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doi: https://doi.org/10.4132/jptm.2019.03.12    [Epub ahead of print]
CpG island methylation in sessile serrated adenoma/polyp of the colorectum: implications for differential diagnosis of molecularly high-risk lesions among non-dysplastic sessile serrated adenomas/polyps
Ji Ae Lee1, Hye Eun Park1, Seung Yeon Yoo1, Seorin Jeong2, Nam-Yun Cho2, Gyeong Hoon Kang1,2, Jung Ho Kim1,2
1Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
2Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
Corresponding Author: Jung Ho Kim ,Tel: 82-2-2072-2828, Fax: 82-2-743-5530, Email: junghokim@snuh.org
Received: February 16, 2019;  Revised: March 9, 2019  Accepted: March 12, 2019.  Published online: March 19, 2019.

Although colorectal sessile serrated adenomas/polyps (SSA/Ps) with morphologic dysplasia are regarded as definite high-risk premalignant lesions, no reliable grading or risk-stratifying system exists for non-dysplastic SSA/Ps. The accumulation of CpG island methylation is a molecular hallmark of progression of SSA/Ps. Thus, we decided to classify non-dysplastic SSA/Ps into risk subgroups based on the extent of CpG island methylation.
The CpG island methylator phenotype (CIMP) status of 132 non-dysplastic SSA/Ps was determined using eight CIMP-specific promoter markers. SSA/Ps with CIMP-high and/or MLH1 promoter methylation were regarded as a high-risk subgroup.
Based on the CIMP analysis results, methylation frequency of each CIMP marker suggested a sequential pattern of CpG island methylation during progression of SSA/P, indicating MLH1 as a late-methylated marker. Among the 132 non-dysplastic SSA/Ps, 34 (26%) were determined to be high-risk lesions (33 CIMP-high and 8 MLH1-methylated cases; seven cases overlapped). All the 34 high-risk SSA/Ps were located exclusively in the proximal colon (100%; P = 0.001) and were significantly associated with older age (≥50 years, 100%; P = 0.003) and a larger histologically measured lesion size (>5 mm, 100%; P = 0.004). In addition, the high-risk SSA/Ps were characterized by a relatively higher number of typical base-dilated serrated crypts.
Both CIMP-high and MLH1 methylation are late-step molecular events during progression of SSA/Ps and rarely occur in SSA/Ps of young patients. Comprehensive consideration of age (≥50), location (proximal colon), and histologic size (>5 mm) may be important for the prediction of high-risk lesions among non-dysplastic SSA/Ps.
Key Words: colorectal neoplasms, DNA methylation, serrated lesion, serrated pathway, serrated polyp
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