CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies
CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies
复制标题
DOI：
10.1136/gut.2005.082933
复制
发表时间：
2006-07-01
期刊：
影响因子：
24.5
通讯作者：
Fuchs, C. S.
中科院分区：
文献类型：
--
作者：
Ogino, S.;Cantor, M.;Fuchs, C. S.
背景：CPG岛甲基表型（CIMP）的概念并未普遍接受。即使特定的临床病理学特征与CIMP有关，研究人员也经常未能证明甲基化标记数量的双峰分布，这将表明CIMP是大肠癌的独特亚型。先前的研究主要使用甲基化特异性聚合酶链反应，该反应可能检测到生物学上微不足道的低水平甲基化。IAM：使用定量DNA甲基化分析证明CIMP结直肠癌的独特遗传特征，可以将高水平与低水平的DNA甲基化区分开：我们开发了定量的实时聚合酶链反应（甲基光）测定和测量的DNA甲基化（甲基化百分比参考）五个精心选择的基因座（CACNA1G，CDKN2A（P16），CrabP1，MLH1和Neurog1的启动子），来自大型前瞻性同胞的460个结直肠癌的癌症。 h）肿瘤根据甲基化启动子的数量，没有肿瘤显示3/5甲基化位点。因此，我们将CIMP定义为> = 4/5甲基化的基因座，而460个肿瘤中有17％（78）被分类为CIMP。 CIMP与女性，MSI，BRAF突变和野生型KRAS显着相关。 CIMP MSI-H肿瘤和CIMP微卫星稳定（MSS）肿瘤的BRAF突变频率（63％和54％）都比非CIMP对应物（非CIMP MSI-H（0％，p <10（-5）） ）和非CIMP MSS肿瘤（分别为6.6％，p <10（-4）））。结论：CIMP最好以定量DNA甲基化分析为特征。 CIMP是结直肠癌的独特表观型，可能比以前报道的不太频繁。
Background: The concept of CpG island methylator phenotype ( CIMP) is not universally accepted. Even if specific clinicopathological features have been associated with CIMP, investigators often failed to demonstrate a bimodal distribution of the number of methylated markers, which would suggest CIMP as a distinct subtype of colorectal cancer. Previous studies primarily used methylation specific polymerase chain reaction which might detect biologically insignificant low levels of methylation.Aim: To demonstrate a distinct genetic profile of CIMP colorectal cancer using quantitative DNA methylation analysis that can distinguish high from low levels of DNA methylation.Materials and methods: We developed quantitative real time polymerase chain reaction (MethyLight) assays and measured DNA methylation (percentage of methylated reference) of five carefully selected loci (promoters of CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1) in 460 colorectal cancers from large prospective cohorts.Results: There was a clear bimodal distribution of 80 microsatellite instability-high (MSI-H) tumours according to the number of methylated promoters, with no tumours showing 3/5 methylated loci. Thus we defined CIMP as having >= 4/5 methylated loci, and 17% (78) of the 460 tumours were classified as CIMP. CIMP was significantly associated with female sex, MSI, BRAF mutations, and wild-type KRAS. Both CIMP MSI-H tumours and CIMP microsatellite stable (MSS) tumours showed much higher frequencies of BRAF mutations (63% and 54%) than non-CIMP counterparts (non-CIMP MSI-H (0%, p < 10(-5)) and non-CIMP MSS tumours (6.6%, p < 10(-4)), respectively).Conclusion: CIMP is best characterised by quantitative DNA methylation analysis. CIMP is a distinct epigenotype of colorectal cancer and may be less frequent than previously reported.