Journal of Pathology and Translational Medicine

Original Article

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 Lee, Hye Eun Park, Seung-Yeon Yoo, Seorin Jeong, Nam-Yun Cho, Gyeong Hoon Kang, Jung Ho Kim; J Pathol Transl Med. 2019;53(4):225-235. Published online March 19, 2019; DOI: https://doi.org/10.4132/jptm.2019.03.12

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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.

Citations

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Immune microenvironmental heterogeneity according to tumor DNA methylation phenotypes in microsatellite instability-high colorectal cancers
Jung Ho Kim, Jiyun Hong, Ji Ae Lee, Minsun Jung, Eunwoo Choi, Nam-Yun Cho, Gyeong Hoon Kang, Sangwoo Kim
Cancer Immunology, Immunotherapy.2024;[Epub] CrossRef
How to "pick up" colorectal serrated lesions and polyps in daily histopathology practice: From terminologies to diagnostic pitfalls
Thai H Tran, Vinh H Nguyen, Diem TN Vo
World Journal of Clinical Oncology.2024; 15(9): 1157. CrossRef
Serrated Colorectal Lesions: An Up-to-Date Review from Histological Pattern to Molecular Pathogenesis
Martino Mezzapesa, Giuseppe Losurdo, Francesca Celiberto, Salvatore Rizzi, Antonio d’Amati, Domenico Piscitelli, Enzo Ierardi, Alfredo Di Leo
International Journal of Molecular Sciences.2022; 23(8): 4461. CrossRef
NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions
Jung Ho Kim, Jeong Hoon Hong, Yoon‐La Choi, Ji Ae Lee, Mi‐kyoung Seo, Mi‐Sook Lee, Sung Bin An, Min Jung Sung, Nam‐Yun Cho, Sung‐Su Kim, Young Kee Shin, Sangwoo Kim, Gyeong Hoon Kang
The Journal of Pathology.2021; 255(4): 399. CrossRef
Evolving pathologic concepts of serrated lesions of the colorectum
Jung Ho Kim, Gyeong Hoon Kang
Journal of Pathology and Translational Medicine.2020; 54(4): 276. CrossRef

Review

CpG Island Hypermethylation in Gastric Carcinoma and Its Premalignant Lesions: Gyeong Hoon Kang; Korean J Pathol. 2012;46(1):1-9. Published online February 23, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.1.1

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Abstract PDF

Gastric cancers arise through a multistep process characterized by the progressive accumulation of molecular alterations in which genetic and epigenetic mechanisms have been implicated. Gastric cancer is one of the human malignancies in which aberrant promoter CpG island hypermethylation is frequently found. Helicobacter pylori and Epstein-Barr virus, which are known carcinogens for gastric cancer, are closely associated with enhanced hypermethylation of CpG island loci in gastric non-neoplastic epithelial cells and cancer cells, respectively. Aberrant CpG island hypermethylation occurs early in the multistep cascade of gastric carcinogenesis and tends to increase with the step-wise progression of the lesion. Approximately 400 genes that are actively expressed in normal gastric epithelial cells are estimated to be inactivated in gastric cancers as a result of promoter CpG island hypermethylation. In this review, a variety of information is summarized regarding CpG island hypermethylation in gastric cancer.

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Francesco Multinu, Jun Chen, Joseph D. Madison, Michelle Torres, Jvan Casarin, Daniel Visscher, Viji Shridhar, Jamie Bakkum-Gamez, Mark Sherman, Nicolas Wentzensen, Andrea Mariani, Marina Walther-Antonio
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Genomic and Epigenomic Profiling of High-Risk Intestinal Metaplasia Reveals Molecular Determinants of Progression to Gastric Cancer
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Decreased Methylation of IFNAR Gene Promoter from Peripheral Blood Mononuclear Cells Is Associated with Oxidative Stress in Chronic Hepatitis B
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Helicobacter pylori CagA induces tumor suppressor gene hypermethylation by upregulating DNMT1 via AKT-NFκB pathway in gastric cancer development
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Original Articles

