers of the lung, oesophagus, stomach and cervix. Werner’s syndrome (WS) is a premature ageing disease caused by a mutation in the WRN gene. The WRN protein acts as a DNA helicase and as an exonuclease. WRN codon 1367 produces variant proteins with an Arg or cysteine (Cys). This polymorphism has been studied, in order to understand the clinical impact of the molecular variants in WS and in age-related disorders. In the present study, the TP53 codon 72 and the WRN codon 1367 polymorphisms were investigated in 54 gastric adenocarcinoma patients (31 diffuse-type and 25 intestinal-type) and 54 controls. DNA samples were extracted, and PCR-RFLP was utilised for genotyping TP53 codon 72 and WRN codon 1367. The allele frequencies of the TP53 polymorphism were: Arg=0.74 and Pro=0.26. The allele frequencies of the WRN polymorphism were: Cys=0.73 and Arg=0.27. The crude genotypic frequencies in gastric cancer patients were similar to those of the controls, but in the WRN codon 1367 polymorphisms the mean age tended to be higher in the Arg/Arg genotypes. There also was an association, although not statistically significant, between the presence of Helicobacter pylori and the genotypes Cys/Cys and Cys/Arg and a higher percentage of cardia cancer among the Arg/Arg genotypes, and of non-cardia cancer among genotypes Cys/Cys and Cys/Arg. These findings may be a reflection of differences in the interaction between WRN codon 1367 polymorphisms and local factors in the stomach. To our knowledge, this is the first study to examine a genetic polymorphism of the WRN gene in cancer. The precise mechanisms of action of the TP53 and WRN polymorphisms involved in the aetiopathogeny of this disease need further investigation.     

p53基因第72位密码子多态性与宫颈癌相关性

目的　探讨 p5 3基因第 72位密码子多态性与新疆汉族人群宫颈癌发生的关系。 方法　采用限制性酶切片段多态性分析 (RFLP)技术检测 72例宫颈癌及正常宫颈石蜡包埋组织中p5 3基因多态性的分布 ,分析两者之间的相关性。结果　p5 3基因 3种基因型Arg/Arg、Pro/Pro、Pro/Arg在宫颈癌中所占比例分别是 2 1 0 % ,39 5 % ,39 5 % ,对照组为 38 2 % ,14 7% ,4 7 1% ,两组总构成比差异有显著性 (χ2 =6 0 1,P <0 0 5 ) ,Pro/Pro在宫颈癌中所占比例高于对照组 ,没有发现Arg/Arg在宫颈癌中所占比例高于对照组 ,在HPV16、18阳性宫颈癌中所占比例分别是 2 2 2 % (4 /18)、5 0 0 % (9/18)、2 7 8% (5 /18) ,Pro/Pro所占比例明显高于其它两型。结论　p5 3Pro/Pro基因型可能是新疆汉族女性宫颈癌主要遗传易感因素。     

Influence of the TP53 codon 72 polymorphism on the cellular responses to X-irradiation in fibroblasts from nonagenarians

In mice, genetic modification of the gene encoding p53 affects both cancer incidence and longevity. In humans, we recently found that a TP53 codon 72 Arginine (Arg) to Proline (Pro) polymorphism affected both cancer incidence and longevity as well. The TP53 codon 72 polymorphism has previously been shown to influence the apoptotic potential of human cells in response to oxidative stress. Here, we studied the influence of this polymorphism on the cellular responses to X-irradiation of fibroblasts obtained from nonagenarians. We found that the average clonogenic survival after X-irradiation was similar for the three TP53 codon 72 genotype groups. As described before, X-irradiation did not induce an appreciable degree of apoptosis in human fibroblasts. However, percentages of senescence-associated (SA)-β-galactosidase positive cells (p < 0.001), micronucleated cells (p < 0.001) and cells displaying abnormal nuclear morphologies (p < 0.001) significantly increased with the radiation dose. Compared to Arg/Arg fibroblasts, Pro/Pro fibroblasts exhibited higher irradiation dose-dependent increases in SA-β-galactosidase positive cells (p_interaction = 0.018), micronucleated cells (p_interaction = 0.005) and cells displaying abnormal nuclear morphologies (p_interaction = 0.029) at 3 days after irradiation. Possibly, these differences in cellular responses to stress between the TP53 codon 72 genotypes contribute to the differences in cancer incidence and longevity observed earlier for these genotypes.     

