Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer
Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer
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DOI：
10.1136/gut.2007.119750
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发表时间：
2007-11-01
期刊：
影响因子：
24.5
通讯作者：
Fuchs, Charles S.
中科院分区：
文献类型：
--
作者：
Ogino, Shuji;Kawasaki, Takako;Fuchs, Charles S.
背景资料：具有广泛启动子甲基化的CpG岛甲基化表型（CIMP或CIMP-高）是结直肠癌中的独特表观遗传表型。相比之下，启动子甲基化不太普遍的表型（CIMP-low）尚未得到很好的表征。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。目的：探讨结直肠癌中MGMT甲基化/沉默的分子相关性（一个CIMP诊断面板; CACNA 1G、CDKN 2A（p16）、CRABP 1、IGF 2、MLH 1、NEUROG 1、RUNX 3和SOCS 1）。具有MGMT甲基化和缺失的肿瘤与MSI-低（p = 0.02）、CIMP-高（>= 6/8甲基化CIMP标记物，p = 0.005）、CIMP-低（1/8-5/8甲基化CIMP标记物，p = 0.002，与具有0/8甲基化标记物的CIMP-0相比）、KRAS G. A突变（p = 0.02），与18 q杂合性缺失呈负相关（p = 0.0002）。肿瘤分为9个MSI/CIMP亚型。在CIMP-低组中，MGMT甲基化和丢失的肿瘤在MSI-低肿瘤（67%，12/18）中的频率远远高于MSI-高肿瘤（5.6%，1/18; p = 0.0003）和微卫星稳定（MSS）肿瘤（33%，52/160; p = 0.008）。然而，没有观察到这样的关系之间的CIMP-high或CIMP-0 groups.Conclusion：MGMT甲基化/沉默和MSI-低之间的关系仅限于CIMP-low肿瘤，支持CIMP-low在结直肠癌中可能是一个不同的分子表型从CIMP-high和CIMP-0的建议。我们的数据支持结肠直肠癌中MSI-低和MSS之间的分子差异，以及CIMP-低，MSI-低，MGMT甲基化/丢失和KRAS突变之间的可能联系。
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 (>= 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.