CpG Island Methylation According to the Histologic Patterns of Early Gastric Adenocarcinoma.: Junjeong Choi, Mee Yon Cho, So Young Jung, Khalilullah Mia Jan, Hyun Soo Kim; Korean J Pathol. 2011;45(5):469-476.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.5.469

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Abstract PDF

BACKGROUND
Although the importance of aberrant DNA methylation in the development of gastric adenocarcinoma has been described, the mechanism of pathogenesis has not been revealed yet. We quantitatively analyzed methylation of four CpG islands and one repetitive DNA element, according to the histologic features of adenocarcinoma with precursor lesions.
METHODS
We divided the cases as adenocarcinoma with intestinal type precursors (type A, n=19 cases) and adenocarcinoma with diffuse type precursors (type B, n=19 cases). We micro-dissected tumor cells and matched non-neoplastic gastric mucosa from the hematoxylin and eosin-stained slides.
RESULTS
A total of 20 CpG sites of long interspersed nucleotide element-1 (LINE1), RAR-related orphan receptor alpha (RORA), Kruppel-like factor 7 (KLF7), mutL homolog 1 (MLH1), MINT25, and CD133 were analyzed. Methylation was determined by bisulfate-pyro-sequencing, and hypomethylation of LINE1 and CD133 was noted in the tumors, compared to the levels in the non-neoplastic gastric mucosa (p=0.014 and p=0.015, respectively). A statistically different methylation pattern of CpG sites at CD133 and KLF7 was noted only in type B lesions, compared to that in matched non-neoplastic gastric mucosa (p=0.027 and p=0.043, respectively).
CONCLUSIONS
Given that aberrant methylation occurs in a relatively early phase of carcinogenesis, different patterns of methylation may determine the carcinoma phenotype. However, further large-scale study is required to clarify the significance of this difference.

Citations

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Molecular function of Krüppel-like factor 7 in biology
Yi Mao, Yuechan Chen, Zhiwei Zhang
Acta Biochimica et Biophysica Sinica.2023; 55(5): 713. CrossRef
DNA methylation status of a distinctively different subset of genes is associated with each histologic Lauren classification subtype in early gastric carcinogenesis
YOSEP CHONG, KHALILULLAH MIA-JAN, HOON RYU, JAMSHID ABDUL-GHAFAR, JIJGEE MUNKHDELGER, SAYAMAA LKHAGVADORJ, SO YOUNG JUNG, MIRA LEE, SUN-YOUNG JI, EUNHEE CHOI, MEE-YON CHO
Oncology Reports.2014; 31(6): 2535. CrossRef

The Loss of E-cadherin is Associated with the Epigenetic Alteration of CDH1 in Breast Cancer and it is also Associated with an Abnormal beta-catenin Expression in Lobular Carcinoma.: Gwangil Kim, Ji Young Kim, Hee Jung An, Haeyoun Kang, Tae Heon Kim, Jung Yon Shim, Jin Hyung Heo, Hai Lin Park, Young Kil Choi; Korean J Pathol. 2009;43(5):400-407.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.5.400

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Abstract PDF

BACKGROUND
APC and E-cadherin are the key molecules in the Wnt/beta-catenin pathway. We attempted to define the epigenetic alteration of APC and CDH1 (the E-cadherin gene) and the expression of Wnt-related molecules in human mammary carcinomas.
METHODS
Sixty-four mammary carcinomas, including 52 invasive ductal carcinomas (IDCs) and 12 invasive lobular carcinomas (ILCs), were evaluated using methylation-specific PCR and immunohistochemistry. We performed immunohistochemistry for E-cadherin, beta-catenin, APC, Wnt1, cyclin D1, ER, PR and C-erb B2.
RESULTS
Hypermethylation of APC and CDH1 was observed in 38 (59%) and 28 (44%) cases, respectively. CDH1 hypermethylation in ILCs was increased compared to that in IDCs (p=0.002) and it was associated with the loss of E-cadherin (p=0.02) and beta-catenin (p=0.042). APC methylation was positively correlated with the ER expression (p=0.021). Abnormal cytoplasmic localization of beta-catenin was found in 10 cases and any expression was not detected in six cases. In ILCs, the E-cadherin or beta-catenin expression was markedly decreased compared to that in IDCs (p<0.001 in both).
CONCLUSIONS
Methylation of APC or CDH1 was relatively frequent in mammary carcinomas. The loss of E-cadherin in mammary carcinoma was associated with CDH1 methylation, and abnormal beta-catenin expression was related to the loss of E-cadherin in ILC.

