Microsatellite instability, MLH1 promoter methylation, and loss of mismatch repair in endometrial cancer and concomitant atypical hyperplasia
Microsatellite instability, MLH1 promoter methylation, and loss of mismatch repair in endometrial cancer and concomitant atypical hyperplasia
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DOI：
10.1006/gyno.2002.6724
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发表时间：
2002-07-01
影响因子：
4.7
通讯作者：
Goodfellow, PJ
中科院分区：
文献类型：
--
作者：
Horowitz, N;Pinto, K;Goodfellow, PJ
目标。MLH1甲基化与子宫内膜癌和非典型子宫内膜增生（癌前前兆）的微卫星不稳定性（MSI）表型相关。甲基化也见于无MSI的非典型子宫内膜增生，这表明甲基化是子宫内膜肿瘤发生的早期事件。我们的目的是确定甲基化是否总是存在于msi阳性非典型增生伴msi阳性，甲基化阳性癌。我们使用激光捕获显微解剖来研究MLH1甲基化和MSI在大量子宫内膜癌病例中的作用，这些病例先前已被证明具有甲基化和MSI-高（MSI- h）表型。我们对27例伴有非典型子宫内膜增生的51例患者的癌灶进行了重新取样。与先前的报道一致，我们在未显示MSI的非典型子宫内膜增生区域发现MLH1甲基化。此外，我们注意到18%的MSI-H非典型子宫内膜增生dna在MLH1启动子中缺乏关键胞嘧啶的甲基化。免疫组织化学研究表明，这些非典型子宫内膜增生的MSI-H未甲基化灶不能表达MLH1，单纯性增生区域也是如此。MLH1启动子的甲基化是子宫内膜肿瘤发生的早期事件。鉴于并非所有msi阳性组织都在胞嘧啶-229和-231位点发生甲基化，看来MLH1沉默和错配修复缺失可能不需要甲基化。(C) 2002 Elsevier Science （USA）。
Objective. MLH1 methylation is associated with the microsatellite instability (MSI) phenotype in endometrial cancer and atypical endometrial hyperplasia, a premalignant precursor to carcinoma. The observation that methylation is also seen in atypical endometrial hyperplasia without MSI suggests that methylation is an early event in endometrial tumorigenesis. Our objective was to determine if methylation is always present in MSI-positive atypical hyperplasia concomitant with MSI-positive, methylation-positive carcinoma.Methods. We used laser capture microdissection to study MLH1 methylation and MSI in a large series of endometrial cancer cases that had previously been shown to have methylation and the MSI-high (MSI-H) phenotype. We resampled areas of carcinoma from 27 patients along with 51 foci of concomitant atypical endometrial hyperplasia.Results. Consistent with previous reports, we saw MLH1 methylation in areas of atypical endometrial hyperplasia that did not show MSI. In addition, we noted that 18% of the MSI-H atypical endometrial hyperplasia DNAs lacked methylation of critical cytosines in the MLH1 promoter. Immunohistochemistry studies showed that these MSI-H unmethylated foci of atypical endometrial hyperplasia failed to express MLH1, as did regions of simple hyperplasia.Conclusion. Methylation of the MLH1 promoter is an early event in endometrial tumorigenesis. Given that not all MSI-positive tissues had methylation at cytosines -229 and -231, it appears that methylation may not be required for MLH1 silencing and loss of mismatch repair. (C) 2002 Elsevier Science (USA).