Frequent CpG Island Hypermethylation in Serrated Polyps, Contrasted with Low Frequency of CpG Island Hypermethylation in Traditional Adenomatous Polyps
HJ Kwon, JM Bae, NY Cho, GH Kang. Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University, Seoul, Korea
Background: Three known molecular mechanisms of colorectal carcinogenesis include chromosomal instability (CIN), CpG island methylator phenotype (CIMP), and microsatellite instability (MSI). Traditional adenoma-carcinoma sequence is a multistep model which explains the carcinogenesis of CIN+ CRCs that are in an exclusive relationship with CIMP+ CRCs or MSI+ CRCs. In contrast to CIN+ CRCs, we don't know well regarding the premalignant lesions of CIMP+ CRCs or MSI+ CRCs. Previous studies investigating CpG island hypermethylation in colonic epithelial polyps used methylation-specific PCR which is a qualitative study and produces inconsistent results in detection of low level methylation. There has been no study which perform quantitative methylation analysis in colonic epithelial neoplastic polyps for their methylation status in reference CpG island loci of CIMP marker panel.
Design: In the present study, we analyzed a total of 198 epithelial polyps, including sessile serrated adenoma (SSA), traditional serrated adenoma (TSA), hyperplastic polyp (HYP), villous adenoma (VA), tubulovillous adenoma (TVA), and tubular adenoma (TA), for their methylation status in eight-CIMP panel markers using real-time PCR-based methylation specific PCR (MethyLight assay) in order to determine which polyp might be premalignant lesions of CIMP+ CRCs.
Results: The mean number of methylated genes was 4.9, 4.0, 2.2, 1.8, 1.1, 0.7, 0.3, and 0.2 for SSA, TSA, HYP, VA, TVA, low grade TA, high grade TA, and normal non-neoplastic mucosa, respectively. The number of genes methylated was significantly higher in TSA and SSA than in HYP and significantly higher in HYP than in TVA, TA, and IEADC. CIMP+ lesions (defined as lesions having methylation at five or more markers) were noted in SSA (73% of 22 cases), TSA (52% of 29), VA (14% of 21), HYP (13% of 30), TVA (5% of 29), and none of low grade and high grade TA and normal colonic mucosa samples. Comparison between right and left sidedness revealed that proximal location was closely associated with enhanced hypermethylation in SSA and HYP.Conclusion: Our results indicate that TSA, SSA, and HYP are epigenetically altered lesions and suggest that these lesions might be precursor lesions of CIMP+ CRCs.
Conclusions: Our results indicate that TSA, SSA, and HYP are epigenetically altered lesions and suggest that these lesions might be precursor lesions of CIMP+ CRCs.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 126, Tuesday Morning