p53基因codon 72多态性与乳腺癌的相关性研究*

目的：研究p53基因codon 72 多态性与乳腺癌患者的年龄、病理分期、淋巴结转移、雌激素受体（ER）、孕激素受体（PR）、c-erbB-2、P53蛋白表达情况的相关性。方法：TaqMan探针方法检测277 例乳腺癌患者血液标本的p53基因codon 72多态性。免疫组化SP法检测匹配肿瘤组织中ER、PR、c-erbB-2 和P53蛋白的表达情况。SPSS16.0 软件行统计学分析,p53基因多态性与病理学特征关系用χ2检验,非条件Logistic回归分析基因多态性与ER、PR、c-erbB-2、P53蛋白表达的相关性,计算OR值及其95% 可信区间（95% CI）。 P<0.05为差异有统计学意义。结果：p53基因codon 72基因型为CC/CG/GG,频率分别为22.0% 、51.3% 和26.7% ,携带CC、CG、GG基因型的患者发病年龄逐渐降低,但无统计学差异;p53基因codon 72多态性与临床病理学特征无关,与ER、PR、c-erbB-2 和P53蛋白表达无相关性（P>0.05）。 肿瘤组织P53蛋白表达与ER、PR、c-erbB-2 蛋白表达密切相关（χ2=13.492,P=0.000;χ2=3.970,P=0.046;χ2=17.956,P=0.000）。 结论：p53基因codon 72多态性与P53蛋白表达及病理学特征无相关性,P53蛋白表达与ER、PR、c-erbB-2 蛋白表达关系密切。p53基因codon 72基因型与患者发病年龄的关系有待扩大样本量进一步研究。     

Effects of p53 Codon 72 and MDM2 SNP309 Polymorphisms on Gastric Cancer Risk among the Iranian Population

Background: Development of gastric cancer (GC) is a multistep process that requires alterations in the expression of oncogenes and tumor suppressor genes, occurring over several decades. The p53 tumor suppressor protein is involved in cell-cycle control, apoptosis and DNA repair. One of the most important regulators of p53 is MDM2, which acts as a negative regulator in the p53 pathway. Based on the key role of p53 and MDM2 in tumor suppression, polymorphisms that cause change in their function might affect cancer risk. We therefore elevated associations of the polymorphisms of p53 (R72P) and MDM2 (SNP309) with GC in Iran. Materials and Methods: A total of 104 patients with gastric cancer and 100 controls were recruited. Genomic DNA was extracted from fresh gastric samples. Genotyping of the p53 and MDM2 genes was performed using allele specific PCR(AS-PCR). Results: There was no significant difference between the p53 codon 72 polymorphism distribution in control and patient groups (p=0.54), but the G allele of MDM2 was found to be over-represented in patients (p=0. 01, Odds Ratio=2. 08, 95% Confidence Interval= 1.37-4.34). Conclusions: The p53 R72P seems not to be a potential risk factor for development of GC among Iranian patients, but our data suggest that MDM2 SNP309 might modify the risk related to GC.     

p53 Codon 72 Polymorphism Interactions with Dietary and Tobacco Related Habits and Risk of Stomach Cancer in Mizoram,India

