p53 codon72多态性与HPV相关宫颈癌易患性的关系

高危型人乳头瘤病毒(humanpapillomavirus，HPV)感染是重要的宫颈癌致病因素。Storey等研究认为p53第4外显子72密码为精氨酸(Arg)纯合子的个体比脯氨酸(Pro)纯合子个体更易于发生HPV相关宫颈癌，但对此研究结果存在广泛争议。研究人群选择、标本取材、实验设计等不同是导致研究结果差异的原因。     

p53codon72多态性在乳腺癌发生发展中的作用

乳腺癌仍是女性发病率和死亡率最高的肿瘤之一,约占全世界女性肿瘤的1/3。其发生率因种族和地理环境而异,其中欧美国家为高发地区,亚洲发病率则明显降低。乳腺癌发病率近年来呈明显上升趋势,但其确切的发病机制尚未阐明。大约50%     

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。      

膀胱移行细胞癌HPV-16/18感染与p53基因改变的关系

目的初步探讨膀胱移行细胞癌(TCC)中HPV-16／18感染与p53基因改变的关系。方法选择已确定为HPV-16／18感染的18例膀胱TCC患者(其中HPV-16／18E7片段阳性者13例，HPV-16／18E7阴性者5例)，采用微卫星方法检测肿瘤组织内与p53基因紧密连锁的TP53位点杂合性缺失(LOH)情况，并采用免疫组织化学方法检测p53蛋白表达情况。结果18例TCC组织中TP53位点杂合率为83．33％(15／18)，其LOH率达46．67％(7／15)；p53蛋白阳性率为50．00％(9／18)。其中，HPV-16／18E7 DNA阳性和p53基因改变[包括TP53位点LOH和(或)p53蛋白阳性]并存者11例，占61.11％(11／18)；仅HPV-16／18E7 DNA阳性或p53基因改变[包括TP53位点LOH和(或)p53蛋白阳性]者5例，占27．78％(5／18)；两者均阴性者2例，占11．11％(2／18)。结论HPV-16／18感染可能通过p53基因改变在TCC的发生发展过程中发挥作用，这种p53基因改变可以是LOH和(或)蛋白异常表达。     

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。     

The Preliminary Study on Relationship between HPV－associated Cervical Cancer and p53 Codon 72 Polymorphism in Sichuan Province

Objective: To study the relationship between HPV-associated cervical cancer and p53 codon 72 polymorphism in Sichuan Province. Methods: Three groups of women were studied: 30 women for normal control; 30 women with ovarian cancer; 50 women with cervical cancer. DNA from peripheral blood samples and from pathologic tissue sections was examined by PCR with allele-specific primers. Results:The proportions of individuals homozygons for the arginine allele, homozygous for the proline allele and heterozygous for the two alleles were 33.3%, 6.7% and 60% respectively among normal women; 40%, 6.7% and 53.3% in women with ovarian cancer respectively; 80%, 6% and 14% in women with cervical cancer respectively. X2 analysis showed significant differences in the proportions. Conclusion: In this population,individuals homozygons for the arginine variant of codon 72 of the p53 gene were at increased risk of cervical cancer.     

食管癌高发区HPV检测及与p53的关系

目的 探讨食管癌高发区中人乳头瘤病毒（HPV）、爱泼斯坦-巴尔病毒（EBV）与食管癌发病的关系。并初步研究HPV感染与p53过表达之间的关系。方法 设计了多对引物进行PCR、原位杂交及原位PCR、免疫组化,并对30例高发区食管癌进行检测,结果 用PCR检出HPV-L1阳性率10.0%,HPV-16-E6阳性率60.0%,HPV-16-E7阳性率63.3%,HPV-18-E6及EBV的检出率分别为6.7%和0,p53蛋白的检出率为73.3%,用原位杂交和原位PCR检出HPV-16-E6阳性率均为53.3%.HPV-L1的低检出率及HPV-16E6、HPV-16-E7基因的较高检出率可能提示,在肿瘤细胞中HPV常以部分丢失的形式整合,而E6、E7常在整合中保留。结论 HPV-16型可能与高发区食管癌发生密切相关,而HPV-18、EBV则关系不大,p53突变在食管癌的发病中起重要作用。但其与HPV感染之间的关系不大。     

