Journal of Pathology and Translational Medicine

Original Articles

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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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

Long Non-coding RNA HOTAIR Expression in Diffuse Large B-Cell Lymphoma: In Relation to Polycomb Repressive Complex Pathway Proteins and H3K27 Trimethylation: Eun Ji Oh, Soo Hee Kim, Woo Ick Yang, Young Hyeh Ko, Sun Och Yoon; J Pathol Transl Med. 2016;50(5):369-376. Published online August 22, 2016; DOI: https://doi.org/10.4132/jptm.2016.06.06

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Abstract PDF

Background
A long non-coding RNA hox transcript antisense intergenic RNA (HOTAIR) is involved in epigenetic regulation through chromatin remodeling by recruiting polycomb repressive complex 2 (PRC2) proteins (EZH2, SUZ12, and EED) that induce histone H3 trimethylation at lysine 27 (H3K27me3). Deregulation of c-MYC and interaction between c-MYC and EZH2 are well known in lymphomagenesis; however, little is known about the expression status of HOTAIR in diffuse large B-cell lymphomas (DLBCLs).
Methods
The expression status of PRC2 (EZH2, SUZ12, and EED), H3K27me3, c-MYC, and BCL2 was analyzed using immunohistochemistry (n = 231), and HOTAIR was investigated by a quantification real-time polymerase chain reaction method (n = 164) in DLBCLs.
Results
The present study confirmed the positive correlation among PRC2 proteins, H3K27me3, and c-MYC in DLBCLs. Expression level of HOTAIR was also positively correlated to EZH2 (p < .05, respectively). Between c-MYC and HOTAIR, and between c- MYC/BCL2 co-expression and HOTAIR, however, negative correlation was observed in DLBCLs (p < .05, respectively). High level of H3K27me3 was determined as an independent prognostic marker in poor overall survival (hazard ratio, 2.0; p = .023) of DLBCL patients. High expression of HOTAIR, however, was associated with favorable overall survival (p = .004) in the univariate analysis, but the impact was not significant in the multivariate analysis. The favorable outcome of DLBCL with HOTAIR high expression levels may be related to the negative correlation with c- MYC expression or c-MYC/BCL2 co-expression.
Conclusions
HOTAIR expression could be one of possible mechanisms for inducing H3K27me3 via EZH2-related PRC2 activation, and induced H3K27me3 may be strongly related to aggressive DLBCLs which show poor patient outcome.

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Long Noncoding RNAs in Diffuse Large B-Cell Lymphoma: Current Advances and Perspectives

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Methylation and Immunoexpression of p16^INK4a Tumor Suppressor Gene in Primary Breast Cancer Tissue and Their Quantitative p16^INK4a Hypermethylation in Plasma by Real-Time PCR: Jae Jun Lee, Eunkyung Ko, Junhun Cho, Ha Young Park, Jeong Eon Lee, Seok Jin Nam, Duk-Hwan Kim, Eun Yoon Cho; Korean J Pathol. 2012;46(6):554-561. Published online December 26, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.6.554

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Abstract PDF

Background

The p16^INK4a gene methylation has been reported to be a major tumorigenic mechanism.

Methods

We evaluated the methylation status of the p16^INK4a genes in 231 invasive breast cancer and 90 intraductal carcinoma specimens using a methylation-specific polymerase chain reaction and p16 protein expression using immunohistochemistry. The quantity of cell-free methylated p16^INK4a DNA in the plasma samples of 200 patients with invasive breast cancer was also examined using a fluorescence-based real-time polymerase chain reaction assay.

Results

The frequencies of p16^INK4a methylation in invasive and intraductal tumors were 52.8% (122/231) and 57.8% (52/90), respectively. The p16 protein was overexpressed in 145 of the 231 invasive carcinomas (62.8%) and 63 of the 90 intraductal carcinomas (70%). High p16 expression in invasive carcinomas correlated significantly with a high histologic grade, a negative estrogen receptor and progesterone receptor status, p53 immunoreactivity and high Ki-67 expression with immunohistochemistry. In addition, the methylation index of p16^INK4a was significantly higher in the cancer patients than the normal controls (p<0.001).

