Profiling CpG island field methylation in both morphologically normal and neoplastic human colonic mucosa
Profiling CpG island field methylation in both morphologically normal and neoplastic human colonic mucosa
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DOI：
10.1038/sj.bjc.6604432
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发表时间：
2008-07-08
影响因子：
8.8
通讯作者：
Johnson, I. T.
中科院分区：
文献类型：
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作者：
Belshaw, N. J.;Elliott, G. O.;Johnson, I. T.
异常CpG岛（CGI）甲基化发生在结直肠肿瘤的早期。应用于活检的定量甲基化特异性PCR分析用于量化无瘤受试者、腺瘤性息肉患者、癌症患者及其肿瘤的形态正常结肠粘膜中18个基因的低水平CGI甲基化。多变量统计分析区分肿瘤和粘膜的敏感性为78.9%，特异性为100%（P=3 × 10 - 7）。在形态正常的粘膜中，观察到APC、AXIN 2、DKK 1、HPP 1、N33、p16、SFRP 1、SFRP 2和SFRP 4基因的年龄依赖性CGI甲基化，并且检测到组间CGI甲基化水平的显著差异。基于正常粘膜CGI甲基化谱的多项逻辑回归模型正确识别了78.9%的癌症患者和87.9%的非癌症（无瘤+息肉）患者（P=4.93 x 10（-7）），使用APC，HPP 1，p16，SFRP 4，WIF 1和ESR 1甲基化作为最具信息量的变量。同样，SFRP 4、SFRP 5和WIF 1的CGI甲基化正确识别了61.5%的息肉患者和78.9%的无肿瘤受试者（P=0.0167）。表现为瘤形成的患者的表面上正常的粘膜区域明显经历了显著的表观遗传修饰。由模型选择的基因的甲基化可能在结直肠肿瘤形成的最早阶段发挥作用。
Aberrant CpG island (CGI) methylation occurs early in colorectal neoplasia. Quantitative methylation-specific PCR profiling applied to biopsies was used to quantify low levels of CGI methylation of 18 genes in the morphologically normal colonic mucosa of neoplasia-free subjects, adenomatous polyp patients, cancer patients and their tumours. Multivariate statistical analyses distinguished tumour from mucosa with a sensitivity of 78.9% and a specificity of 100% (P=3 x 10(-7)). In morphologically normal mucosa, age-dependent CGI methylation was observed for APC, AXIN2, DKK1, HPP1, N33, p16, SFRP1, SFRP2 and SFRP4 genes, and significant differences in CGI methylation levels were detected between groups. Multinomial logistic regression models based on the CGI methylation profiles from normal mucosa correctly identified 78.9% of cancer patients and 87.9% of non-cancer (neoplasia-free+polyp) patients (P=4.93 x 10(-7)) using APC, HPP1, p16, SFRP4, WIF1 and ESR1 methylation as the most informative variables. Similarly, CGI methylation of SFRP4, SFRP5 and WIF1 correctly identified 61.5% of polyp patients and 78.9% of neoplasia-free subjects (P=0.0167). The apparently normal mucosal field of patients presenting with neoplasia has evidently undergone significant epigenetic modification. Methylation of the genes selected by the models may play a role in the earliest stages of the development of colorectal neoplasia.