Mutations of the BRAF gene in ulcerative colitis-related colorectal carcinoma
Mutations of the BRAF gene in ulcerative colitis-related colorectal carcinoma
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DOI：
10.1002/ijc.20925
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发表时间：
2005-07-10
影响因子：
6.4
通讯作者：
Tannapfel, A
中科院分区：
文献类型：
--
作者：
Aust, DE;Haase, M;Tannapfel, A
Raf/MEK/ERK （MAPK）信号转导级联是包括生长、增殖和存活在内的许多细胞命运的重要介质。BRAF基因被致癌Ras激活，导致细胞响应生长因子信号的协同效应。我们的研究旨在阐明BRAF在溃疡性结肠炎（UC）相关结直肠癌发生中的可能功能。在33例uc相关结直肠癌中，通过显微解剖后的直接DNA测序分析，确定了BRAF和KRAS突变。通过免疫组织化学检测主要错配修复蛋白hMLH1、hMSH2和hMSH6，以及BAT25和BAT26位点的微卫星分析，评估错配修复缺陷。还检测了hMLH1启动子的超甲基化。所得结果与组织病理变量相关。激活BRAF错义突变在3/33（9%）的uc相关癌症中被发现，其中2例表现出hMLH1蛋白表达缺失和hMLH1启动子的高甲基化。这些患者相应的非发育不良uc -粘膜未显示BRAF突变。在6/33（18%）的UC癌症中发现了KRAS突变。所有6例发生KRAS突变的UC癌症都有一个完整的BRAF基因，因为3例发生BRAF突变的癌症都有一个完整的KRAS基因。BRAF或KRAS状态与临床病理变量无显著相关性。我们的数据表明，BRAF突变不是uc相关癌变的起始事件，而是通过hmlh1启动子超甲基化与错配修复缺陷相关。在27%的uc相关癌症中检测到Raf/MEK/ERK （MAPK）激酶通路的破坏（通过RAS或BRAF突变），因此在uc相关癌变中起重要作用。©2005 Wiley-Liss, Inc
The Raf/MEK/ERK (MAPK) signal transduction cascade is an important mediator of a number of cellular fates including growth, proliferation and survival. The BRAF gene is activated by oncogenic Ras, leading to cooperative effects in cells responding to growth factor signals. Our study was performed to elucidate a possible function of BRAF in ulcerative colitis (UC)-related colorectal carcinogenesis. Mutations of BRAF and KRAS were determined in 33 UC-related colorectal cancers by direct DNA sequencing analyses after microdissection. Mismatch-repair deficiency, was assessed by immunohistochemistry for major mismatch-repair proteins hMLH1, hMSH2 and hMSH6 and microsatellite analyses of the BAT25 and BAT26 loci. Hypermethylation of the hMLH1 promoter was also tested. The results obtained were correlated with histopathologic variables. Activating BRAF missense mutations were identified in 3/33 UC-related cancers (9%), 2 of which exhibited a loss of hMLH1-protein expression and hypermethylation of the hMLH1 promoter. Corresponding nondysplastic UC-mucosa of these patients did not show BRAF mutations. KRAS mutations were found in 6/33 (18%) UC cancers. All 6 UC cancers with KRAS mutations had an intact BRAF gene as the 3 cancers with BRAF mutations had an intact KRAS gene. There was no significant correlation between BRAF or KRAS status and clinicopathologic variables. Our data indicate that BRAF mutations are not an initiating event in UC-related carcinogenesis and are associated with mismatch-repair deficiency through hMLH1-promoter hypermethylation. Disruption of the Raf/MEK/ERK (MAPK) kinase pathway-either through RAS or BRAF mutation-was detected in 27% of all UC-related cancers and thus plays an important role in UC-related carcinogenesis. © 2005 Wiley-Liss, Inc.