Association of DRD4 uVNTR and TP53 codon 72 polymorphisms with schizophrenia: a case-control study

Background  

The tumour supressor gene TP53 is thought to be involved in neural apoptosis. The polymorphism at codon 72 in TP53 and the long form variants of the upstream variable number of tandem repeats (uVNTR) polymorphism in the dopamine D4 receptor (DRD4) gene are reported to confer susceptibility to schizophrenia.     

TP53 mutations in astrocytic gliomas: an association with histological grade,TP53 codon 72 polymorphism and p53 expression

TP53 mutations and polymorphisms have been widely related to many cancers as long as these alterations may impair its capacity to induce cell cycle arrest, DNA repair mechanisms, and apoptosis. Although TP53 alterations have been studied in astrocytic tumors, there is a lack of analysis considering specific TP53 mutations and their associations with p53 immunostainning, polymorphisms and their significance among the histological grades. Thus, we analyzed TP53 alterations in exons 2–11, including the codon 72 polymorphism, using DNA sequencing in 96 astrocytic gliomas (18 grade I, 20 grade II, 14 grade III, and 44 grade IV). Also, immunohistochemistry was assessed to evaluate the p53 protein expression. In this study, we found that the higher histological grades were statistically associated with TP53 mutations. Some of these mutations, such as TP53 P98T and TP53 G244S, seemed to be a specific marker for the higher grades, and the TP53 E286K mutation appears to be a World Health Organization grade III–IV progression marker. Also, the TP53 P98T mutation, in exon 4, is very likely to be important on the stabilization of the p53 protein, leading to its immunopositivity and it is potentially associated with the TP53 72Pro/Pro genotype.     

p53 codon 72 polymorphism and risk of cervical carcinoma in Korean women

A common polymorphism of the wild type p53 is known at codon 72 of exon 4, with 2 alleles encoding either arginine (CGC, p53Arg) or proline (CCC, p53Pro). A recent study suggested that this polymorphism affects the susceptibility of p53 protein to human papillomavirus E6 oncoprotein mediated degradation and that individuals homozygous for p53Arg are seven times more susceptible to HPV-associated carcinogenesis of the cervix than heterozygotes. To examine whether the p53Arg genotype could be a risk factor for HPV-associated cervical carcinomas in the Korean population, we analyzed the p53 codon 72 polymorphism status of HPV-positive invasive cervical carcinomas from 52 Korean women and 103 healthy control samples. The proportion of individuals homozygous for p53Arg, homozygous for p53Pro, and heterozygous for the two alleles were 40%, 19%, and 41% in normal healthy controls; 42%, 17%, and 40% in women with HPV-positive invasive cervical carcinoma. There were no significant differences in the distribution of p53 genotypes between controls and cervical carcinomas. This finding indicates that the p53Arg genotype is not associated with an increased susceptibility to cervical carcinoma in Korean women.     

TP53 codon 72 polymorphism, p53 expression, and 1p/19q status in oligodendroglial tumors

The functional single-nucleotide polymorphism (SNP) in codon 72 of TP53 has been shown to be both a risk factor and a prognostic biomarker in various cancers. Such results were also reported in brain tumors, notably in astrocytomas. This SNP has never been precisely investigated in oligodendroglial tumors. We retrospectively analyzed blood samples of 275 oligodendroglial tumor patients for the TP53 codon 72 polymorphism and compared them with a series of 144 healthy controls. Arg/Arg, Arg/Pro, and Pro/Pro genotypes were found in 54.2 versus 60.4%, 39.3 versus 34.0%, and 7.3 versus 5.6% of patients and controls, respectively. This suggests no association between oligodendroglial tumors and the SNP in codon 72 of TP53. Similarly, no correlation was found among the TP53 codon 72 polymorphism and prognosis, p53 expression, and chromosomes 1p and 19q status.     

An extended Li-Fraumeni kindred with gastric carcinoma and a codon 175 mutation in TP53.

We present an extended family with Li-Fraumeni syndrome characterised by gastric and breast carcinoma, glioma, sarcoma, and leukaemia. This family showed strong evidence of linkage to TP53, and three of four tumours analysed showed loss of the wild type allele. A codon 175 missense mutation was identified in exon 5 in all available affected subjects. Counselling, screening, and issues surrounding presymptomatic testing are discussed.     

