Comprehensive Biostatistical Analysis of CpG Island Methylator Phenotype in Colorectal Cancer Using a Large Population-Based Sample

来自 EBSCO

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作者：

K Nosho，N Irahara，K Shima，S Kure，GJ Kirkner，ES Schernhammer，A Hazra，DJ Hunter，J Quackenbush，D Spiegelman

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摘要：

The CpG island methylator phenotype (CIMP) is a distinct phenotype associated with microsatellite instability (MSI) andBRAFmutation in colon cancer. Recent investigations have selected 5 promoters (CACNA1G,IGF2,NEUROG1,RUNX3andSOCS1) 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 plusCDKN2A(p16),CHFR,CRABP1,HIC1,IGFBP3,MGMT, MINT1, MINT31,MLH1, p14 (CDKN2A/ARF) andWRN] was quantified in 904 colorectal cancers by real-time PCR (MethyLight). In unsupervised hierarchical clustering analysis, the 5 markers (CACNA1G,IGF2,NEUROG1,RUNX3andSOCS1),CDKN2A,CRABP1, MINT31,MLH1, p14 andWRNwere generally clustered with each other and with MSI andBRAFmutation.KRASmutation 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,BRAFmutation, 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,KRASmutation 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 thatKRASmutation is related with a random CpG island methylation pattern which may lead to CIMP-low tumors.

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关键词：

Humans Colorectal Neoplasms ras Proteins Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins Data Interpretation, Statistical Cohort Studies Prospective Studies CpG Islands Phenotype