Ogino Shuji, Odze Robert D, Kawasaki Takako, Brahmandam Mohan, Kirkner Gregory J, Laird Peter W, Loda Massimo, Fuchs Charles S
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Am J Surg Pathol. 2006 Sep;30(9):1175-83. doi: 10.1097/01.pas.0000213266.84725.d0.
Extensive gene promoter methylation in colorectal carcinoma has been termed the CpG island methylator phenotype (CIMP). Previous studies on CIMP used primarily methylation-specific polymerase chain reaction (PCR), which, unfortunately, may detect low levels of methylation that has little or no biological significance. Utilizing quantitative real-time PCR (MethyLight), we measured DNA methylation in a panel of 5 CIMP-specific gene promoters (CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1) in 459 colorectal carcinomas obtained from 2 large prospective cohort studies. CIMP was defined as tumors that showed methylation in >or=4/5 promoters. CIMP was significantly associated with the presence of mucinous or signet ring cell morphology, marked Crohn's-like lymphoid reaction, tumor infiltrating lymphocytes, marked peritumoral lymphocytic reaction, tumor necrosis, tumor cell sheeting, and poor differentiation. All these features have previously been associated with microsatellite instability (MSI). Therefore, we divided the 459 colorectal carcinomas into 6 subtypes, namely, MSI-high (MSI-H)/CIMP, MSI-H/non-CIMP, MSI-low (MSI-L)/CIMP, MSI-L/non-CIMP, microsatellite stable/CIMP, and micro satellite sstable/non-CIMP. Compared with MSI-H/non-CIMP, MSI-H/CIMP was associated with marked tumor infiltrating lymphocytes, tumor necrosis, sheeting, and poor differentiation (all P<or=0.05). Compared with MSI-L/non-CIMP, MSI-L/CIMP was associated with tumors that had <50% signet ring cell component, marked tumor infiltrating lymphocytes, and poor differentiation (all P<0.05). In conclusion, several pathologic features that have previously been shown to be associated with MSI are also significantly associated with CIMP. Both MSI and CIMP appear to play a role in the pathogenesis of specific morphologic patterns of colorectal carcinoma.
结直肠癌中广泛的基因启动子甲基化被称为CpG岛甲基化表型（CIMP）。以往关于CIMP的研究主要使用甲基化特异性聚合酶链反应（PCR），但遗憾的是，该方法可能检测到低水平的甲基化，而这种甲基化几乎没有或根本没有生物学意义。我们利用定量实时PCR（MethyLight）技术，对来自2项大型前瞻性队列研究的459例结直肠癌中一组5个CIMP特异性基因启动子（CACNA1G、CDKN2A（p16）、CRABP1、MLH1和NEUROG1）的DNA甲基化进行了检测。CIMP被定义为在≥4/5个启动子中显示甲基化的肿瘤。CIMP与黏液或印戒细胞形态、显著的克罗恩样淋巴反应、肿瘤浸润淋巴细胞、显著的肿瘤周围淋巴细胞反应、肿瘤坏死、肿瘤细胞成片以及低分化显著相关。所有这些特征此前都与微卫星不稳定性（MSI）有关。因此，我们将459例结直肠癌分为6个亚型，即微卫星高度不稳定（MSI-H）/CIMP型、MSI-H/非CIMP型、微卫星低度不稳定（MSI-L）/CIMP型、MSI-L/非CIMP型、微卫星稳定/CIMP型和微卫星稳定/非CIMP型。与MSI-H/非CIMP型相比，MSI-H/CIMP型与显著的肿瘤浸润淋巴细胞、肿瘤坏死、成片以及低分化相关（所有P≤0.05）。与MSI-L/非CIMP型相比，MSI-L/CIMP型与印戒细胞成分<50%、显著的肿瘤浸润淋巴细胞以及低分化的肿瘤相关（所有P<0.05）。总之，一些先前已被证明与MSI相关的病理特征也与CIMP显著相关。MSI和CIMP似乎都在结直肠癌特定形态模式的发病机制中发挥作用。