Conclusions

High p16 immunoreactivity correlated with a loss of differentiation in breast carcinomas and high frequency of p16^INK4a promoter methylation in both invasive and intraductal carcinomas, suggesting it may be involved in the pathogenesis of breast cancer.

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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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Cellular and Molecular Life Sciences.2023;[Epub] CrossRef
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Helicobacter pylori severely reduces expression of DNA repair proteins PMS2 and ERCC1 in gastritis and gastric cancer
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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

MGMT Gene Promoter Methylation Analysis by Pyrosequencing of Brain Tumour.: Young Zoon Kim, Young Jin Song, Ki Uk Kim, Dae Cheol Kim; Korean J Pathol. 2011;45(5):455-462.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.5.455

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Abstract PDF

BACKGROUND
The aim of this study was to determine whether pyrosequencing (PSQ) might be useful to achieve O6-methyl guanine methyltransferase (MGMT) promoter methylation using 1- to 13-year-old archival tissues as a clinical biomarker in routine practice.
METHODS
The study included 141 formalin-fixed paraffin-embedded (FFPE) glial tumors from the archives of the Pathology Department from 1997-2010.
RESULTS
The average percentage of methylation (MP) of the 141 cases was 14.0+/-16.8%, and methylated cases were 32.3+/-14.9%. The average MP of each year did not show a linear increasing or decreasing pattern according to the age of the FFPE block (p=0.771). The average MP of methylated glioblastomas was 35.8+/-14.7%, 31.8+/-15.5% for anaplastic astrocytomas, and 22.4+/-15.1% for astrocytoma. A tendency was observed toward an increasing pattern of average MP with World Health Organization (WHO) grade (p=0.063) in astrocytic tumors. A correlation was observed between average MP and WHO grade (p=0.038) and a bimodal distribution was observed between the methylated and unmethylated cases, using a 9% cut-off value (p<0.001).
CONCLUSIONS
The results showed that a quantitative approach for MGMT promoter methylation yielded a 100% success rate for FFPE tissues from archives. PSQ can be used in a retrospective trial, but the cut-off value and calculation method should be further validated.

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Immunohistochemical Classification of Primary and Secondary Glioblastomas
Kyu Sang Lee, Gheeyoung Choe, Kyung Han Nam, An Na Seo, Sumi Yun, Kyung Ju Kim, Hwa Jin Cho, Sung Hye Park
Korean Journal of Pathology.2013; 47(6): 541. CrossRef

A Consideration of MGMT Gene Promotor Methylation Analysis for Glioblastoma Using Methylation-Specific Polymerase Chain Reaction and Pyrosequencing.: Sang Hwa Lee, Tae Sook Hwang, Young Cho Koh, Wook Youn Kim, Hye Seung Han, Wan Seop Kim, Young Sin Ko, So Dug Lim; Korean J Pathol. 2011;45(1):21-29.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.1.21

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Abstract PDF

BACKGROUND
O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation is currently the most promising predictive marker for the outcome and benefit from temozolomide treatment in patients with glioblastoma, but there is no consensus on the analysis method for assessing the methylation status in the molecular diagnostic field. The objective of this study was to evaluate methylation-specific polymerase chain reaction (MSP) and pyrosequencing methods for assessing MGMT gene promotor methylation of glioblastoma as well as assessing the MGMT protein expression by immunohistochemistry.
METHODS
Twenty-seven cases of glioblastoma from the archives at the Department of Pathology Konkuk University Hospital were selected. MGMT promoter methylation was evaluated by MSP and the pyrosequencing methods. The MGMT expression was also measured at the protein level by immunohistochemistry.
RESULTS
Overall, MGMT hypermethylation was observed in 44.4% (12/27 cases) of the case of glioblastoma using either MSP or pyrosequencing. The concordant rate was 70.3% (19/27 cases) between MSP and pyrosequencing for MGMT methylation. There was no correlation between MGMT methylation and the protein expression. No significant differences in progression free survival and overall survival were seen between the methylated group and the unmethylated group by using either MSP or pyrosequencing. The status of the MGMT protein expression was correlated with progression free survival (p=0.026).
CONCLUSIONS
In this study the concordance rate between MSP and the pyrosequencing methods for assessing MGMT gene promotor methylation was relatively low for the cases of glioblastoma. This suggests that more reliable techniques for routine MGMT methylation study of glioblastoma remain to be developed because of quality control and assurance issues.

