Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers
Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers
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DOI：
10.1093/jnci/92.11.924
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发表时间：
2000-06-07
影响因子：
10.3
通讯作者：
Eng, C
中科院分区：
文献类型：
--
作者：
Mutter, GL;Lin, MC;Eng, C
背景：PTEN抑癌基因突变是子宫内膜腺癌中最常见的遗传性病变。然而，检验PTEN功能改变先于子宫内膜腺癌出现的假设一直很困难，部分原因是癌前诊断的不确定性。研究方法：两个系列的子宫内膜癌和癌前病变（子宫内膜上皮内瘤变，通过计算机形态分析诊断）组织样本进行了研究，一个通过使用变性梯度凝胶电泳和另一个通过免疫组化的PTEN蛋白表达的PTEN突变。子宫内膜改变高雌激素水平，不反对孕激素-条件已知增加癌症的风险-也进行了研究，免疫组化，费舍尔的精确检验用于统计分析。结果如下：PTEN基因突变率为83%（25/30）在子宫内膜样腺癌和55%（16/29），突变数量的差异具有统计学意义（双侧P = .025），没有正常的人显示PTEN突变，尽管大多数癌前病变和癌症仅在一个PTEN等位基因中具有突变，61%（20/33）的子宫内膜样腺癌中PTEN蛋白表达完全缺失，97%（32/33）的病例中至少有一些表达减少。癌症和大多数癌前病变表现出连续的PTEN阴性腺体组，而由非对抗性雌激素改变的卵巢癌显示出孤立的PTEN阴性腺体。结论：突变或其他机制导致的PTEN功能丧失是子宫内膜肿瘤发生的早期事件，可能与已知的内分泌风险因素有关，并为癌前病变提供了信息丰富的免疫组织化学生物标志物。雌激素暴露的子宫内膜中单个PTEN阴性腺体是子宫内膜癌发生的最早可识别阶段，随后增殖成密集簇，形成离散的癌前病变。
Background: PTEN tumor suppressor gene mutations are the most frequent genetic lesions in endometrial adenocarcinomas of the endometrioid subtype. Testing the hypothesis that altered PTEN function precedes the appearance of endometrial adenocarcinoma has been difficult, however, partly because of uncertainties in precancer diagnosis. Methods: Two series of endometrial cancer and precancer (endometrial intraepithelial neoplasia, as diagnosed by computerized morphometric analysis) tissue samples were studied, one for PTEN mutations by the use of denaturing gradient gel electrophoresis and another for PTEN protein expression by immunohistochemistry. Endometria altered by high estrogen levels that are unopposed by progestins-conditions known to increase cancer risk-were also studied by immunohistochemistry, Fisher's exact test was used for statistical analysis. Results: The PTEN mutation rate was 83% (25 of 30) in endometrioid endometrial adenocarcinomas and 55% (16 of 29) in precancers, and the difference in number of mutations was statistically significant (two-sided P = .025), No normal endometria showed PTEN mutations, Although most precancers and cancers had a mutation in only one PTEN allele, endometrioid endometrial adenocarcinomas showed complete loss of PTEN protein expression in 61% (20 of 33) of cases, and 97% (32 of 33) showed at least some diminution in expression. Cancers and most precancers exhibited contiguous groups of PTEN-negative glands, while endometria altered by unopposed estrogens showed isolated PTEN-negative glands. Conclusions: Loss of PTEN function by mutational or other mechanisms is an early event in endometrial tumorigenesis that may occur in response to known endocrine risk factors and offers an informative immunohistochemical biomarker for premalignant disease, Individual PTEN-negative glands in estrogen-exposed endometria are the earliest recognizable stage of endometrial carcinogenesis, Proliferation into dense clusters that form discrete premalignant lesions follows.