MGMT methylation is associated primarily with the germline C > T SNP (rs16906252) in colorectal cancer and normal colonic mucosa
MGMT methylation is associated primarily with the germline C > T SNP (rs16906252) in colorectal cancer and normal colonic mucosa
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DOI：
10.1038/modpathol.2009.130
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发表时间：
2009-12-01
期刊：
影响因子：
7.5
通讯作者：
Hitchins, Megan P.
中科院分区：
文献类型：
--
作者：
Hawkins, Nicholas J.;Lee, James H-F;Hitchins, Megan P.
O-6-甲基鸟嘌呤 DNA 甲基转移酶 (MGMT) 是一种 DNA 修复蛋白，可将突变的 O-6-甲基鸟嘌呤恢复为鸟嘌呤。 MGMT 甲基化经常在散发性结直肠癌中观察到，最近与启动子转录增强子元件内 SNP rs16906252 处的 C > T 等位基因相关。 MGMT 甲基化也与 KRAS 突变有关，特别是 G > A 转变。我们研究了 1123 例结直肠癌，以确定与 MGMT 甲基化相关的分子和临床病理学特征。此外，我们通过使用SNP rs16906252研究MGMT甲基化的等位基因模式，以及选定肿瘤和匹配的正常结肠粘膜中10q26内邻近基因的甲基化状态，评估了结直肠癌发展中促成MGMT甲基化的因素。通过联合亚硫酸氢盐限制性分析在 28% 的肿瘤中检测到 MGMT 甲基化，该甲基化与许多特征相关，包括 CDKN2A 甲基化、缺乏淋巴管间隙侵袭和 KRAS 突变（但不特别与 KRAS G > A 转换相关）。在针对年龄和性别进行调整的多变量分析中，MGMT甲基化与SNP rs16906252（P T SNP）的T等位基因相关。我们表明，SNP rs16906252处的T等位基因是结直肠癌中MGMT甲基化发生的关键决定因素，而MGMT和CDKN2A甲基化的关联表明这些位点可能与 表观遗传失调的常见机制的目标。现代病理学(2009)22, 1588-1599; doi:10.1038/modpathol.2009.130； 2009 年 9 月 4 日在线发布
O-6-methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that restores mutagenic O-6-methylguanine to guanine. MGMT methylation is frequently observed in sporadic colorectal cancer and was recently correlated with the C > T allele at SNP rs16906252, within the transcriptional enhancer element of the promoter. MGMT methylation has also been associated with KRAS mutations, particularly G > A transitions. We studied 1123 colorectal carcinoma to define the molecular and clinicopathological profiles associated with MGMT methylation. Furthermore, we assessed factors contributing to MGMT methylation in the development of colorectal cancer by studying the allelic pattern of MGMT methylation using SNP rs16906252, and the methylation status of neighbouring genes within 10q26 in selected tumours and matched normal colonic mucosa. MGMT methylation was detected by combined bisulphite restriction analysis in 28% of tumours and was associated with a number of characteristics, including CDKN2A methylation, absent lymphovascular space invasion and KRAS mutations (but not specifically with KRAS G > A transitions). In a multivariate analysis adjusted for age and sex, MGMT methylation was associated with the T allele of SNP rs16906252 (P T SNP. We show that the T allele at SNP rs16906252 is a key determinant in the onset of MGMT methylation in colorectal cancer, whereas the association of methylation at MGMT and CDKN2A suggests that these loci may be targets of a common mechanism of epigenetic dysregulation. Modern Pathology (2009) 22, 1588-1599; doi:10.1038/modpathol.2009.130; published online 4 September 2009