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Prognostic Role of Methylation Status of theMGMTPromoter Determined Quantitatively by Pyrosequencing in Glioblastoma Patients
Dae Cheol Kim, Ki Uk Kim, Young Zoon Kim
Journal of Korean Neurosurgical Society.2016; 59(1): 26. CrossRef
Distinct genetic alterations in pediatric glioblastomas
Sun-ju Byeon, Jae Kyung Myung, Se Hoon Kim, Seung-Ki Kim, Ji Hoon Phi, Sung-Hye Park
Child's Nervous System.2012; 28(7): 1025. CrossRef
MGMTGene Promoter Methylation Analysis by Pyrosequencing of Brain Tumour
Young Zoon Kim, Young Jin Song, Ki Uk Kim, Dae Cheol Kim
The Korean Journal of Pathology.2011; 45(5): 455. CrossRef

Prognostic Significance of Methylation Profiles in Urothelial Carcinomas of the Bladder.: Hee Jung Park, Eui Jin Lee, Sang Yun Ha, Ghee Young Kwon, Young Lyun Oh, Kyoung Mee Kim, Dae Shick Kim, Seongil Seo, Hyun Moo Lee, Han Yong Choi; Korean J Pathol. 2010;44(6):623-630.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.6.623

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Abstract PDF

BACKGROUND
Study on epigenetics of urothelial carcinomas has expanded and allowed better understanding of their correlation with clinicopathologic features. The aim of this study was to determine reliable predictive epigenetic markers for patients with urothelial carcinoma of urinary bladder.
METHODS
In 64 urothelial carcinomas of the urinary bladder, methylationspecific polymerase chain reaction with RAS association domain family 1A (RASSF1A), adenomatous polyposis coli (APC), death-associated protein-kinase (DAPK), runt-related transcription factor 3 (RUNX3), p14, p16 and MGMT was performed and correlated the results with p53 mutations, DNA ploidy, clinicopathologic parameters and recurrences.
RESULTS
Hypermethyation of RASSF1A, APC, DAPK, RUNX3, p14, p16 and MGMT promoters was observed in 35 (54.7%), 29 (45.3%), 18 (28.1%), 18 (28.1%), 9 (14.1%), 2 (3.1%), and 6 (9.4%) cases, respectively. Hypermethylation of RUNX3 and APC was significantly associated with high histologic grades and aneuploidy. Methylation of DAPK was significantly associated with muscle invasion. Methylation of DAPK and RUNX3 genes was significantly associated with recurrence. In survival analyses, methylation of RUNX3 gene and methylation-high (methylation at two or more loci) phenotype was significantly associated with poor recurrence-free survival.
CONCLUSIONS
Methylation of RUNX3 gene and methylation-high phenotype are significant indicator of recurrence.

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DAPK Promoter Methylation and Bladder Cancer Risk: A Systematic Review and Meta-Analysis
Lihe Dai, Chong Ma, Zhensheng Zhang, Shuxiong Zeng, Anwei Liu, Shijie Tang, Qian Ren, Yinghao Sun, Chuanliang Xu, Shengtao Zhou
PLOS ONE.2016; 11(12): e0167228. CrossRef

Utility of Promoter Hypermethylation for Differentiating Malignant and Benign Effusions in Liquid-Based Cytology Specimens.: Ga Eon Kim, Jo Heon Kim, Yeong Hui Kim, Chan Choi, Ji Shin Lee; Korean J Pathol. 2010;44(3):315-321.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.3.315

