Iacopetta Barry, Grieu Fabienne, Li Wei, Ruszkiewicz Andrew, Caruso Maria, Moore James, Watanabe Goh, Kawakami Kazuyuki
School of Surgery and Pathology, University of Western Australia, Nedlands, Australia.
Int J Cancer. 2006 Nov 15;119(10):2272-8. doi: 10.1002/ijc.22237.
The notion of a CpG island methylator phenotype (CIMP) was proposed to describe a subset of colorectal cancers (CRC) displaying frequent and concordant methylation of CpG islands located within gene promoter regions. Some workers have failed to observe associations between CIMP and specific clinicopathological features of CRC, possibly because of the choice of genes used to define this phenotype. The aim of the current study was to determine whether the aberrant methylation of 6 genes implicated in CRC development was associated with the same phenotypic features of this tumour type. The MethyLight assay was used to provide quantitative estimates of MLH1, P16, TIMP3, P14, DAPK and APC methylation levels in 199 unselected colorectal tumours. The methylation of MLH1, P16, TIMP3 and P14 was highly concordant (p < 0.0001 for each pair) but that of DAPK and APC was not. An inverse association was observed between the methylation of APC and TIMP3 (p = 0.004). Methylation of the MLH1, P16, TIMP3 and P14 genes was associated with tumour infiltrating lymphocytes (p < 0.05), microsatellite instability (p < 0.001), BRAF mutation (p < 0.0001) and elevated concentrations of the methyl group carriers tetrahydrofolate (THF) and 5,10-methylene THF (p < 0.05). In contrast, APC methylation was associated with wildtype BRAF (p = 0.003) and with lower concentrations of methyl group carriers (p < 0.05). These findings highlight the importance of gene selection in studies that aim to characterize the biological features and clinical behaviour of CIMP+ tumours.
CpG岛甲基化表型（CIMP）的概念被提出来描述一类结直肠癌（CRC），这类癌症表现出位于基因启动子区域的CpG岛频繁且一致的甲基化。一些研究人员未能观察到CIMP与CRC特定临床病理特征之间的关联，这可能是由于用于定义该表型的基因选择所致。本研究的目的是确定6个与CRC发生相关的基因的异常甲基化是否与该肿瘤类型的相同表型特征相关。采用甲基化荧光定量分析法对199例未经选择的结直肠肿瘤中MLH1、P16、TIMP3、P14、DAPK和APC的甲基化水平进行定量评估。MLH1、P16、TIMP3和P14的甲基化高度一致（每对基因的p<0.0001），但DAPK和APC的甲基化不一致。观察到APC和TIMP3甲基化之间呈负相关（p = 0.004）。MLH1、P16、TIMP3和P14基因的甲基化与肿瘤浸润淋巴细胞相关（p<0.05）、微卫星不稳定性相关（p<0.001）、BRAF突变相关（p<0.0001）以及甲基载体四氢叶酸（THF）和5,10-亚甲基四氢叶酸浓度升高相关（p<0.05）。相比之下，APC甲基化与野生型BRAF相关（p = 0.003）且与甲基载体浓度较低相关（p<0.05）。这些发现突出了基因选择在旨在表征CIMP+肿瘤生物学特征和临床行为的研究中的重要性。
