Genome Science Division, Research Center for Advanced Science and Technology (RCAST), Graduate School of Medicine, The University of Tokyo, Toyko, Japan.
Am J Pathol. 2012 Feb;180(2):616-25. doi: 10.1016/j.ajpath.2011.10.010. Epub 2011 Nov 21.
A subset of colorectal cancer shows significant accumulation of aberrant promoter methylation. Previously, we developed two groups of methylation markers that classified colorectal cancer into three epigenotypes: i) high-, ii) intermediate-, and iii) low-methylation epigenotypes. High-methylation epigenotype, with methylation of both group 1 and group 2 markers, correlates to BRAF-mutation((+)). Intermediate-methylation epigenotype, with methylation of group 2 markers, but not group 1, correlates to KRAS-mutation((+)). To gain insight into epigenotype development in colorectal carcinogenesis, especially intermediate-methylation epigenotype and its correlation to KRAS-mutation((+)) in adenoma, we analyzed methylation levels of group 1 and group 2 markers quantitatively by matrix assisted laser desorption ionization-time of flight mass spectrometry, in 51 adenomas, 13 aberrant crypt foci, and 26 normal mucosa samples, and we compared them to 149 previously analyzed colorectal cancer samples. Three serrated adenomas were all BRAF-mutation((+)), showing great methylation of group 1 and group 2 markers, thus high-methylation epigenotype. Forty-eight conventional adenomas were not methylated in group 1 markers and were classified into two clusters with higher and lower methylation of group 2 markers, thus into intermediate- and low-methylation epigenotypes, respectively. Adenoma with intermediate-methylation epigenotype correlated to KRAS-mutation((+)). Methylation levels of group 2 markers in adenoma were higher than aberrant crypt foci and normal samples, but similar to cancer. These data suggested that epigenotype development occur at an earlier stage than carcinoma formation, and already be completed at the adenoma stage. Intermediate methylation epigenotype and its correlation to KRAS-mutation((+)) were developed in conventional adenoma.
结直肠癌的一个亚组表现出明显的异常启动子甲基化积累。此前，我们开发了两组甲基化标记物，将结直肠癌分为三种表观遗传型：i）高甲基化、ii）中甲基化和 iii）低甲基化。高甲基化表观遗传型，同时甲基化组 1 和组 2 标记物，与 BRAF 突变(+)相关。中甲基化表观遗传型，仅甲基化组 2 标记物，与 KRAS 突变(+)相关。为了深入了解结直肠癌变中的表观遗传型发展，特别是中甲基化表观遗传型及其与腺瘤中 KRAS 突变(+)的相关性，我们通过基质辅助激光解吸电离飞行时间质谱定量分析了 51 个腺瘤、13 个异常隐窝病灶和 26 个正常黏膜样本中组 1 和组 2 标记物的甲基化水平，并将其与 149 个先前分析的结直肠癌样本进行了比较。三个锯齿状腺瘤均为 BRAF 突变(+)，组 1 和组 2 标记物高度甲基化，因此为高甲基化表观遗传型。48 个传统腺瘤中组 1 标记物未甲基化，分为两组，组 2 标记物的甲基化水平较高和较低，因此分别为中甲基化和低甲基化表观遗传型。具有中甲基化表观遗传型的腺瘤与 KRAS 突变(+)相关。腺瘤中组 2 标记物的甲基化水平高于异常隐窝病灶和正常样本，但与癌症相似。这些数据表明，表观遗传型的发展发生在癌前形成的早期阶段，并且已经在腺瘤阶段完成。中甲基化表观遗传型及其与 KRAS 突变(+)的相关性是在传统腺瘤中发展起来的。
