Abstract
Abstract Aberrant DNA methylation event is known to be early and frequent process in tumorigenesis and could therefore serve as a convenient biomarker for early detection of cancers. For the identification of novel methylation markers we compared each methylation profiles in super normal tissues (n=2) of healthy individuals and primary tumors and their matched normal appearing adjacent tissues (non-tumor) from colorectal cancer patients (n=12) relative to that of common reference DNA through genome-wide CpG microarray analysis following methylated DNA enrichment with a minimum size of methyl binding domain. Unsupervised hierarchical clustering of with entire methylation pattern data successfully discriminated normal, match-paired normal and primary tumors. We then statistically selected novel methylation candidates showing high frequency of methylation in primary tumor samples and intermediate in non-tumor but no methylation in supernormal tissues for early detection and confirmed in colorectal cancer cell lines by quantitative pyrosequencing-based methylation assay. For final candidates with high specificity, we selected 4 genes, GABRA1, gt-SD, gt-SI, gt-SO which showed a low methylation level in 2 healthy normal tissues. All of 4 genes appeared to be much more frequently hypermethylated in primary tumors than in non-tumor tissues in pyrosequencing assay. For the applicability into non-invasive sample we analyzed methylation status of 4 genes in stool DNAs obtained from patients with colorectal cancer (n=106) and healthy volunteers (n=10) by modified two-round nested MSP for improving analytic sensitivity. The sensitivity and specificity of each of 4 genes were estimated as 50.5% to 60.2% and 85.7% to 100%, respectively. The sensitivity of the four-gene panel was 88.7% (94/106) and its specificity was 80.0% (2/10) in detecting colorectal cancer with stool DNA. Consequently, 4 novel genes have a great potential in noninvasive stool DNA testing for colorectal cancer screening. Further large-scale clinical validation will be needed for clinical setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-91.
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