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Abstract PDF

BACKGROUND
Making the cytologic differentiation between benign and malignant effusions can be difficult. Because promoter hypermethylation of tumor suppressor genes is a frequent epigenetic event in many human cancers, it could serve as a marker for the diagnosis of cancer. The aim of this study was to investigate the feasibility of detecting promoter hypermethylation as a diagnostic tool with using liquid-based cytology samples for differentiating between malignant and benign effusions.
METHODS
A multiplex, nested, methylation-specific polymerase chain reaction analysis was used to examine promoter methylation of 4 genes (retinoic acid receptor-beta, [RAR-beta], adenomatous polyposis coli [APC], Twist and high in normal-1 [HIN-1]) in malignant (n = 85) and benign (n = 31) liquid-based cytology samples.
RESULTS
The frequencies of hypermethylation of RAR-beta, APC, Twist and HIN-1 were significantly higher in the malignant effusions than in the benign effusions (p < 0.001 for each). On the receiver-operating characteristic analysis, the area under the curve (AUC) for APC was the greatest. The AUC for the best two-gene combination (APC/HIN-1) was not statistically different from the AUC for the best individual tumor suppressor gene (APC).
CONCLUSIONS
This study suggests that promoter methylation analysis on residual liquid-based effusion samples may be a feasible approach to detect malignant effusions, and that APC is the best marker for differentiating between malignant and benign effusions.

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A comparative analysis of conventional cytopreparatory and liquid based cytological techniques (Sure Path) in evaluation of serous effusion fluids
Hrishikesh Dadhich, Pampa Ch Toi, Neelaiah Siddaraju, Kalidas Sevvanthi
Diagnostic Cytopathology.2016; 44(11): 874. CrossRef

Aberrant Promoter Methylation of the Vimentin Gene in Colorectal Cancer Associated with the Adenoma-Carcinoma Sequence.: Mi Hee Cho, Yu Mi Lee, Jin Sook Kim, Hyun Soo Kim, Kyung Hwa Lee, Sang Woo Juhng, Jae Hyuk Lee; Korean J Pathol. 2010;44(2):179-186.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.2.179

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Abstract PDF

BACKGROUND
DNA hypermethylation is a common epigenetic finding in human cancers and is closely associated with transcriptional silencing. In the present study, we investigated the proportion of colorectal neoplasms that showed the adenoma-carcinoma progression and vimentin gene methylation.
METHODS
Methylation status of the vimentin gene was examined in nontumoral mucosa, adenomas, and adenocarcinomas from 45 colorectal cancer patients who had adenoma and adenocarcinoma together. Methylation status was determined by bisulfite modification and the methylation-specific polymerase chain reaction. The expression of the vimentin gene product was also examined by immunohistochemistry.
RESULTS
Promoter methylation of vimentin was detected in 80% (36 out of 45 cases) of adenocarcinomas, 82.2% (37 of 45) of adenomas, and 28.9% (13 of 45) of normal epithelia, and the difference between neoplastic and normal specimens was statistically significant (p < 0.001). However, no significant correlations were observed between methylation frequency and clinicopathologic variables. Immunohistochemically, vimentin expression was not observed in either normal epithelial cells or tumor cells. Protein expression and vimentin promoter methylation were not associated.
CONCLUSIONS
The frequency of aberrant methylation of the vimentin gene was high in colonic adenomas and adenocarcinomas. This result suggests that the methylation status of vimentin may be clinically beneficial in screening for colorectal cancer patients and may be helpful in clarifying colorectal cancer biology.

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Epigenetic Modifications as Biomarkers of Tumor Development, Therapy Response, and Recurrence across the Cancer Care Continuum
Margaret Thomas, Paola Marcato
Cancers.2018; 10(4): 101. CrossRef
Aberrant promoter methylation of beta‐1,4 galactosyltransferase 1 as potential cancer‐specific biomarker of colorectal tumors
Maria Luana Poeta, Emanuela Massi, Paola Parrella, Pasquale Pellegrini, Mariangela De Robertis, Massimiliano Copetti, Carla Rabitti, Giuseppe Perrone, Andrea Onetti Muda, Francesca Molinari, Elena Zanellato, Stefano Crippa, Damiano Caputo, Marco Caricato,
Genes, Chromosomes and Cancer.2012; 51(12): 1133. CrossRef