Background: This study was carried out to investigate the interaction of p53 codon 72 polymorphism, dietaryand tobacco habits with reference to risk of stomach cancer in Mizoram, India. A total of 105 histologicallyconfirmed stomach cancer cases and 210 age, sex and ethnicity matched healthy population controls wereincluded in this study. Materials and Methods: The p53 codon 72 polymorphism was detected by PCR-RFLPand sequencing. H. pylori infection status was determined by ELISA. Information on various dietary and tobaccorelated habits was recorded with a standard questionnaire. Results: This study revealed that overall, the Pro/Pro genotype was significantly associated with a higher risk of stomach cancer (OR, 2.54; 95%CI, 1.01-6.40) ascompared to the Arg/Arg genotype. In gender stratified analysis, the Pro/Pro genotype showed higher risk (OR,7.50; 95%CI, 1.20-47.0) than the Arg/Arg genotype among females. Similarly, the Pro/Pro genotype demonstratedhigher risk of stomach cancer (OR, 6.30; 95%CI, 1.41-28.2) among older people (>60 years). However, no suchassociations were observed in males and in individuals <60 years of age. Smoke dried fish and preserved meat(smoke dried/sun dried) consumers were at increased risk of stomach cancer (OR, 4.85; 95%CI, 1.91-12.3and OR, 4.22; 95%CI, 1.46-12.2 respectively) as compared to non-consumers. Significant gene-environmentinteractions exist in terms of p53 codon 72 polymorphism and stomach cancer in Mizoram. Tobacco smokerswith Pro/Pro and Arg/Pro genotypes were at higher risk of stomach cancer (OR, 16.2; 95%CI, 1.72-153.4 andOR, 9.45; 95%CI, 1.09-81.7 respectively) than the non-smokers Arg/Arg genotype carriers. The combination oftuibur user and Arg/Pro genotype also demonstrated an elevated risk association (OR, 4.76; 95%CI, 1.40-16.21).Conclusions: In conclusion, this study revealed that p53 codon 72 polymorphism and dietary and tobacco habitinteractions influence stomach cancer development in Mizoram, India.     

Allelic Frequency of p53 Gene Codon 72 Polymorphism in Urologic Cancers

Alterations in the p53 tumor suppressor gene appear to be important in the development of many human tumors. The wild-type p53 gene has a polymorphism at codon 72 that presents the arginine (CGC) or proline (CCC) genotype, which recently has been reported to be associated with genetically determined susceptibility to smoking-related lung cancers. To determine whether this p53 genotype influences individual risk of urologic cancer and/or its progression, we used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis to assay the allelic frequencies of this polymorphism in 85 renal cell carcinoma patients, 151 urothelial cancer patients, 33 testicular cancer patients, 28 prostatic cancer patients and 56 patients without neoplastic disease. The allelic distributions of the three genotypes (Arg/Arg, Arg/Pro, Pro/Pro) in patients with renal cell carcinoma (29.4%, 55.3%, 15.3%), urothelial cancers (45.7%, 39.7%, 14.6%), testicular cancer (45.4%, 48.5%, 6.1%) or prostate cancer (42,9%, 50.0%, 7.1%) did not differ significantly from those in the normal controls. However, Pro/Pro genotype in renal cell carcinoma and urothelial cancer (smoking-related cancers) was more frequent than that in prostate cancer and testicular cancer (smoking-unrelated cancers) with borderline significance (P=0.0881). There was no particular correlation between frequency of the three genotypes and grade or stage of each type of tumor. The association of genetic predisposition to urologic cancers with p53 gene codon 72 polymorphism is not so clear as the previous study of Japanese lung cancer patients, but this polymorphism may play some role in urothelial cancers and renal cell carcinoma, in which smoking is an epidemiological risk factor.     

TP53 Codon 72 Polymorphisms and Lung Cancer Risk in the Bangladeshi Population

Objective: To assess associations between codon 72 polymorphisms (Pro or B and Arg or b alleles) of theTP53 gene and lung cancer risk among Bangladeshis. Materials and Methods: The distribution of the BB, Bb,and bb genotypes and the frequencies of the B and b alleles were determined by PCR-RFLP method using DNAextracted from leucocytes of 50 confirmed lung cancer patients and 50 age-matched controls and the data wereanalysed. Results: The ratio of BB, Bb, and bb genotypes were in Hardy-Weinberg equilibrium except for themale patients (χ2=4.6). The B allele is overrepresented among all patients (OR=2.0, p=0.02) and the femalepatients (OR=4.1, p≤0.01) compared to the controls. The BB/bb ratio was also higher among the patients (OR=3.0,p=0.03). The relative risk of cancer for having BB over bb genotype was 1.8 (p=0.04) but no effect was observedfor the Bb genotype. The B allele was overrepresented among patients with adenocarcinomas (OR=2.4, p≤0.01)and squamous cell carcinomas (OR=2.7, p≤0.01) over the controls but the difference was not significant for thosewith small cell lung carcinomas (OR=1.1, p=0.66). The B allele was overrepresented among patients age 50 oryounger (OR=2.7, p≤0.01), but not for older patients (OR=1.7, p=0.07), and among smokers compared to thecontrols (OR=1.8-10.0, p≤0.01-0.03). However, no correlation between increasing pack-years and lung cancerwas observed. Conclusions: The Pro/Pro (BB) genotype and the B allele are risk factors for lung cancer amongBangladeshis, particularly for people under age 50, women and smokers.     