Citations

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Wnt/β-catenin signaling pathway activation reverses gemcitabine resistance by attenuating Beclin1-mediated autophagy in the MG63 human osteosarcoma cell line
Hao Tao, Feng Chen, Haifei Liu, Yanling Hu, Yingzhen Wang, Haiyan Li
Molecular Medicine Reports.2017; 16(2): 1701. CrossRef

The Relationship between the Methylenetetrahydrofolate Reductase Genotypes and the Methylation Status of the CpG Island Loci, LINE-1 and Alu in Prostate Adenocarcinoma.: Jung Ho Kim, Nam Yun Cho, Baek Hee Kim, Wook Youn Kim, Bo Sung Kim, Kyung Chul Moon, Gyeong Hoon Kang; Korean J Pathol. 2009;43(1):26-35.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.1.26

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Abstract PDF

BACKGROUND
Genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR), in association with the influence of MTHFR upon DNA methylation, may cause differences of the methylation profile of cancer. Thus, we investigated the relationship between the methylation status of prostate adenocarcinoma and the genetic polymorphism of MTHFR.
METHODS
We examined 179 cases of prostate adenocarcinoma for determining the genotypes of MTHFR 677 and 1298, the methylation status of 16 CpG island loci and the methylation levels of the LINE-1 and Alu repeats with using polymerase chain reaction/restriction fragment length polymorphism, methylation-specific polymerase chain reaction and combined bisulphite restriction analysis, respectively.
RESULTS
There was a higher proportion of the CT genotype of MTHFR 677 in the prostate adenocarcinoma than that in the normal control. The TT genotype of MTHFR 677 showed the highest frequency of methylation in six out of nine major CpG island loci, and these were which were frequently hypermethylated in prostate adenocarcinoma. The CT type showed the lowest methylation levels of LINE-1 and Alu among the MTHFR 677 genotypes. Interestingly, the CC type of MTHFR 1298 demonstrated favorable prognostic factors.
CONCLUSIONS
Our study is the first to examine the methylation profile of prostate adenocarcinoma according to the MTHFR genotypes. The differences of the cancer risk, the genomic hypomethylation and the prognosis between the MTHFR genotypes in prostate adenocarcinoma should be further explored.

Citations

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Association Between MTHFR 1298A>C Polymorphism and Spontaneous Abortion with Fetal Chromosomal Aneuploidy
Shin Young Kim, So Yeon Park, Ji Won Choi, Do Jin Kim, Shin Yeong Lee, Ji Hyae Lim, Jung Yeol Han, Hyun Mee Ryu, Min Hyoung Kim
American Journal of Reproductive Immunology.2011; 66(4): 252. CrossRef
Distinctive patterns of age-dependent hypomethylation in interspersed repetitive sequences
Pornrutsami Jintaridth, Apiwat Mutirangura
Physiological Genomics.2010; 41(2): 194. CrossRef

Methylotion Analysis of p16/INK4A in Gastric Low-Grade Mucosa-Associated Lymphoid Tissue Lymphomas after Helicobacter pylori Eradication Therapy.: Young A Kim, Sung Shin Park, Bo Young Lee, You Sun Kim, In Sung Song, Chul Woo Kim; Korean J Pathol. 2002;36(1):13-20.