DNA Methylation Profiles of MGMT, DAPK1, hMLH1, CDH1, SHP1, and HIC1 in B-Cell Lymphomas.: Sung Sun Kim, Young Hyo Choi, Chang Woo Han, Yoo Duk Choi, Youngkyu Park, Je Jung Lee, Hyeoung Joon Kim, Il Kwon Lee, Ji Shin Lee, Sang Woo Juhng, Chan Choi; Korean J Pathol. 2009;43(5):420-427.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.5.420

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Abstract PDF

BACKGROUND
This study was designed to examine the prevalence of aberrant promoter methylation in a selected panel of genes potentially involved in lymphoid tumors.
METHODS
The promoter hypermethylation status of MGMT, DAPK1, hMLH1, CDH1, SHP1, and HIC1 was measured by methylation-specific PCR for 82 cases of B-cell lymphoma. Immunohistochemical staining using MGMT and SHP1 antibodies was conducted on 43 out of 82 cases.
RESULTS
The number of MGMT aberrant methylations was lower in diffuse large B-cell lymphoma (DLBCL) than in other malignant lymphomas. The methylation of DAPK1 was frequently detected in follicular lymphoma (FL), marginal zone B-cell lymphoma (MZL) and DLBCL. With one exception, methylation of hMLH1 was not observed in B-cell lymphomas. The methylation frequency of CDH1, and HIC1 was similar in B-cell lymphomas. However, the methylation of SHP1 gene was more frequently observed in cases of FL, DLBCL, and MZL than in chronic lymphocytic lymphoma. MGMT and SHP1 promoter methylation were inversely correlated with the protein expression observed upon immunohistochemical staining.
CONCLUSIONS
Aberrant promoter methylation of multiple genes occurs with variable frequency throughout the B-cell lymphomas, and methylation of hMLH1 is rarely observed in B-cell lymphomas.

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Plasma DNA methylation of p16 and shp1 in patients with B cell non-Hodgkin lymphoma
Kai Ding, Xiaoshuang Chen, Yihao Wang, Hui Liu, Wenjing Song, Lijuan Li, Guojin Wang, Jia Song, Zonghong Shao, Rong Fu
International Journal of Clinical Oncology.2017; 22(3): 585. CrossRef
Hypermethylation of p15 Gene in Diffuse – Large B‐Cell Lymphoma: Association with Less Aggressiveness of the Disease
Milena Krajnović, Maja Peruničić Jovanović, Biljana Mihaljević, Boško Anđelić, Olivera Tarabar, Slavica Knežević‐Ušaj, Koviljka Krtolica
Clinical and Translational Science.2014; 7(5): 384. 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.

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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 Overexpression of Histone Deacetylase 1 and Its Relationship with p16INK4a Gene Hypermethylation in Pulmonary Squamous Cell Carcinoma and Adenocarcinoma.: Jong Hyeok Park, Young Seoub Hong, Phil Jo Choi, Na Young Kim, Kyung Eun Lee, Mee Sook Roh; Korean J Pathol. 2009;43(2):107-112.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.2.107

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Abstract PDF

BACKGROUND
DNA methylation and histone modification are dynamically linked in the epigenetic control of gene silencing and they play an important role in tumorigenesis.
METHODS
To evaluate the role of histone deacetylase 1 (HDAC1) in the development of lung cancer and the relationship between a HDAC1 overexpression and p16INK4a hypermethylation, we performed immunohistochemical staining for HDAC1 in 76 lung cancer specimens (39 squamous cell carcinomas and 37 adenocarcinomas) that had been previously evaluated for their p16INK4a methylation status by real-time quantitative polymerase chain reaction.
RESULTS
A HDAC1 overexpression (>50% of HDAC1 immunoreactive cells) was detected in 65 (85.5%) out of the 76 cases and it was more frequently seen in the squamous cell carcinomas (97.4%) than in the adenocarcinomas (73.0%) (p=0.002). The incidence of HDAC1 overexpression tended to be higher in the heavy smokers with more than 20 pack-years (p=0.067). Although there was no statistical significance, the frequency of p16INK4a hypermethylation in the cases with a HDAC1 overexpression (27.7%) tended to be higher than that in the cases without a HDAC1 overexpression (9.0%) (p=0.175).
CONCLUSIONS
A HDAC1 overexpression might be involved in lung carcinogenesis, and especially in a subgroup of smoking and squamous cell carcinoma patients, and a HDAC1 overexpression may be associated with p16INK4a hypermethylation.