Risk of cervical cancer is not increased in Chinese carrying homozygous arginine at codon 72 of p53.

Homozygous arginine at codon 72 (HA72) of p53 was found in 22% of normal cervices and 30.0% of cervical cancers and no significant difference was detected between normal and cervical cancer with or without HPV 16/18. There was no correlation between HA72 and risk of cervical cancer in Chinese.     

p53 Codon 72 polymorphism in gastric cancer susceptibility in patients with Helicobacter pylori-associated chronic gastritis

p53 codon 72, which produces variant proteins with an arginine (Arg) or proline (Pro), has been reported to be associated with cancers of the lung, esophagus and cervix. However, there have been no reports on the p53 codon 72 polymorphism in gastric cancer susceptibility in patients with Helicobacter pylori-associated chronic gastritis (H. pylori-CG). We, therefore, examined the polymorphism in 117 gastric cancer patients (72 intestinal type and 45 diffuse type) with H. pylori-CG and 116 H. pylori-CG patients without gastric cancer as controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed to analyze the p53 codon 72 polymorphism. The crude genotypic frequencies in the gastric cancer patients were similar to those of the controls. However, when gastric cancers were classified by histologic subtype, the Pro/Pro was more frequent in the patients with diffuse type gastric cancer than in the controls (22.2% of cases vs. 12.1% of controls). The Pro/Pro genotype was associated with a 2.98-fold higher risk of diffuse-type cancer compared to the Arg/Arg genotype (95% confidence interval [CI] 1.07-8.32, p = 0.038). These results suggest that the Pro/Pro genotype at p53 codon 72 contributes to susceptibility for diffuse-type gastric cancer in patients with H. pylori-CG. The p53 codon 72 polymorphism may serve as the genetic marker for the risk assessment of the diffuse-type gastric cancer development in patients with H. pylori-CG.     

Association between p53 Gene Variants and Oral CancerSusceptibility in Population from Gujarat,West India

Background: p53 gene variants i.e. 16 bp duplication in intron 3, Arg72Pro in exon 4 and G>A in intron 6have been reported to modulate susceptibility to various malignancies. Therefore, the present study evaluatedthe role of these p53 polymorphisms in oral cancer susceptibility in a population from Gujarat, West India.Method: Genotype frequencies at the three p53 loci in 110 controls and 79 oral cancer cases were determinedby the PCR-RFLP method. Results: Heterozygous individuals at exon 4 showed protection from developingoral cancer. Homozygous wild and heterozygous individuals at intron 3 and those heterozygous at exon 4 incombination appeared to be at lowered risk. Furthermore, carriers of the 16 bp duplication allele at intron 3,proline allele at exon 4 and G allele at intron 6 were protected from oral cancer development. Conclusion: p53polymorphisms, especially Arg72Pro in exon 4 could significantly modify the risk of oral cancer developmentin Gujarat, West Indian population.     

p53codon72单核苷酸多态性与肝细胞癌发病风险的关系

[目的]探讨广西地区p53基因codon72单核苷酸多态性(SNP)与肝细胞癌(HCC)发病风险的关系。[方法]采用TaqMan MGB探针等位基因分型技术对985例肝癌病例和相匹配的992例非肿瘤对照的p53 codon72(Arg>Pro,rs1042522)基因型进行检测,并分析该SNP与肝癌发病风险的关系。[结果]p53 codon72多态性与肝癌发病风险之间无统计学关联(Arg/Pro:校正OR=1.15,95%CI:0.83～1.59;Pro/Pro:校正OR=1.16,95%CI:0.80～1.68;Arg/Pro+Pro/Pro:校正OR=1.15,95%CI:0.85～1.57)。按是否吸烟、饮酒、HBV和HCV感染分层分析,亦未发现p53 codon72多态性与肝癌发病风险有关。但基因—环境交互作用显示,该基因多态性与吸烟、饮酒和HBV感染存在交互作用,OR值分别为2.42(95%CI:1.47～3.97)、2.96(95%CI:1.82～4.80)和62.74(95%CI:34.39～114.46)。[结论]p53codon72的单独效应可能与肝癌易感性无关联,但该SNP与吸烟、饮酒和HBV感染存在基因—环境交互作用,增加肝癌的发病风险。     

