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。     

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。     

p53和p21基因蛋白表达与胃癌侵袭力的关系

采用免疫组织化学方法研究了６８例胃癌中癌细胞ｐ５３和ｐ２１基因蛋白表达与癌细胞侵袭力的关系。结果表明：６８例胃癌中有３６例ｐ５３基因蛋白染色阳性（５２．９％）,４８例ｐ２１基因蛋白染色阳性（７０．６％）;浸润于浆膜层和肌层的癌细胞ｐ５３蛋白染色的阳性程度明显高于粘膜层癌细胞（Ｐ＜０．０５）;浸润性生长的癌细胞中ｐ５３和ｐ２１蛋白阳性程度均明显强于膨胀性生长的癌细胞（Ｐ＜０．０５）;淋巴结转移病例的癌细胞其ｐ５３和ｐ２１蛋白染色阳性率（分别为５４．３％和７３．９％）与无淋巴结转移的病例（分别为５０．０％和６３．６％）无显著性差异（Ｐ＞０．０５）;有淋巴结转移的病例中,原发癌ｐ５３蛋白阳性强度与转移癌正相关（γ＝０．６８,Ｐ＜０．０１）。结果提示：ｐ５３和ｐ２１基因蛋白染色阳性程度较高的胃癌细胞具有较强的侵袭力。     

胃癌患者p53基因甲基化的研究

作者应用限制性内切酶ＨｐａⅡ和ＭｓｐⅠ酶切胃癌组织及正常胃组织ＤＮＡ，经ＰＣＲ扩增ｐ５３基因第５外显子，琼脂糖凝胶电泳分析其电泳图谱，比较胃癌组织及正常胃组织ｐ５３基因第５外显子特定序列５′－ＣＣＧＧ－３′位点甲基化差异。结果显示：１５例胃癌组织中１２例ｐ５３基因第５外显子出现高甲基化状态，而１０例正常胃组织为低甲基化状态，结果提示，ｐ５３基因高甲基化状态与胃癌发生有关。     

p53基因第72位密码子多态性与肺癌临床病理特征及预后关系的Meta分析

目的 系统评价p53基因第72位密码子的多态性与肺癌临床病理特征及预后的关系。方法计算机检索PubMed、中国知网、维普、万方等数据库,收集有关p53基因第72位密码子多态性与肺癌临床病理特征及预后关系的研究。检索时限均从各文献数据库建库时间至2013年12月20日。由2名研究者按照纳入与排除标准独立筛选文献、提取资料和质量评价后,采用RevMan50软件进行Meta分析,计算比值比（OR）及其95%可信区间（CI）并行敏感性分析和发表偏倚评估。结果 纳入11项研究,共2730例患者。Meta分析结果显示,男性患者中p53基因第72位密码子Arg／Arg 或Arg／Pro表型多见,与女性患者相比,差异有统计学意义（OR=1.58,95％CI：1.04～2.40,P=0.03）。p53基因第72位密码子Pro／Pro表型在非鳞癌患者中居多,与鳞癌患者相比,差异有统计学意义（OR=0.69,95％CI：0.49～0.97,P=0.03）。而p53基因第72位密码子多态性与肺癌患者的吸烟史、临床分期、3年生存率无明显相关（P＞0.05）。结论 p53基因第72位密码子的多态性与肺癌患者的预后无明显相关。由于纳入研究的质量和数量有限,降低了本系统评价的证据强度,本系统评价的结论仅供临床研究与实践参考。     

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。     

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。      

ras p21及p53基因的表达与胃癌生物学行为关系的探讨

应用SP免疫组化法检测1980～1989年存档的33例胃癌及其癌旁组织石蜡包埋标本的ras p21和p53基因表达情况，并与临床、病理和随访资料进行对比分析。结果显示：胃癌标本的ras p21阳性表达7例(21．21％)，p53蛋白的阳性表达11例(33．33%)。ras p21的阳性表达与病理类型、性别、年龄、民族以及肿瘤部位无关，但肿瘤浸润深度及有无淋巴结转移与ras p21阳性表达之间显著相关。生存不足1年组的ras p21表达阳性率(50%)明显高于1～5年组(22．22％)和5年以上组，表明P21蛋白的表达与胃癌的浸润、进展和预后有关，提示ras p21的检测有可能成为胃癌预后指标，并有指导临床治疗的意义。p53蛋白的表达与患者的临床病理状况无显著相关，提示p53基因的改变可能主要发生在癌变早期，对胃癌的发生起关键作用，但并不影响胃癌细胞的生物学行为。p53蛋白的表达与ras p21蛋白表达之间无明显关系。     

