Molecular analysis of DNA mismatch repair gene on human malignant lymphoma occurring in maxillo-facial and oral region

人颌面部恶性淋巴瘤DNA错配修复基因的分子分析

• 批准号: 11671795
• 负责人: ICHINOHASAMA Ryo
• 金额: $ 2.18万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671795/
• 关键词: hMSH2; knock our mouse; TGFβR-II gene; BAX gene; mutation

Microsatellite instability has been reported in human lymphomas of follicular center cell origin suggesting that deficient DNA mismatch repair may play a role in the development of these tumors. However, a link between loss of MMR gene expression and abnormalities in tumor suppressor genes targeted by deficient MMR gene function has not been established in follicular lymphoma (FL). We evaluated 22 human t(14;18) chromosomal translocation positive FL cases for abnormalities in hMSH2 and hMLH1 expression and insertion/deletion (ID) mutations within the coding region nucleotide repeats of the BAX and TGF-b receptor type two (TbR-II) genes. Loss of hMSH2 or hMLH1 protein expression within the malignant follicles was identified in 6 of 22 (27%) FL cases by immunohistochemistry (IHC). Sequencing of the entire coding regions of hMSH2 and hMLH1 identified mutations in 2 of 2 FL cases that showed loss of hMSH2 protein expression and in 1 of 4 FL cases that showed loss of hMLH1 protein expressio … More n. There were no mutations in either hMSH2 or hMLH1 in six control FL cases that showed normal expression of these proteins. All six FL cases showing loss of hMSH2 or hMLH1 protein expression were evaluated for ID mutations within the BAX and TRb-II repeats using high fidelity PCR amplification over the repeat areas followed by blunt end cloning and sequencing. ID mutations within the BAX (G)8 and /or TbR-II (A)10 repeats were identified in five of these FL cases whereas all six control FL cases with normal hMSH2 and hMLH1 protein expression lacked ID mutations. Assessment of BAX protein expression by IHC showed absent or markedly diminished expression in 4 of 6 (67%) FL cases that had evidence of deficient MMR gene function, including both FL cases with BAX ID mutations. In contrast, only 3 of 16 (19%) FL cases that lacked evidence of deficient MMR gene function showed absent or diminished expression of BAX protein. These findings implicate deficient MMR gene function in the pathogenesis of human FL and suggest that IHC screening for hMSH2 and hMLH1 protein expression may represent an efficient method to identify FL cases that arise via this pathway. Less

据报道，在人类滤泡中心细胞起源的淋巴瘤中存在微卫星不稳定性，这表明DNA错配修复缺陷可能在这些肿瘤的发展中起作用。然而，在滤泡性淋巴瘤（FL）中，MMR基因表达缺失与MMR基因功能缺陷所靶向的肿瘤抑制基因异常之间的联系尚未建立。我们评估了22例人类t（14;18）染色体易位阳性FL病例的hMSH 2和hMLH 1表达异常以及BAX和TGF-b受体2型（TbR-II）基因编码区核苷酸重复序列内的插入/缺失（ID）突变。免疫组化结果显示，22例FL中6例（27%）的恶性滤泡内hMSH 2或hMLH 1蛋白表达缺失。对hMSH 2和hMLH 1的整个编码区进行测序，在2例显示hMSH 2蛋白表达缺失的FL病例中发现了2例突变，在4例显示hMLH 1蛋白表达缺失的FL病例中发现了1例突变。 ...更多信息 n.有没有突变，无论是在hMSH 2或hMLH 1在6个控制FL的情况下，显示这些蛋白质的正常表达。使用高保真PCR扩增重复区域，然后进行平端克隆和测序，评价所有6例显示hMSH 2或hMLH 1蛋白表达缺失的FL病例的BAX和TRb-II重复内的ID突变。在这些FL病例中的5例中鉴定了BAX（G）8和/或TbR-II（A）10重复内的ID突变，而所有6例具有正常hMSH 2和hMLH 1蛋白表达的对照FL病例均缺乏ID突变。通过IHC评估BAX蛋白表达显示，6例（67%）FL病例中有4例（67%）MMR基因功能缺陷的证据，包括2例BAX ID突变的FL病例，其表达缺失或明显减少。与此相反，只有3 16例（19%）FL的情况下，缺乏证据的缺陷MMR基因功能表现出缺乏或减少BAX蛋白的表达。这些研究结果表明，在人类FL的发病机制缺乏MMR基因的功能，并建议免疫组化筛选hMSH 2和hMLH 1蛋白的表达可能是一种有效的方法来确定FL的情况下，通过这一途径出现。少

项目成果

Lowsky R, Magliocco A, Ichinohasama R, et al.: "MSH2-deficient murine lymphomas harbor insertion/deletion mutations in the transforming growth factor beta receptor type 2 gene and display low not high frequency microsatellite instability"Blood. 95巻5号. 176

Lowsky R、Magliocco A、Ichinohasama R 等人：“MSH2 缺陷型小鼠淋巴瘤在转化生长因子 β 受体 2 型基因中存在插入/缺失突变，并表现出低频率而非高频率的微卫星不稳定性”，《血液》第 95 卷。 . 5. 176

Lowsky R, Magliocco A, Rvo Ichinohasama et al.: "MSH2 deficient murine lymphoma harbor insertion/deletion mutations in the transforming growth factor beta receptor type II gene and display low not high microsatellite instability"Blood. 95 (5). 1767-1772 (

Lowsky R、Magliocco A、Rvo Ichinohasama 等人：“MSH2 缺陷型小鼠淋巴瘤在转化生长因子 β 受体 II 型基因中存在插入/缺失突变，并表现出低而不是高的微卫星不稳定性”血液。

Lowsky R,Magliocco A,Ichinohasama R, et al.: "MSH2-deficient murine lymphomas harbor insertion/deletion mutations in the transforming growth factor beta receptor type 2 gene and display low not high frequency microsatellite instability."Blood. 95巻5号. 1767

Lowsky R、Magliocco A、Ichinohasama R 等人：“MSH2 缺陷型小鼠淋巴瘤在转化生长因子 β 受体 2 型基因中存在插入/缺失突变，并表现出低频率而不是高频率的微卫星不稳定。” 1767 年 5 号

Lowsky R.,Magliocco A.,Ichinohasama R.et al.: "MSH2-deficient murine lymphomas harbor insertion/deletion mutations in the transforming growth factor beta receptor type 2 gene and display low not high frequency microsatellite instability"Blood. 95巻5号. 1767

Lowsky R.、Magliocco A.、Ichinohasama R. 等人：“MSH2 缺陷型鼠淋巴瘤在转化生长因子 β 受体 2 型基因中存在插入/缺失突变，并表现出低频率而非高频率的微卫星不稳定性”，《Blood》第 95 卷。 、5号1767号