Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation
Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation
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DOI：
10.1200/jco.2004.02.154
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发表时间：
2004-11-15
影响因子：
45.3
通讯作者：
Matsubara, N
中科院分区：
文献类型：
--
作者：
Nagasaka, T;Sasamoto, H;Matsubara, N
目的BRAF突变在散发性结直肠癌（CRC）中很常见，其DNA不匹配修复（MMR）缺乏症，这是由于HMLH1的启动子甲基化引起的，而KRAS突变在MMR熟练的CRC中很常见，与MGMT的启动子甲基化相关。这项研究的目的是进一步研究RAS/RAF/ERK途径中的遗传改变与潜在的表观遗传障碍之间的联系。鉴定了BRAF和KRAS突变的患者和方法与包括11个基因座的启动子甲基化（包括MINT11）相关，并相关，mint2，mint31，cacnaig，p16（ink4a），p14（arf），cox2，dapk MGMT和HMLH1中的两个区域在468个CRC中并匹配正常的粘膜。反应BRAF V599E突变在234个CRC中的21个（9％）中鉴定出来，在234个CRC的72（31％）中鉴定出KRAS突变。在同一肿瘤中从未发现过BRAF和KRAS中的突变。具有BRAF突变的CRC在多个基因座中显示出高级启动子甲基化，在11个基因座中，平均数量的甲基化基因座为7.2（95％Cl，6.6至7.9）（p <.0001）。具有KRAS突变的肿瘤显示出低水平的启动子甲基化，而没有突变的CRC均表现出与启动子甲基化的较弱相关性，平均甲基化基因座数量为1.8（95％Cl，1.5至2.1）和1.0（95％CL，0.79到1.3），分别是CRC的判断，可以通过了解BRAF的知识来预测多个启动子的甲基化状态，并且在较小程度上是KRAS激活突变，表明这些突变与不同的DNA高甲基化模式密切相关。这些变化可能是结直肠肿瘤发生的重要事件。 （c）2004年美国临床肿瘤学会。
Purpose BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1, whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder.Patients and Methods Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNAIG, p16(INK4a), p14(ARF), COX2, DAPK MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa.Results BRAF V599E mutations were identified in 21 (9%) of 234 CRCs, and KRAS mutations were identified in 72 (31%) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95% Cl, 6.6 to 7.9) among 11 loci examined (P < .0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95% Cl, 1.5 to 2.1) and 1.0 (95% Cl, 0.79 to 1.3), respectively.Conclusion In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis. (C) 2004 by American Society of Clinical Oncology.