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Abstract PDF: BACKGROUND
Inactivation of p16 has been associated with promoter region hypermethylation in different types of malignancies, including non-Hodgkin's lymphomas (NHLs). This loss of p16 was found frequently in cases of mucosa-associated lymphoid tissue (MALT) lymphomas. Recent studies indicate that promoter hypermethylation is often an early event in tumor progression in the follow-up of NHLs.
METHODS
To investigate the usefulness of p16 methylation in the diagnosis and follow-up of gastric low-grade MALT lymphomas, we analyzed methylation status of p16 using methylation-specific polymerase chain reaction methods in the sequential biopsy specimens of 13 patients with gastric low-grade MALT lymphomas undergoing Helicobacter pylori eradication therapy.
RESULTS
Five of thriteen cases showed p16 hypermethylation upon diagnosis. In four of five methylation positive cases, abnormal methylation was detected in the specimen even after the treatment, although there were no histologic evidence of disease. This methylation disappeared in the later samples of two of the cases, and they have remained in complete remission. Immunohistochemically, the loss of p16 protein expression was detected in one of three methylation-positive cases, and in none of the methylation-negative cases.
CONCLUSIONS
These results suggest that p16 methylation is relatively fequent in low-grade gastric MALT lymphomas, and it may have clinical applications in the management and follow-up of low-grade gastric MALT lymphomas.

Inactivation Pattern of p16 Gene in Non-Hodgkin's Lymphomas.: Hyun Deuk Cho, In Sun Kim; Korean J Pathol. 2002;36(6):365-373.

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Abstract PDF: BACKGROUND
Loss of heterozygosity (LOH) and mutation of the p16 tumor suppressor gene have been detected in non-Hodgkin's lymphomas (NHLs). Recently, hypermethylation of the p16 gene has been reported. The role of p16 gene alterations in the genesis of NHLs and their high-grade transformations require explanation.
METHODS
LOH of D9S171 and IFNA microsatellite markers, DNA hypermethylation, and mutation of exon 1 and 2A were assessed in 43 cases of NHLs. The genetic abnormalities were compared with the protein expression by immunohistochemistry, and they were evaluated according to the histologic subtypes, grades and immunophenotypes.
RESULTS
DNA hypermethylation was the most common p16 gene abnormality and was found in 30 of 39 cases (76.9%). Eight cases (18.6%) showed LOH in one or both microsatellite markers, and five cases (11.6%) showed mutations in exon 1 or 2A. Loss of protein expression was seen in 17 cases (39.5%) and was associated with mutation and LOH. Loss of protein was more frequent in high-grade lymphomas than in low-grade lymphomas.
CONCLUSION
These results suggest that the functional loss of the p16 gene contributes to the development of NHLs, especially to the development of high-grade lymphomas.

Diffuse Large B Cell Lymphoma Shows Distinct Methylation Profiles of the Tumor Suppressor Genes among the Non-Hodgkin's Lymphomas.: Sun Och Yoon, Young A Kim, Yoon Kyung Jeon, Ji Eun Kim, Gyeong Hoon Kang, Chul Woo Kim; Korean J Pathol. 2008;42(1):16-20.

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Abstract PDF: BACKGROUND
Aberrant methylation of CpG islands in promoter regions is one of the major mechanisms for silencing of tumor suppressor genes in various types of human cancers including non-Hodgkin's lymphomas (NHL). In this study, we investigated the aberrant promoter methylation status of known or suspected tumor suppressor genes in NHLs and compared the methylation profiles between B-cell and T/NK-cell NHLs.
METHODS
54 cases of B-cell NHLs and 16 cases of T/NK-cell NHLs were examined for the methylation status of eight genes using methylation specific PCR.
RESULTS
CpG islands methylation was variously found in eight genes as follows; DAPK (71%), MT1G (70%), p16 (53%), CDH1 (53%), THBS1 (56%), MGMT (27.1%), COX2 (13%), and RUNX3 (11.4%). In six cases (8 %), methylation was not observed in any of these genes. Overall methylation index of B-cell NHLs (0.48) was significantly higher than that of T/NK-cell NHLs (0.32). Of eight genes tested, THBS1 and CDH1 methylations were much more prominent in diffuse large B-cell lymphomas than in T/NK-cell NHLs or other B-cell NHLs.
CONCLUSION
This study suggests that aberrant CpG island methylation is a frequent event in NHLs, and diffuse large B-cell lymphomas show overlapping but distinct methylation profiles.

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