Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample.
Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample.
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DOI：
10.1371/journal.pone.0003698
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Ogino S
中科院分区：
文献类型：
--
作者：
Nosho K;Irahara N;Shima K;Kure S;Kirkner GJ;Schernhammer ES;Hazra A;Hunter DJ;Quackenbush J;Spiegelman D;Giovannucci EL;Fuchs CS;Ogino S
CpG岛甲基表型（CIMP）是与微卫星不稳定性（MSI）相关的明显表型，并且在结肠癌中选择了5个启动子（Cacna1g，igf2，neurog1，runx3 and runx3和socs1）。但是，没有研究全面评估了一组扩展的甲基化标记（包括这5个标记）或决定了由经过验证的标记面板确定的CIMP高的复杂临床和分子关联。
DNA甲基化在16 CpG岛[上述5加CDKN2A（P16），CHFR，CRABP1，HIC1，IGFBP3，MGMT，MINT1，MINT1，MINT31，MINT31，MLH1，P14（CDKN2A/ARF）和WRN]在904年结型Cancers中量化时间PCR（Methlight）。 Crabp1，Mint31，MLH1，P14和WRN通常彼此聚集，MSI和BRAF突变与任何甲基化标记都没有聚集。标记面板（包括5个标记），多元逻辑回归表明，CIMP-High与老年人独立相关，近端位置，分化差，MSI-HIGH，BRAF突变以及与线1甲基化和β-catenin（CTNNB1）激活相反。 。
我们的研究为CIMP特异性甲基化标记的使用提供了有价值的数据。可能导致CIMP-LOW肿瘤的模式。
The CpG island methylator phenotype (CIMP) is a distinct phenotype associated with microsatellite instability (MSI) and BRAF mutation in colon cancer. Recent investigations have selected 5 promoters (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1) as surrogate markers for CIMP-high. However, no study has comprehensively evaluated an expanded set of methylation markers (including these 5 markers) using a large number of tumors, or deciphered the complex clinical and molecular associations with CIMP-high determined by the validated marker panel. DNA methylation at 16 CpG islands [the above 5 plus CDKN2A (p16), CHFR, CRABP1, HIC1, IGFBP3, MGMT, MINT1, MINT31, MLH1, p14 (CDKN2A/ARF) and WRN] was quantified in 904 colorectal cancers by real-time PCR (MethyLight). In unsupervised hierarchical clustering analysis, the 5 markers (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1), CDKN2A, CRABP1, MINT31, MLH1, p14 and WRN were generally clustered with each other and with MSI and BRAF mutation. KRAS mutation was not clustered with any methylation marker, suggesting its association with a random methylation pattern in CIMP-low tumors. Utilizing the validated CIMP marker panel (including the 5 markers), multivariate logistic regression demonstrated that CIMP-high was independently associated with older age, proximal location, poor differentiation, MSI-high, BRAF mutation, and inversely with LINE-1 hypomethylation and β-catenin (CTNNB1) activation. Mucinous feature, signet ring cells, and p53-negativity were associated with CIMP-high in only univariate analysis. In stratified analyses, the relations of CIMP-high with poor differentiation, KRAS mutation and LINE-1 hypomethylation significantly differed according to MSI status. Our study provides valuable data for standardization of the use of CIMP-high-specific methylation markers. CIMP-high is independently associated with clinical and key molecular features in colorectal cancer. Our data also suggest that KRAS mutation is related with a random CpG island methylation pattern which may lead to CIMP-low tumors.
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影响因子：
2
作者：
DURRLEMAN, S;SIMON, R
通讯作者：
SIMON, R
影响因子：
24.5
作者：
Ogino, S.;Cantor, M.;Fuchs, C. S.
通讯作者：
Fuchs, C. S.
影响因子：
45.3
作者：
Nagasaka, T;Sasamoto, H;Matsubara, N
通讯作者：
Matsubara, N
影响因子：
78.5
作者：
Issa, JP
通讯作者：
Issa, JP
影响因子：
7.5
作者：
Kawasaki, Takako;Ohnishi, Mutsuko;Ogino, Shuji
通讯作者：
Ogino, Shuji