CpG island methylator phenotype-low (CIMP-Low) in colorectal cancer:: Possible associations with male sex and KRAS mutations
CpG island methylator phenotype-low (CIMP-Low) in colorectal cancer:: Possible associations with male sex and KRAS mutations
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DOI：
10.2353/jmoldx.2006.060082
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发表时间：
2006-11-01
影响因子：
4.1
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.
具有广泛启动子甲基化的CpG岛甲基化表型（CIMP或CIMP-high）似乎是结直肠癌的一种独特的表观基因型。然而，目前还没有研究全面考察过启动子甲基化程度较低（称为“CIMP-low”）的结直肠癌的特征。使用实时聚合酶链反应（MethyLight），我们定量了840个相对无偏倚的、基于人群的结直肠癌样本中5个cmp特异性基因启动子[CACNA1G、CDKN2A （p16）、CRABP1、MLH1和NEUROG1]的DNA甲基化，这些样本来自两项大型前瞻性队列研究。cmp -低（定义为1/5至3/5甲基化启动子）结直肠癌在男性（38%对30%，女性，P = 0.01）和KRAS-突变肿瘤（KRAS/BRAF野生型肿瘤，44%对30%，P = 0.0003； BRAF-突变肿瘤，19%,P < 0.0001）中更为常见。此外，KRAS突变在cimp -低肿瘤（47%）中比在cimp -高肿瘤（>= 4/5甲基化启动子，12%,P < 0.0001）和CIMP-0肿瘤（0/5甲基化启动子，37%,P = 0.007）中更常见。在微卫星不稳定状态对肿瘤进行分层后，低cimp肿瘤与男性和KRAS突变的关联仍然存在。综上所述，cimp -低的结直肠癌与男性和KRAS突变有关。关于cimp -低肿瘤与cimp -高和CIMP-0肿瘤不同的假设需要进一步验证。
The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation seems to be a distinct epigenotype of colorectal cancer. However, no study has comprehensively examined features of colorectal cancer with less extensive promoter methylation (designated as "CIMP-low"). Using real-time polymerase chain reaction (MethyLight), we quantified DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1] in 840 relatively unbiased, population-based colorectal cancer samples, obtained from two large prospective cohort studies. CIMP-low (defined as 1/5 to 3/5 methylated promoters) colorectal cancers were significantly more common among men (38 versus 30% in women, P = 0.01) and among KRAS-mutated tumors (44 versus 30% in KRAS/BRAF wild-type tumors, P = 0.0003; 19% in BRAF-mutated tumors, P < 0.0001). In addition, KRAS mutations were significantly more common in CIMP-low tumors (47%) than in CIMP-high tumors (with >= 4/5 methylated promoters, 12%, P < 0.0001) and CIMP-0 tumors (with 0/5 methylated promoters, 37%, P = 0.007). The associations of CIMP-low tumors with male sex and KRAS mutations still existed after tumors were stratified by microsatellite instability status. In conclusion, CIMP-low colorectal cancer is associated with male sex and KRAS mutations. The hypothesis that CMIP-low tumors are different from CIMP-high and CIMP-0 tumors needs to be tested further.