p53基因第72位密码子多态性与HPV相关宫颈癌

流行病学研究显示，感染人乳头状瘤病毒(HPV)后，细胞内P53蛋白失活在宫颈癌发生中起关键作用。近年来国外关于p53基因第72位密码子的多态性与HPV相关宫颈癌发生的遗传易感性研究众多，但结果不尽一致。现主要综述该位点多态性在宫颈癌发生机制中的研究进展。     

宫颈腺癌HPV16／18感染与ki67、p53蛋白表达的关系

目的研究人宫颈腺癌组织中ki67、p53蛋白表达,分析HPV16／18感染与ki67、p53蛋白表达的关系。方法采用组织微阵列技术结合原位杂交和免疫组化（二步法）检测24例慢性宫颈炎和86例宫颈腺癌HPV16／18-E6DNA和ki67、p53蛋白表达情况。结果HPV16／18-E6DNA与ki67、p53蛋白表达在宫颈腺癌组织中的阳性率分别为65．1％、51．2％、45．3％,均显著高于慢性宫颈炎组织8．3％、0．0％、0．0％（P〈0．01）。HPV16／18感染与宫颈腺癌的病理分级和组织学类型无关,但与ki67表达呈正相关（P〈0．05）,与p53表达呈负相关（P〈0．05）。ki67、p53蛋白表达与宫颈腺癌的病理分级有关,G2、G3组阳性表达率均明显高于G1组（P〈0．05）。ki67、p53蛋白表达与宫颈腺癌组织学类型无相关性。结论宫颈腺癌的发生发展与HPV16／18感染及ki67、p53蛋白表达异常相关。     

乳腺浸润性导管癌组织中 HPV18 DNA 及 p53 蛋白的表达

目的：探讨人乳腺浸润性导管癌组织中HPV18DNA和p53蛋白的表达及二者间的关系。方法：采用分子原位杂交和免疫组化技术检测60例乳腺浸润性导管癌、30例乳腺腺病和30例正常乳腺组织中HPV18DNA和p53蛋白。结果：癌组中HPV18DNA阳性和HPV18DNA阴性两组间p53蛋白的阳性表达均有显著性差异（P〈0．03），HPV18DNA阳性组与p53蛋白阳性表达呈显著负相关（r=-0．2954、P〈0．04）。结论：HPV18感染后导致野生型p53的灭活和降解可能涉及HPV18感染后人乳腺上皮细胞癌变的转化过程。     

p53基因BstUⅠ位点多态性与非小细胞肺癌易感性及放射敏感性的相关性研究

背景与目的肺癌是世界上发病率和死亡率增长较快的恶性肿瘤。近几年来随着分子生物学的蓬勃发展，人们对疾病的认识达到了基因水平。通过分子生物学方法发现某一基因与肺癌之间的关联性并加以利用，为早期诊断及治疗肺癌提供了一个新的思路。本研究拟探讨p53肿瘤抑制基因BstUⅠ位点多态性与非小细胞肺癌（NSCLC）易感性及放射敏感性的相关性。方法采用PCR-RFLP方法检测50例NSCLC患者及50例健康对照p53基因序列中的BstUⅠ位点单核苷酸多态性（SNP）。并采用病例对照方法分析p53基因BstUⅠ位点的多态性与肺癌的易感性，以及NSCLC患者p53基因BstUⅠ位点的多态性与放疗疗效的相关性。结果不同p53基因BstUⅠ基因型的NSCLC患者对放疗的有效率不尽相同。杂合子（A1／A2）基因型的患者对放疗的有效率低．仅为25．0％，而纯合子（A1／A1，A2／A2）基因型的患者对放疗的有效率较高，分别为71．4％和70．0％，三者之间的差异有显著性（χ^2=9．2，P〈0．05）。肺癌组的A1／A1、A1／A2及A2／A2基因型频率分别为28．0％、32．0％及40．0％，对照组为32．0％、42．0％及26．0％，但两组间纯合子的频率差异并无统计学意义（P均〉0．05），并且未观察到p53基因BstUⅠ的多态性与NSCLC易感性有密切的相关关系。结论p53基因BstUⅠ位点多态性可能与NSCLC发生无关，但NSCLC患者的p53基因BstUⅠ SNP可能与放射敏感性有关。     

