p53 codon 72 polymorphism and risk of intra-epithelial and invasive cervical neoplasia in Greek women
p53 codon 72 polymorphism and risk of intra-epithelial and invasive cervical neoplasia in Greek women
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DOI：
10.1097/00008469-200004000-00007
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发表时间：
2000-04-01
影响因子：
2.4
通讯作者：
Bontis, JN
中科院分区：
文献类型：
--
作者：
Agorastos, T;Lambropoulos, AF;Bontis, JN
1998 年，Storey 和同事提出，p53 基因密码子 72 处精氨酸 (Arg) 纯合子的个体对人乳头瘤病毒 (HPV) 相关癌症的易感性比杂合子高约七倍。此后，北欧、日本和美国的几项研究未能证明类似的相关性。相比之下，巴西的一项研究以及最近对意大利和瑞典人群的一项研究显示出强烈的正相关性。我们检查了侵袭性宫颈肿瘤和上皮内宫颈肿瘤 (CIN) 样本中 p53 密码子 72 多态性的频率，并将其与健康对照样本进行了比较。所有 88 个样本均来自具有希腊种族背景的女性。组织标本是从组织学诊断为低级别 CIN (LGCIN)、高级别 CIN (HGCIN) 或宫颈癌 (CxCa) 的档案材料中采集的。作为对照，我们使用细胞刷从 30 名细胞学和阴道镜检查正常的健康女性的宫颈中新收集的细胞材料。 p53 Arg 纯合性 (Arg/Arg) 单独与 LGCIN、HGCIN 或侵袭性癌症的风险增加四倍、六倍或八倍相关。 p53Arg/Arg 基因型和脯氨酸 (Pro) 等位基因的频率根据病变的严重程度显示出显着的线性趋势（分别为 P = 0.0007 和 P = 0.0009）。排除 10 例 HPV16/18 阴性病例并没有显着改变各组之间的 Arg/Arg 频率，也没有显着的线性趋势。我们的结果证实了斯托里和同事的初步发现，以及巴西和最近欧洲研究的数据，但与上述其他研究的数据不一致。种族背景、实验室表现、HPV 状态验证、对照定义和样本量的差异是这一争议最合理的解释。在我们所有的样本中，p53 等位基因的分布符合 Hardy-Weinberg 平衡，并且我们对照中 Pro 等位基因的 0.48 频率与之前报告的不同种族群体的百分比非常一致，作为假定的南北谱系的特征。一些作者声称，结果的差异不能归因于方法的差异；然而，巴西的研究强调了实验室间差异在检测 p53 多态性与宫颈癌之间的关联方面的影响。至于对照组，我们的样本仅来自女性，其细胞学和阴道镜检查均为良性宫颈上皮。我们认为，在不了解宫颈上皮状况的情况下，简单地选择“正常志愿者”来采集对照 DNA 血液样本，确实可能会产生偏差。最后，p53 基因座杂合性的丧失不太可能成为干扰等位基因型分布的因素。我们目前的小型研究结果表明了生物学相关的关联，提供了强有力的证据，证明 p53 密码子 72 处的纯合精氨酸可能赋予 HPV 相关的上皮内和浸润性宫颈肿瘤更高的易感性。 (C) 2000 Lippincott Williams & Wilkins。
In 1998, Storey and co-workers suggested that individuals homozygous for arginine (Arg) at codon 72 of the p53 gene are about seven times more susceptible to human papillomavirus (HPV)-related carcinogenesis than heterozygotes. Since then, several studies from Northern Europe, Japan and the USA have failed to demonstrate a similar correlation. By contrast, a study in Brazil as well as one recent study in Italian and Swedish populations showed strong positive associations. We examined the frequency of p53 codon 72 polymorphism in samples from both invasive and intra-epithelial cervical neoplasias (CIN), and compared them with samples from healthy controls. All 88 samples came from women with a Greek ethnic background. Tissue specimens were collected from archival material with histologically diagnosed low-grade CIN (LGCIN), high-grade CIN (HGCIN) or cervical cancer (CxCa). As a control, we used cellular material newly collected by cytobrush from the cervices of 30 healthy women with normal cytological and colposcopical examinations. p53 Arg homozygosity (Arg/Arg) alone was associated with four-, six- or eight-fold increased risks for LGCIN, HGCIN or invasive cancer, respectively. The frequency of the p53Arg/Arg genotype and of the proline (Pro) allele showed significant linear trends according to the degree of severity of the lesion (P = 0.0007 and P = 0.0009, respectively). Exclusion of the ten HPV16/18-negative cases did not substantially alter the Arg/Arg frequency among the groups nor the significant linear trend. Our results confirm the initial findings of Storey and co-workers, as well as the data of the Brazilian and the recent European study, but do not accord with those of the other aforementioned studies. Variations in ethnic background, laboratory performance, verification of the HPV status, definition of controls, and sample size are the most plausible explanations for this controversy. In all our samples, the distribution of the p53 alleles fits the Hardy-Weinberg equilibrium and the 0.48 frequency of the Pro allele in our controls accords well with the percentages previously reported for different ethnic groups as characteristic of the assumed north-south cline. Some authors assert that the discrepancy in the results could not be attributed to differences in the methods; however, the Brazilian study emphasized the effect of inter-laboratory variation in detecting the association between p53 polymorphism and cervical cancer. Regarding the control group, our samples were only from women,vith a cytologically and colposcopically benign cervical epithelium. We think that simply choosing 'normal volunteers' for collecting control DNA blood samples without knowing the status of their cervical epithelium is indeed a possible source of bias. Finally, it is very unlikely that loss of heterozygosity at the p53 locus could be a factor interfering with the allelotype distribution. Our present small study results, which suggest a biologically relevant association, provide strong evidence that homozygous arginine at codon 72 of p53 may confer a higher susceptibility to HPV-associated intra-epithelial and invasive cervical neoplasia. (C) 2000 Lippincott Williams & Wilkins.