p53 Codon 72 polymorphism and the risk of esophageal squamous cell carcinoma

The polymorphisms of the tumor suppressor gene p53 have been extensively investigated in numerous malignant tumors, particularly carcinomas associated with human papillomavirus (HPV) infection. However, the results remain controversial. To address a potential correlation between the p53 genotypes and the risk of esophageal squamous cell carcinoma (ESCC), we investigated the p53 codon 72 polymorphism in 435 patients with ESCC and 550 cancer-free subjects from the same geographical region. p53 Arg/Arg genotype was significantly increased in ESCC cases compared with control subjects (85.7 vs. 49.6%, P < 0.001), resulting in an elevated ESCC risk (OR = 6.48, 95% CI = 4.65-9.03). In addition, among p53 Arg/Arg carriers, HPV infection, smoking, and drinking might further increase the risk of ESCC development.     

Effect of p53 codon 72 genotype on breast cancer survival depends on p53 gene status

In vitro studies suggest that p53 codon 72 genotype alters the apoptotic capacity of p53 protein, with the 72 arginine (R) form of wild-type p53 harboring a greater apoptosis-inducing potential than the 72 proline (P) variant. The aim of this study was to investigate whether the association between the p53 codon 72 genotype and breast cancer survival was modified by p53 gene status. In our study, we examined the p53 codon 72 genotype and p53 mutations (through exons 4-9) in paraffin-embedded specimens from 414 breast cancer patients with a median follow-up of 8.2 years. We report that the p53 codon 72 genotype was significantly associated with disease-free survival (DFS, p = 0.02) but not with disease-specific survival (DSS, p = 0.24) in the entire study population (n = 414). In contrast, the codon 72 genotype was strongly associated with both DFS (p = 0.001) and DSS (p = 0.04) among patients with a wild-type p53 tumor (n = 346), patients with the P/P variant had worse DFS and DSS than did those with the P/R or R/R variant in this subgroup of patients. More importantly, as compared with the P/R or R/R variant, the P/P variant remained an independent prognostic factor of DFS among patients with a wild-type p53 tumor (HR = 2.5; 95%CI = 1.4-4.4; p = 0.003). We conclude that the effect of p53 codon 72 genotype on breast cancer survival is dependent on p53 gene status, the P/P variant is strongly associated with poor prognosis among patients with a wild-type p53 tumor.     

Association of TP53 Codon 72 Arg>Pro Polymorphism with Breast and Lung Cancer Risk in the South Asian Population: A Meta-Analysis

Background: A transversion missense polymorphism of the TP53 tumor suppressor gene at the codon 72 codes proline instead of arginine causes an altered p53 protein expression and has been found to be associated with an elevated risk of various cancer; especially breast and lung cancer. As the previous case-control studies on the South Asian population have shown controversial results, we performed a meta-analysis to evaluate a precise estimation of the relationship between the TP53 Arg72Pro polymorphism with breast and lung cancer. Methods: A total of 12 related studies on the South Asian population have been included through comprehensive database searching. Six studies were selected for breast cancer meta-analysis involving 950 cases and 882 controls; the other six studies were for lung cancer meta-analysis including 975 cases and 1397 controls. The results have been determined by using the Review Manager (RevMan) 5.3. Additionally, the stability of our analysis was assessed by heterogeneity, publication bias analysis and sensitivity testing. Results: A significantly increased risk of breast cancer was found in Pro allele (Pro vs. Arg), co-dominant model 2 (Pro/Pro vs. Arg/Arg), dominant model (Pro/Pro + Arg/Pro vs. Arg/Arg). In case of lung cancer, significantly increased risk was found in the allele, co-dominant 1, co-dominant 2, co-dominant 3, dominant, and recessive models. No association with other genetic models with breast and lung cancer risk was found in the South Asian population. Conclusions: Our results indicate that TP53 Arg72Pro polymorphism is a risk factor for the development of breast cancer and lung cancer in the South Asian population.     

