J Pathol Transl Med.  2019 Jul;53(4):225-235. 10.4132/jptm.2019.03.12.

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

Affiliations
  • 1Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. junghokim@snuh.org
  • 2Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Abstract

BACKGROUND
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.
METHODS
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.
RESULTS
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 34 high-risk SSA/Ps were located exclusively in the proximal colon (100%, p = .001) and were significantly associated with older age (≥ 50 years, 100%; p = .003) and a larger histologically measured lesion size (> 5 mm, 100%; p = .004). In addition, the high-risk SSA/Ps were characterized by a relatively higher number of typical base-dilated serrated crypts.
CONCLUSIONS
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.

Keyword

Colorectal neoplasms; DNA methylation; Serrated lesion; Serrated pathway; Serrated polyp

MeSH Terms

Colon
Colorectal Neoplasms
CpG Islands*
Diagnosis, Differential*
DNA Methylation
Humans
Methylation*
Phenotype

Figure

  • Fig. 1. Histomorphometric analyses used in this study. (A) A representative example for measurement of maximum size of a sessile serrated adenomas/polyp (SSA/P). (B) A representative example for counting of typical base-dilated serrated crypts. The total number of typical crypts in an SSA/P was used as a variable in this study. Asterisks indicate typical crypts. (C) A representative example for measurement of diameters of typical base-dilated serrated crypts. The largest diameter of typical crypts in an SSA/P was used as a variable in this study.

  • Fig. 2. An inference of developmental pattern of CpG island methylation in colorectal serrated neoplasia pathway. (A) Frequencies of methylation-positive cases for each CpG island methylator phenotype (CIMP) marker, based on the number of concurrently methylated markers in 132 non-dysplastic sessile serrated adenomas/polyps (SSA/Ps). Group A markers can be methylated independently and alone, whereas methylation of group C markers accompanies at least two or three other methylated markers. (B) A sequence model of methylation of CIMP markers during progression of SSA/Ps.

  • Fig. 3. The high-risk subgroup of non-dysplastic sessile serrated adenomas/polyps (SSA/Ps) is characterized by old age and proximal colonic location. (A) Percentages of CpG island methylator phenotype (CIMP)-high, -low, and -negative subsets of non-dysplastic SSA/Ps in the different age subgroups. Note the presence of CIMP-high cases only in ≥50 years age subgroups. (B) Frequencies of high-risk SSA/Ps according to the lesion location bowel subsites. Note the presence of high-risk SSA/Ps only in the proximal colon. (C) Frequencies of low-risk SSA/Ps according to the lesion location bowel subsites. (D) Two-dimensional (age-location) scatter plot of 132 non-dysplastic SSA/Ps. S-colon, sigmoid colon; D-colon, descending colon; SF, splenic flexure; T-colon, transverse colon; HF, hepatic flexure; A-colon, ascending colon.

  • Fig. 4. Differences in histologically measured lesion size and number of typical base-dilated serrated crypts between high-risk and low-risk subgroups of 132 non-dysplastic sessile serrated adenomas/polyps (SSA/Ps). (A) A box-whisker-scatter plot for histologically measured lesion size. The p-value was obtained using the Student’s t test. (B) Frequencies of high-risk SSA/Ps and low-risk SSA/Ps according to histologically measured lesion size. (C) A box-whisker-scatter plot for number of typical base-dilated serrated crypts. The p-value was obtained using the Mann-Whitney U test. (D) Frequencies of high-risk SSA/Ps and low-risk SSA/Ps according to number of typical base-dilated serrated crypts.

  • Fig. 5. A graphical summary of this study. Age, location, and size are potential predictive factors for a high-risk subgroup of non-dysplastic sessile serrated adenomas/polyps (SSA/Ps). CIMP, CpG island methylator phenotype; MSI, microsatellite instability.


Cited by  1 articles

Evolving pathologic concepts of serrated lesions of the colorectum
Jung Ho Kim, Gyeong Hoon Kang
J Pathol Transl Med. 2020;54(4):276-289.    doi: 10.4132/jptm.2020.04.15.


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