Microsatellite instability and expression of MLH1 and MSH2 in normal and malignant endometrial and ovarian epithelium in hereditary nonpolyposis colorectal cancer family members
Microsatellite instability and expression of MLH1 and MSH2 in normal and malignant endometrial and ovarian epithelium in hereditary nonpolyposis colorectal cancer family members
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DOI：
10.1016/s0165-4608(98)00252-0
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发表时间：
1999-07-01
影响因子：
--
通讯作者：
Lynch, HT
中科院分区：
文献类型：
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作者：
Ichikawa, Y;Lemon, SJ;Lynch, HT
错配修复缺陷是遗传性非息肉病性结直肠癌 (HNPCC) 的一个特征性分子发现，并且已在结直肠癌和良性腺瘤中得到证实。子宫内膜癌和卵巢癌是该综合征中常见的结肠外肿瘤；然而，很少有研究调查 HNPCC 家族成员的组织学正常子宫内膜和卵巢上皮是否发生遗传变化。如果存在早期基因变化，它们可能会被用作分子标记来检测子宫内膜癌和卵巢癌的易感性。在本研究中，我们分析了 20 个组织学正常上皮细胞（12 个子宫内膜和 8 个卵巢）和 8 个癌症（4 个子宫内膜和 4 个卵巢）中的微卫星不稳定性 (MSI) 以及 MLH1 和 MSH2 免疫组织化学表达，这些上皮细胞取自代表 7 个不相关的 HNPCC 家族的 20 个人。虽然在子宫内膜癌 (75%) 和卵巢癌 (100%) 中观察到 MSI，但没有确定在组织学正常的子宫内膜或卵巢上皮细胞中表现出 MSI。同样，在 MLH1 和 MSH2 的免疫组织化学表达中，组织学正常的上皮没有导致恶性肿瘤的遗传变化。在癌症病例中，MLH1 和 MSH2 的表达、hMLH1 和 hMSH2 基因种系突变的存在以及肿瘤 MSI 的存在之间存在相关性。这些数据表明，MSI、MLH1 和 MSH2 表达对于未患癌症的 HNPCC 种系突变携带者的子宫内膜和卵巢恶性肿瘤的早期检测并不是有用的生物标志物。需要对正常和癌前病变的其他遗传变化进行进一步研究。 (C) 1999 Elsevier Science, Inc. 保留所有权利。
Mismatch repair deficiency is a characteristic molecular finding in hereditary nonpolyposis colorectal cancer (HNPCC), and has been demonstrated in both colorectal cancers and benign adenomas. Endometrial and ovarian cancers are common extracolonic tumors in this syndrome; however, few studies have investigated whether genetic changes occur in histologically normal endometrial and ovarian epithelia from HNPCC family members. If early genetic changes exist, they might be used as molecular markers to detect susceptibility to endometrial and ovarian cancers. In this study, we analyzed microsatellite instability (MSI) and MLH1 and MSH2 immunohistochemical expression in 20 histologically normal epithelia (12 endometrial and 8 ovarian) and 8 cancers (4 endometrial and 4 ovarian) obtained from 20 individuals representing 7 unrelated HNPCC families. While MSI in as observed in endometrial (75%) and ovarian (100%) cancers, no case n as determined to exhibit MSI in histologically normal epithelia of the endometrium or ovary. Similarly, in immunohistochemical expressions for MLH1 and MSH2, histologically normal epithelia had no genetic changes predisposing to malignancy. In cancer cases, a correlation existed between the expression of MLH1 and MSH2, the presence of germline mutations in the hMLH1 and hMSH2 genes, and the presence of tumor MSI. These data suggest that MSI and MLH1 and MSH2 expression are not useful biomarkers for the early detection of endometrial and ovarian malignancy in cancer-unaffected HNPCC germline mutation carriers. Further studies of other genetic changes in normal and premalignant precursor lesions are needed. (C) 1999 Elsevier Science, Inc. All rights reserved.