The p53 codon 72 proline allele is endowed with enhanced cell-death inducing potential in cancer cells exposed to hypoxia

The preferential retention of the arginine allele at the p53 codon 72 locus is commonly observed in tumours from arginine/proline heterozygotes. Considering that cancer cells are harboured in a hypoxic environment in vivo, we here tested the hypothesis that the p53 codon 72 proline allele confers a survival disadvantage in presence of hypoxia. Here, we show that the transient transfection of the proline allele in p53 null cancer cells exposed to low oxygen tension or to the hypoxia-mimetic drug Desferoxamine induces a higher amount of cell death than the arginine allele. Accordingly, proline allele transiently transfected cell lines express lower levels of hypoxia pro-survival genes (HIF-1alpha, carbonic anhydrase IX, vascular endothelial growth factor, heme oxygenase-I, hepatocyte growth factor receptor, vascular endothelial growth factor receptor 2), compared to those transiently transfected with the arginine allele. Further, we report that the exposure of the arginine/proline heterozygote MCF-7 breast cancer cell line to cytotoxic concentration of Desferoxamine for several weeks, gives raise to hypoxia-resistant clones, carrying the arginine, but not the proline allele. These data indicate that the p53 codon 72 proline allele is less permissive for the growth of cancer cells in a hypoxic environment, and suggest that the preferential retention of the arginine allele in the tumour tissues of arginine/proline heterozygous patients may depend upon its lowered capacity to induce cell death in a hypoxic tumour environment.     

p53基因codon 72多态性与乳腺癌术后放化疗疗效相关性分析

目的:分析p53基因codon 72多态性与乳腺癌患者术后放化疗的预后相关性。方法:选取北京大学肿瘤医院乳腺癌患者术后接受放化疗427 例,采用聚合酶链反应- 限制性片段长度多态性（PCR-RFLP ）方法分析其p53基因codon 72多态性,比较不同基因型患者间复发及生存的差异。结果:全部患者基因型分布为Pro/Pro 型18.3%（78/427）、Pro/Arg型44.0%（188/427）、Arg/Arg型37.7%（161/427）。3 种基因型间无局部复发生存（LRFS）、无局部区域复发生存（LRRFS ）、无远处转移生存（DDFS）及总生存（OS）均无显著性差异（均P>0.05）。 427 例患者中雌激素受体（ER）阳性为303 例,其中Arg/Arg基因型患者OS明显优于Pro/Pro 基因型患者（χ2=6.330,P=0.042）。 在多因素分析中p53基因codon 72多态性是ER阳性患者LRFS、LRRFS 、DDFS及OS的独立预后因素,Pro/Pro 基因型的患者较Arg/Arg基因型的局部复发风险增加5.9 倍（HR= 5.9,95%CI 1.1～31.1,P=0.036）,局部区域复发风险增加3.1 倍（HR= 3.1,95%CI 1.1～9.1,P=0.039）,远处转移风险增加2.8 倍（HR= 2.8,95%CI 1.3～6.0,P=0.010）,死亡风险增加4 倍（HR= 4.0,95%CI 1.3～12.0,P=0.013）。 结论:在ER阳性的乳腺癌术后接受放化疗患者中,Pro/Pro 基因型的局部及局部区域复发风险、远处转移风险、死亡风险均高于Arg/Arg基因型。      