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Deciphering the Mysterious Relationship between the Cross-Pathogenetic Mechanisms of Neurodegenerative and Oncological Diseases
Yulia Aleksandrova, Margarita Neganova
International Journal of Molecular Sciences.2023; 24(19): 14766. CrossRef
Microbiome dysbiosis and epigenetic modulations in lung cancer: From pathogenesis to therapy
Faizan Haider Khan, Basharat Ahmad Bhat, Bashir Ahmad Sheikh, Lubna Tariq, Roshan Padmanabhan, Jay Prakash Verma, Amritesh Chandra Shukla, Afshin Dowlati, Ata Abbas
Seminars in Cancer Biology.2022; 86: 732. CrossRef
Histone deacetylase HDAC1 expression correlates with the progression and prognosis of lung cancer
Lin-Lin Cao, Xiaoxu Song, Lin Pei, Lianhua Liu, Hui Wang, Mei Jia
Medicine.2017; 96(31): e7663. CrossRef
The synthesis and evaluation of N1-(4-(2-[18F]-fluoroethyl)phenyl)-N8-hydroxyoctanediamide ([18F]-FESAHA), A PET radiotracer designed for the delineation of histone deacetylase expression in cancer
Brian M. Zeglis, NagaVaraKishore Pillarsetty, Vadim Divilov, Ronald A. Blasberg, Jason S. Lewis
Nuclear Medicine and Biology.2011; 38(5): 683. 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.

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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

Methylation Abnormality in Body Fluid Cytology: A Supplemental Molecular Marker for the Diagnosis of Malignant Mesothelioma.: Joon Seon Song, Jin Kyung Jung, Ji Hye Kang, Ilseon Hwang, Se Jin Jang; Korean J Cytopathol. 2008;19(2):126-135.; DOI: https://doi.org/10.3338/kjc.2008.19.2.126

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Abstract PDF

Malignant mesothelioma (MM) is a highly lethal neoplasm arising in pleura and the peritoneum and a rapid and accurate diagnosis is crucial for treatment of the disease. However, the sensitivity of cytological analysis using pleural or ascitic fluid is relatively low, yielding an accurate diagnosis in only 32~79% of cases. We tested the diagnostic value of epigenetic alterations in body fluid cytology as a supplement to conventional methods. Paraffin-embedded tissue blocks from 21 MM patients and associated body fluid cytology slides considered no evidence of malignancy were used to test for epigenetic alteration. Using methylation-specific PCR, we detected methylation of RASSF1A and p16 in 47.6% (10/21) of both surgically resected tumor samples, respectively. Body fluid samples of MM also showed abnormal methylation of RASSF1A and p16INK4a genes in 38.1% (8/21) and 33.3% (7/21) of cases. The concordance in the rates of RASSF1A and p16INK4a gene-methylation abnormalities determined from cytology samples and tissue samples were 61.9% (13/21) and 66.7% (14/21), respectively. Combining both genes increases the sensitivity of the test to 57.1% (12 of 21) of cases. Our results suggest that testing for methylation abnormalities in selected individual genes or gene combinations has diagnostic value as an alternative or adjunct method to conventional cytological diagnosis.

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Utility of Promoter Hypermethylation for Differentiating Malignant and Benign Effusions in Liquid-Based Cytology Specimens
Ga-Eon Kim, Jo-Heon Kim, Yeong-Hui Kim, Chan Choi, Ji Shin Lee
The Korean Journal of Pathology.2010; 44(3): 315. CrossRef

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