p53基因多态性与乳腺癌的相关性研究进展

 【摘要】　乳腺癌为危害妇女生命健康的恶性肿瘤之一,肿瘤抑制基因p53是迄今发现的与人类恶性肿瘤关系最密切的基因之一。位于p53基因第4外显子上的第72位密码子多态性与多种肿瘤密切相关,是近年来研究的热点。国内关于p53基因多态性的研究多为肺癌、子宫颈癌、食管癌、卵巢癌等方面,乳腺癌方面的报道少见。现就其与乳腺癌相关性的生物学功能作一总结。     

p53 codon 72 polymorphism and the risk of lung cancer in a Korean population

The aim of this study was to assess whether p53 codon 72 polymorphism is associated with an increased risk of lung cancer (LC) in a South Korean population. We conducted a population-based, large-scale, case-control study including 3939 patients with LC and 1700 controls. P53 codon 72 polymorphism was determined by real-time polymerase chain reaction (PCR). The frequencies of p53 codon 72 polymorphisms (Arg/Arg, Arg/Pro, and Pro/Pro) in LC were 37.0%, 46.2%, and 16.7%, respectively; frequencies in the controls were 43.2%, 45.6%, and 11.2%, respectively (p < 0.01). The Arg/Pro and Pro/Pro genotype were significantly associated with increased risk of LC (odds ratio (OR) = 1.22, 95% confidence interval (CI) = 1.06-1.14 and OR = 1.83, 95% CI = 1.48-2.26, respectively) compared with the Arg/Arg genotype. Risk was compared in different subgroups. The OR of Pro/Pro genotype was significantly higher in small cell lung cancer (SCC) and squamous cell carcinoma (SQC) than in adenocarcinoma (ADC). Higher OR of Pro/Pro genotype was also seen among males. However, relationships between gender, age, smoking, and genotypes were not found. P53 codon 72 polymorphism was associated with an increased risk of LC in this Korean population; the association was especially noteworthy in SQC, SCC, and males.     

P53 codon 72 polymorphism and gastric cancer: a meta-analysis of the literature

Studies investigating the association between p53 codon 72 polymorphism and gastric cancer risk report conflicting results. The objective of this study was to quantitatively summarize the evidence for such a relationship. Two investigators independently searched the Medline and Embase databases. This meta-analysis included 12 case-control studies, which included 1,665 gastric cancer cases and 2,358 controls. The combined results based on all studies showed that there was no significant difference in genotype distribution [Arg/Arg odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.79, 1.16; Pro/Pro (OR = 1.21, 95% CI = 0.92, 1.58); Pro/Arg (OR = 0.95, 95% CI = 0.79, 1.14)] between gastric cancer and noncancer patients. When stratifying for race, results were similar except that patients with gastric cancer had a significantly lower frequency of Arg/Arg (OR = 0.84, 95% CI = 0.72, 0.99) than noncancer patients among Asians. Stratified the various studies by the location, stage, Lauren's classification, and histological differentiation of gastric cancer, we found that (i) patients with cardia gastric cancer had a significantly higher frequency of Pro/Pro (OR = 3.20, 95% CI = 1.46,7.01) than those with noncardia gastric cancer among Asians; (ii) patients with advanced (stage III/IV) gastric cancer had a significantly higher frequency of Arg/Arg (OR = 1.48, 95% CI = 1.01, 2.16) than those with early (stage I/II) gastric cancer among Asians; (iii) patients with poor differentiation had a significantly lower frequency of Pro/Pro (OR = 0.13, 95% CI = 0.03, 0.64) than those with well differentiation among Caucasians. This meta-analysis suggests that the p53 codon 72 polymorphism may be associated with gastric cancer among Asians, and that difference in genotype distribution may be associated with the location, stage, and histological differentiation of gastric cancer.     