四川地区P53 Codon 72多态性与宫颈癌关系的初步研究

目的 探讨抑癌基因P53 Codon 72多态性与HPV有关的宫颈癌的关系。 方法 应用聚合酶链反应法分别对30例卵巢浆液性囊腺癌、50例宫颈鳞状细胞癌和30例正常妇女的P53 Codon 72多态性进行检测。 结果 P53 Arg纯合子、P53 Arg/P53 Pro杂合子和P53Pro纯合子正常妇女对照组分别为33.3％、60％和6.7％;而在卵巢癌组分别为40％、53.3％和6.7％;在宫颈癌组分别为80％、14％和6％。上述人群中,宫颈癌P53 Arg纯合子明显高于卵巢癌组和正常妇女对照组(P<0.05)。 结论 p53 Arg纯合子可作为与HPV感染有关的宫颈癌的危险因素。     

Proline homozygosity in codon 72 of p53 is a factor of susceptibility for thyroid cancer

A common germline polymorphism of p53 gene produces an Arginine to Proline change at aminoacid position 72. The resulting codon 72 variants have been reported associated with tumor susceptibility since they reduce p53 ability to activate apoptosis. Codon 72 polymorphism may play a role in subside vulnerability to different carcinogens and might account for ethnic variations in cancer frequency. Using an allele-specific polymerase chain reaction (PCR), we tested peripheral blood samples from 98 patients with thyroid cancer, including 21 follicular (FC) and 77 papillary carcinomas (PC), 44 patients with benign nodules, including 14 follicular adenomas and 30 goiters and 153 healthy individuals from the same geographical region. Data on lifetime occupational history, smoking history, general health conditions, previous diseases and other anamnestic data were obtained through interviews. Patients with FC (Pro/Pro=19.0%, Arg/Arg=42.9%, Arg/Pro=38%) and with PC (Pro/Pro=10.3%, Arg/Arg=36.36%, Arg/Pro=53.24%) showed a significant overrepresentation of codon 72 variants compared to the control population (Pro/Pro=1.9%, Arg/Arg=33.3%, Arg/Pro=64.7%) (P=0.0015). The Pro/Pro genotype, after adjusting for gender, age, tobacco and drugs, was associated with a markedly higher risk of FC (OR=9.714; CI: 2.334–40.436) and of PC (OR=5.299; CI: 2.334–40.436). These results provide evidence that p53 polymorphism is implicated in thyroid carcinogenesis and that individuals harboring the Pro/Pro genotype have an increased risk of developing thyroid cancer.     

Polymorphism of p53 Gene Codon 72 in Endometrial Cancer: Correlation with Tumor Grade and Histological Type

Background: Endometrial cancer is the fourth most common cancer among women in developed countries.Patients with endometrial cancer may benefit from systemic chemotherapy alone or in combination with targetedtherapies if the disease is clinically diagnosed prior to spread and metastasis to other organs. The aim of thisstudy was to evaluate the prognostic role of p53 polymorphism and its correlation with tumor grade in humanuterine endometrial carcinomas. Materials and Methods: A total of 75 patients with endometrial carcinomaswere studied for possible mutations in exon 4 of the p53 gene using polymerase chain reaction and restrictingfragment length polymorphism techniques and sequencing. Results: In recent study, The rate of homozygotegenotype of pro/pro or Arg/Arg in high grade group was higher than in comparison with low grade one. Inaddition samples that were undigested in RFLP, showed mutation in exone 4. Conclusions: Our findings showedthat high grade endometrial carcinomas are highly associated with TP53 polymorphisms in comparison withlow grades.     

Risk Factors for Oral Cancer in Northeast Thailand

Oral cancer is a common site of head and neck cancer, and is relatively frequent in Northeast Thailand.The objective of this hospital-based, case-control study was to determine associations with risk factors. A totalof 104 oral cancer cases diagnosed between July 2010 and April 2011 in 3 hospitals were matched with controlsubjects by age, sex and hospital. Data were collected by personal interview. There were significant associationsbetween oral cancer and tobacco smoking (OR=4.47; 95%CI=2.00 to 9.99), alcohol use among women (OR=4.16;95%CI=1.70 to 10.69), and betel chewing (OR=9.01; 95%CI=3.83 to 21.22), and all three showed dose-responseeffects. Smoking is rare among Thai women (none of the control women were smokers), but betel chewing,especially among older women, is relatively common. We did not find any association between practicing oralsex and oral cancer.