吸烟、饮酒与胃癌关系的病例对照研究

目的 探讨吸烟、饮酒与胃癌发生的关系。方法 采用全人群病例对照研究,共调查1999年4月－1999年10月期间诊断的上海市区新发胃癌病例311例,对照1579例（注：本课题为“九五”中乳腺癌、肺癌及胃癌病例－对照之一,对照共用）。采用非条件logistic回归分析,调整可能的混杂因素,以估计吸烟、饮酒对胃癌发生的比数比和95％的可信区间。结果 吸烟与男性胃癌发生有关,调整OR为1．67（95％CI：1．14－2．460,并且随着吸烟年龄的提前（P＜0．01）、吸烟年限的延长（P＜0．05）、每日吸烟量的增加（P＜0．05）和吸烟包－年（P＜0．01）,患胃癌的危险性显著增大;未发现女性吸烟与胃癌发生有显著性联系。进一步调整整烟,发现饮酒与胃癌无密切关系,但重度饮酒可能与女性胃癌发生有关。进一步研究饮酒的作用,分析吸烟与饮酒状况及吸烟支数与酒精克数不同剂量分层之间的交互作用,调整年龄、文化程度（仅女性）、腌制食品、新鲜水果及慢性胃炎后,发现男性饮酒与吸烟不同剂量之间有交互作用存在,交互项χ^2值为5．20,P＝0．02,即饮酒增加男性吸烟者患癌的危险。结论 进一步证实吸烟是胃癌发生的危险因素;单独饮酒与胃癌发生无明显关系,饮酒不是胃癌的一项独立危险因素;饮酒增加吸烟患胃癌的危险,两者有协同作用。     

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.     

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.     

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.     

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.     

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。     

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.     

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.     

云南省住院肺癌患者HPV16/18感染及p53codon72多态性检测分析

目的分析云南省住院肺癌患者HPV16/18感染以及p53codon72位点基因多态性。方法收集2012-12-01-2013-09-30昆明医科大学第一附属医院胸外科手术切除的63例肺癌组织和24例肺良性病变组织,采用聚合酶链反应(polymerase chain reaction,PCR)分别检测肺癌组织和肺良性病变组织中HPV16/18以及p53codon72的DNA。结果肺癌组织的HPV16/18阳性检出率为47.63%,显著高于肺良性病变组织8.33%,χ2=11.535,P=0.001。HPV16/18感染仅与肿瘤分化程度相关,u=6.853,P=0.021;与性别(χ2=0.640,P=0.424)、年龄(χ2=0.049,P=0.825)、吸烟史(χ2=0.965,P=0.326)、肿瘤类型(u=0.593,P=0.764)、肿瘤分期(u=0.885,P=0.625)和转移情况(χ2=0.688,P=0.407)无关。p53condon72Arg/Arg、Pro/Pro和Arg/Pro在肺癌组织的分布频率分别为28.57%、53.97%和17.46%,肺良性病变组织的分布频率分别为29.17%、29.17%和41.67%,差异有统计学意义,χ2=6.489,P=0.038。p53condon72Arg/Arg、Pro/Pro和Arg/Pro在HPV阳性肺癌组织的分布频率分别为16.67%、70.00%和13.33%,在HPV阴性肺癌组织的分布频率分别为39.39%、39.39%和21.21%,差异有统计学意义,χ2=6.127,P=0.046。结论云南省住院肺癌患者中高危HPV16/18型呈高感染,p53Pro/Pro基因分型高表达,两者均为该地区肺癌发生的高危因素。