p53 condon72基因多态性与胃癌危险度关系--病例对照研究

目的 :探讨p53密码子 72基因多态性与胃癌危险度的关系 ,及其不同基因型与环境危险因素交互作用对胃癌发病的影响。方法 :在江苏省泰兴市进行以人群为基础的病例对照研究 ,胃癌病例 2 0 4例 ,对照 41 5例。结果 :病例中p53密码子 72的Pro Pro基因型的比例较对照中高 ,Pro Pro或Pro Arg两种基因型与Arg Arg比较OR为 1 50 (1 0 1～ 2 2 3)。p53基因还可与吸烟、饮酒、饮河水、嗜烫食等发生相乘或相加交互作用 ,影响胃癌发病。结论 :p53的Pro等位基因可能与胃癌危险度有关 ,并与其他环境危险因素交互作用 ,增加胃癌发病的危险。     

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 p53 codon 72 polymorphism with advanced lung cancer: the Arg allele is preferentially retained in tumours arising in Arg/Pro germline heterozygotes

The association of p53 codon 72 polymorphism with cancer has been investigated by several scientific groups with controversial results. In the present study, we examined the genotypic frequency of this polymorphism in 54 patients with advanced lung cancer and 99 normal controls from the geographical region of Greece. Sputum and bronchial washing samples from each patient were assayed for the presence of human papillomavirus. Codon 72 heterozygous (Arg/Pro) patients were also analysed for loss of heterozygosity at the TP53 locus, in order to determine the lost p53 allele (Arg or Pro). p53 Arg/Arg genotype was significantly increased in lung cancer patients compared to normal controls (50% vs 24.2%, P<0.002). Human papillomavirus was detected only in two patients (3.7%). Loss of heterozygosity at the TP53 locus was found in 14 out of 27 Arg/Pro patients (51.85%). The Pro allele was lost in 11 cases (78.6%), while the Arg allele was lost in three (21.4%). Our results suggest that p53 codon 72 Arg homozygosity is associated with advanced lung cancer, and that the Arg allele is preferentially retained in patients heterozygous for this polymorphism. On the other hand, human papillomavirus infection does not seem to play an important role in lung carcinogenesis.     

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.     

p53Arg72Pro多态性与HPV相关宫颈癌发生机制

[目的]探讨p53Arg72Pro多态性与HPV相关宫颈癌发生机制的关系。[方法]采用PCR技术检测210例宫颈癌和95例正常宫颈组织的HPV16DNA．采用免疫组化方法及TUNEL检测p53Arg72Pro三种基因型中p53、p21、Bax、Ki-67蛋白（P1）表达以及细胞凋亡（AI）。[结果]宫颈癌HPV16阳性率为70．5％,与正常宫颈组织（7．4％）相比差异具有统计学意义（P〈0．05）。HPV16阳性的宫颈癌中：①p53蛋白阴性和弱阳性表达率（73．6％）高于强阳性率（26．4％）,其中p53Arg的阴性表达率（39．2％）高于p53Pro（16．7％）,差异有统计学意义（P〈0．05）;②p21蛋白阴性和弱阳性组中,p53Pro型中PI高于p53Arg型,差异有统计学意义（P〈0．05）;④Bax蛋白阴性和弱阳性组中,p53Pro型中AI低于p53Arg型,差异有统计学意义（P〈0．05）。[结论]p53蛋白可被HPV16E6蛋白降解,其中p53Arg蛋白更易被降解;p53Arg和p53Pro蛋白被降解后,两者抑制细胞增殖能力的降低和诱导细胞凋亡能力的降低程度不同．其中p53Pro蛋白转录激活p21和Bax基因的功能及细胞周期阻滞作用的降低更明显。