Predisposition to HPV16/18-related cervical cancer because of proline homozygosity at codon 72 of p53 among Indian women is influenced by HLA-B*07 and homozygosity of HLA-DQB1*03

This study was undertaken to examine whether predisposition to human papillomavirus (HPV)16/18-related cervical cancer (CaCx) because of p53 proline homozygosity (Pro72Pro) among Indian women was mediated singly or jointly with immunogenetic risk factors such as HLA-B*07 or homozygosity of HLA-DQB1*03. Molecular detection of all three genetic factors was performed by polymerase chain reaction-restriction fragment length polymorphism using DNA from (i) 114 CaCx samples (78 HPV16/18 positive) and (ii) 195 cytologically normal cervical scrapes (116 HPV-negative and 79 HPV16/18-positive samples). Multiple logistic regression analyses were performed to examine independent effects of the three factors and to determine age-adjusted odds ratio (OR) [95% confidence interval (CI)] and P-values. HLA-B*07 was observed to be significantly associated with HPV16/18 infection in asymptomatic controls (OR(age-adjusted) = 4.73; 95% CI: 1.55-14.45; P = 0.006) and CaCx (OR(age-adjusted) = 6.14; 95% CI: 2.15-17.53; P < 0.001) in this enhanced sample set of CaCx cases. There was a lack of association between HLA-B*07 and HLA-DQB1*03 in our study samples. The association of p53Pro72Pro with CaCx was non-significant in the absence of HLA-B*07 in HPV16/18-positive women. In this group, prevalence of p53Pro72Pro and HLA-B*07 together was significantly higher (7.0%) among CaCx cases (OR(age-adjusted) = 14.05; 95% CI: 1.11-177.30; P = 0.04), compared with controls (1.3%) lacking both factors. HLA-DQB1*03 homozygosity (OR(age-adjusted) = 4.75; 95% CI: 1.17-19.30; P = 0.03) or p53Pro72Pro (OR(age-adjusted) = 5.84; 95% CI: 1.18-28.99; P = 0.03) was found to be significantly associated with CaCx, each in the absence of the other in this group but not when present jointly in contrast to those lacking both factors (P = 0.214). Thus, modulation of p53Pro72Pro-mediated susceptibility to CaCx by immunogenetic factors could possibly be mediated through cross talk between HPV16/18-induced immune evasion and cell transformation.     

TP53 and gastric carcinoma: a review

In this article, we survey the major p53 (TP53) alterations identified in gastric carcinomas and their precursors. These include p53 expression, mutations, and loss of heterozygosity (LOH). Not only are the various abnormalities summarized, but in addition there is a survey of the literature with respect to the impact of these changes on patient prognosis and treatment response. The majority of published studies involve the immunohistochemical detection of the protein. These use different antibodies, different detection techniques, and different methods of interpretation. Therefore not surprisingly, the results of many of the studies are contradictory with one another. Overall, however, it appears that p53 alterations occur early in the development of gastric carcinoma, being present even in the nonneoplastic mucosa and they increase in frequency as one progresses along the pathway of gastric carcinoma development. p53 immunoreactivity is seen in 17%-90.7% of invasive gastric carcinomas. p53 alterations occur much more commonly in proximal lesions than in distal ones, suggesting that the molecular events leading to the development of gastric carcinoma may be very different in proximal vs. distal tumors. p53 mutations occur in 0%-77% of gastric carcinomas. The mutations are distributed widely across the gene from exons 4-11 with hot spots of mutation at codons 175, 248, 273, 282, 245, and 213. G:C>A:T transitions at CpG sites are the commonest type of mutation. At least 60% of carcinomas with mutations also exhibit p53 LOH.     

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.     

P53 codon 72 polymorphism as a risk factor in the development of HPV-associated non-melanoma skin cancers in immunocompetent hosts

Human papilloma virus (HPV) has been implicated in skin cancer. Also, in human populations, the p53 gene is polymorphic at amino acid 72 of the protein that it encodes. The association between p53 polymorphisms and HPV-associated skin cancer risk has been examined, but the results were conflicting. It was revealed that the arginine form of p53 is more susceptible to degradation by the HPV E6 protein than the proline form and that patients with the arginine form have a higher risk of developing cancer than those with the proline form. The purpose of this study was to examine whether p53 Arg at the polymorphic position 72 could represent a risk factor for patients with high risk HPV-associated malignant skin lesions. The study was conducted on 29 high risk HPV-related skin lesions from Greece. Blood samples from 61 healthy individuals were used as controls. HPV-8 was the most frequent type. There was a difference in the distribution of p53 genotypes between high risk HPV-skin lesions and the controls, and the allele frequency of p53 Arg/Arg was much higher than the controls (65.5% versus 20%). Therefore, it is suggested that p53 Arg homozygosity could represent a potential risk factor for tumorigenesis of the skin.