与MGMT启动子甲基化和沉默相关的分子支持结直肠癌中的低CpG岛甲基化表型（CIMP-low）。
Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer.
作者信息
Ogino Shuji, Kawasaki Takako, Kirkner Gregory J, Suemoto Yuko, Meyerhardt Jeffrey A, Fuchs Charles S
机构信息
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 75 Francis St, BWH Pathology, Boston, MA 02115, USA.
出版信息
Gut. 2007 Nov;56(11):1564-71. doi: 10.1136/gut.2007.119750. Epub 2007 Mar 5.
BACKGROUND
The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer. In contrast, a phenotype with less widespread promoter methylation (CIMP-low) has not been well characterised. O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and silencing have been associated with G>A mutations and microsatellite instability-low (MSI-low).
AIM
To examine molecular correlates with MGMT methylation/silencing in colorectal cancer.
METHODS
Utilising MethyLight technology, we quantified DNA methylation in MGMT and eight other markers (a CIMP-diagnostic panel; CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) in 920 population-based colorectal cancers.
RESULTS
Tumours with both MGMT methylation and loss were correlated positively with MSI-low (p = 0.02), CIMP-high (>or=6/8 methylated CIMP markers, p = 0.005), CIMP-low (1/8-5/8 methylated CIMP markers, p = 0.002, compared to CIMP-0 with 0/8 methylated markers), KRAS G>A mutation (p = 0.02), and inversely with 18q loss of heterozygosity (p = 0.0002). Tumours were classified into nine MSI/CIMP subtypes. Among the CIMP-low group, tumours with both MGMT methylation and loss were far more frequent in MSI-low tumours (67%, 12/18) than MSI-high tumours (5.6%, 1/18; p = 0.0003) and microsatellite stable (MSS) tumours (33%, 52/160; p = 0.008). However, no such relationship was observed among the CIMP-high or CIMP-0 groups.
CONCLUSION
The relationship between MGMT methylation/silencing and MSI-low is limited to only CIMP-low tumours, supporting the suggestion that CIMP-low in colorectal cancer may be a different molecular phenotype from CIMP-high and CIMP-0. Our data support a molecular difference between MSI-low and MSS in colorectal cancer, and a possible link between CIMP-low, MSI-low, MGMT methylation/loss and KRAS mutation.
背景
具有广泛启动子甲基化的CpG岛甲基化表型（CIMP或高CIMP）是结直肠癌中一种独特的表观遗传表型。相比之下，启动子甲基化程度较低的表型（低CIMP）尚未得到充分表征。O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）启动子甲基化和沉默与G>A突变及微卫星不稳定性低（MSI低）相关。
目的
研究结直肠癌中与MGMT甲基化/沉默相关的分子关联。
方法
利用甲基化荧光定量技术，我们对920例基于人群的结直肠癌中MGMT及其他八个标志物（一个CIMP诊断面板；CACNA1G、CDKN2A（p16）、CRABP1、IGF2、MLH1、NEUROG1、RUNX3和SOCS1）的DNA甲基化进行了定量分析。
结果
同时存在MGMT甲基化和缺失的肿瘤与MSI低（p = 0.02）、高CIMP（≥6/8个甲基化CIMP标志物，p = 0.005）、低CIMP（1/8 - 5/8个甲基化CIMP标志物，与0/8个甲基化标志物的CIMP-0相比，p = 0.002）、KRAS G>A突变（p = 0.02）呈正相关，与18号染色体杂合性缺失呈负相关（p = 0.0002）。肿瘤被分为九种MSI/CIMP亚型。在低CIMP组中，同时存在MGMT甲基化和缺失的肿瘤在MSI低的肿瘤中（67%，12/18）比MSI高的肿瘤（5.6%，1/18；p = 0.0003）和微卫星稳定（MSS）肿瘤（33%，52/160；p = 0.008）更为常见。然而，在高CIMP或CIMP-0组中未观察到这种关系。
结论
MGMT甲基化/沉默与MSI低之间的关系仅限于低CIMP肿瘤，支持结直肠癌中的低CIMP可能是一种与高CIMP和CIMP-0不同的分子表型的观点。我们的数据支持结直肠癌中MSI低和MSS之间的分子差异，以及低CIMP、MSI低、MGMT甲基化/缺失和KRAS突变之间可能存在的联系。
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