Microsatellite instability, MLH1 promoter methylation, and BRAF mutation analysis in sporadic colorectal cancers of different ethnic groups in Israel.
Microsatellite instability, MLH1 promoter methylation, and BRAF mutation analysis in sporadic colorectal cancers of different ethnic groups in Israel.
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DOI：
10.1002/cncr.24019
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发表时间：
2009-02-15
期刊：
影响因子：
6.2
通讯作者：
Boland, C. Richard
中科院分区：
文献类型：
--
作者：
Vilkin, Alex;Niv, Yaron;Nagasaka, Takeshi;Morgenstern, Sarah;Levi, Zohar;Fireman, Zvi;Fuerst, Florentine;Goel, Ajay;Boland, C. Richard
结直肠癌（CRC）的分子机制包括微卫星不稳定性（MSI）、染色体不稳定性和CpG岛甲基化表型。有证据表明，CRC的发病率在全球不同种族人群中存在差异。该报告的作者假设，不同种族群体之间的环境因素和生活方式差异可能会对CRC中肿瘤抑制基因的表观遗传调控产生不同的影响。在目前的研究中，对来自以色列患者（85名犹太人和43名阿拉伯人）的128份CRC样本进行了显微切割和DNA提取。MSI分析、mutL homolog 1（MLH 1）和mutS homolog 2（MSH 2）蛋白表达水平以及MLH 1启动子甲基化通过联合亚硫酸氢盐限制性分析进行研究。通过直接DNA测序研究了v-raf小鼠肉瘤病毒癌基因同源物B1（BRAF）第600位残基的缬氨酸至谷氨酸突变。高MSI（MSI-H）、MLH 1甲基化和BRAF突变分别见于11.6%、9.4%和23.5%的犹太人和16.2%、17.6%和20.9%的阿拉伯人（P值无显著性）。在22.6%的微卫星稳定（MSS）肿瘤和53.8%的MSI-H肿瘤中观察到MLH 1启动子甲基化（P <0.015）。在所有MSI-H肿瘤中均存在广泛的甲基化（覆盖5′和3′启动子区域），MLH 1表达缺失。BRAF突变在MSS肿瘤和MSI-H肿瘤中分别为15.6%和46.1%（P <0.007）。BRAF突变分别见于66%、22.2%和14.7%的MLH 1启动子广泛甲基化、仅5′区甲基化或无甲基化的肿瘤患者（P <0.006）。在以色列，犹太人和阿拉伯人CRC患者的分子特征没有差异。广泛的启动子甲基化与MLH 1失活、MSI和BRAF突变相关。
The molecular mechanisms that underlie colorectal cancer (CRC) include microsatellite instability (MSI), chromosomal instability, and the CpG island methylator phenotype. There is evidence to suggest that CRC incidence varies among different ethnic populations worldwide. The authors of this report hypothesized that environmental factors and lifestyle differences among various ethnic groups may differentially influence the epigenetic regulation of tumor suppressor genes in CRC. In the current study, microdissection and DNA extraction were performed on 128 samples of CRC from Israeli patients (85 Jews and 43 Arabs). MSI analysis, mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) protein expression levels, and MLH1 promoter methylation were investigated by combined bisulfite restriction analysis. The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) valine-to-glutamic acid mutation at residue 600 was investigated by direct DNA sequencing. High MSI (MSI-H), MLH1 methylation, and BRAF mutations were observed in 11.6%, 9.4%, and 23.5% of Jews, respectively, and in 16.2%, 17.6%, and 20.9% of Arabs, respectively (P value nonsignificant). MLH1 promoter methylation was observed in 22.6% of microsatellite-stable (MSS) tumors and in 53.8% of MSI-H tumors (P < .015). Extensive methylation (covering both 5′ and 3′ promoter regions) was present in all MSI-H tumors with loss of MLH1 expression. BRAF mutation was observed in 15.6% and 46.1% of MSS tumors and MSI-H tumors, respectively (P < .007). BRAF mutation was observed in 66%, 22.2%, and 14.7% of patients who had tumors with extensive MLH1 promoter methylation, methylation of the 5′ region alone, or without methylation, respectively (P < .006). There was no difference in molecular signatures examined between Jewish and Arab patients with CRC in Israel. Extensive promoter methylation was associated with MLH1 inactivation, MSI, and BRAF mutation.
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影响因子：
64.8
作者：
Rajagopalan, H;Bardelli, A;Velculescu, VE
通讯作者：
Velculescu, VE
影响因子：
6.4
作者：
Koinuma, K;Shitoh, K;Mano, H
通讯作者：
Mano, H
影响因子：
30.8
作者：
Weisenberger, Daniel J.;D Siegmund, Kimberly;Laird, Peter W.
通讯作者：
Laird, Peter W.
DOI：
10.1073/pnas.97.2.710
发表时间：
2000-01-18
影响因子：
11.1
作者：
Toyota, M;Ohe-Toyota, M;Issa, JPJ
通讯作者：
Issa, JPJ
影响因子：
45.3
作者：
Nagasaka, T;Sasamoto, H;Matsubara, N
通讯作者：
Matsubara, N