Cancer Research and Treatment

Original Articles

Gastrointestinal cancer

Gemcitabine Inhibits the Progression of Pancreatic Cancer by Restraining the WTAP/MYC Chain in an m6A-Dependent Manner: Pei Cao, Weigang Zhang, Junyi Qiu, Zuxiong Tang, Xiaofeng Xue, Tingting Feng; Cancer Res Treat. 2024;56(1):259-271. Published online August 16, 2023; DOI: https://doi.org/10.4143/crt.2022.1600

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Purpose
Pancreatic cancer (PC) is a common malignant tumor of the digestive system, and its 5-year survival rate is only 4%. N6-methyladenosine (m6A) RNA methylation is the most common post-transcriptional modification and dynamically regulates cancer development, while its role in PC treatment remains unclear.
Materials and Methods
We treated PC cells with gemcitabine and quantified the overall m6A level with m6A methylation quantification. Real-time quantitative reverse transcription polymerase chain reaction and Western blot analyses were used to detect expression changes of m6A regulators. We verified the m6A modification on the target genes through m6A-immunoprecipitation (IP), and further in vivo experiments and immunofluorescence (IF) assays were applied to verify regulation of gemcitabine on Wilms’ tumor 1–associated protein (WTAP) and MYC.
Results
Gemcitabine inhibited the proliferation and migration of PC cells and reduced the overall level of m6A modification. Additionally, the expression of the “writer” WTAP was significantly downregulated after gemcitabine treatment. We knocked down WTAP in cells and found target gene MYC expression was significantly downregulated, m6A-IP also confirmed the m6A modification on MYC. Our experiments showed that m6A-MYC may be recognized by the “reader” IGF2BP1. In vivo experiments revealed gemcitabine inhibited the tumorigenic ability of PC cells. IF analysis also showed that gemcitabine inhibited the expression of WTAP and MYC, which displayed a significant trend of co-expression.
Conclusion
Our study confirmed that gemcitabine interferes with WTAP protein expression in PC, reduces m6A modification on MYC and RNA stability, thereby inhibiting the downstream pathway of MYC, and inhibits the progression of PC.

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The biological roles and molecular mechanisms of m6A reader IGF2BP1 in the hallmarks of cancer
Li Qiu, Shourong Wu, Lei Zhang, Wenfang Li, Debing Xiang, Vivi Kasim
Genes & Diseases.2025; : 101567. CrossRef
WTAP-mediated N6-methyladenosine modification promotes the inflammation, mitochondrial damage and ferroptosis of kidney tubular epithelial cells in acute kidney injury by regulating LMNB1 expression and activating NF-κB and JAK2/STAT3 pathways
Fan Huang, Yuchen Wang, XiaoLi Lv, Chenda Huang
Journal of Bioenergetics and Biomembranes.2024; 56(3): 285. CrossRef

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Aberrant DNA Methylation Maker for Predicting Metachronous Recurrence After Endoscopic Resection of Gastric Neoplasms: Cheol Min Shin, Nayoung Kim, Hyuk Yoon, Yoon Jin Choi, Ji Hyun Park, Young Soo Park, Dong Ho Lee; Cancer Res Treat. 2022;54(4):1157-1166. Published online January 18, 2022; DOI: https://doi.org/10.4143/crt.2021.997

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Purpose
This study aimed to investigate whether MOS methylation can be useful for the prediction of metachronous recurrence after endoscopic resection of gastric neoplasms.
Materials and Methods
From 2012 to 2017, 294 patients were prospectively enrolled after endoscopic resection of gastric dysplasia (n=171) or early gastric cancer (n=123). When Helicobacter pylori was positive, eradication therapy was performed. Among them, 124 patients completed the study protocol (follow-up duration > 3 years or development of metachronous recurrence during the follow-up). Methylation levels of MOS were measured at baseline using quantitative MethyLight assay from the antrum.
Results
Median follow-up duration was 49.9 months. MOS methylation levels at baseline were not different by age, sex, and current H. pylorii infection, but they showed a weak correlation with operative link on gastritis assessment (OLGA) or operative link on gastric intestinal metaplasia assessment (OLGIM) stages (Spearman’s ρ=0.240 and 0.174, respectively; p < 0.05). During the follow-up, a total of 20 metachronous gastric neoplasms (13 adenomas and 7 adenocarcinomas) were developed. Either OLGA or OLGIM stage was not useful in predicting the risk for metachronous recurrence. In contrast, MOS methylation high group (≥ 34.82%) had a significantly increased risk for metachronous recurrence compared to MOS methylation low group (adjusted hazard ratio, 4.76; 95% confidence interval, 1.54 to 14.79; p=0.007).
Conclusion
MOS methylation can be a promising marker for predicting metachronous recurrence after endoscopic resection of gastric neoplasms. To confirm the usefulness of MOS methylation, validation studies are warranted in the future (ClinicalTrials No. NCT04830618).

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MIR124-3 and NKX6-1 hypermethylation profiles accurately predict metachronous gastric lesions in a Caucasian population
Catarina Lopes, Tatiana C. Almeida, Catarina Macedo-Silva, João Costa, Sofia Paulino, Carmen Jerónimo, Diogo Libânio, Mário Dinis-Ribeiro, Carina Pereira
Clinical Epigenetics.2024;[Epub] CrossRef
The methylation signature of hepatocellular carcinoma trajectory based on pseudotime and chronological time for predicting precancerous patients
Kang Li, Chaoran Zang, Yanan Zhao, Dandan Guo, Wanting Shi, Tingting Mei, Ang Li, Yonghong Zhang
The Oncologist.2024;[Epub] CrossRef
Risk assessment of metachronous gastric cancer development using OLGA and OLGIM systems after endoscopic submucosal dissection for early gastric cancer: a long-term follow-up study
Yun Suk Na, Sang Gyun Kim, Soo-Jeong Cho
Gastric Cancer.2023; 26(2): 298. CrossRef

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CNS cancer

Hypo-trimethylation of Histone H3 Lysine 4 and Hyper-tri/dimethylation of Histone H3 Lysine 27 as Epigenetic Markers of Poor Prognosis in Patients with Primary Central Nervous System Lymphoma: Hoon Gi Kim, Minseok S. Kim, Young Sam Lee, Eun Hee Lee, Dae Cheol Kim, Sung-Hun Lee, Young Zoon Kim; Cancer Res Treat. 2022;54(3):690-708. Published online November 17, 2021; DOI: https://doi.org/10.4143/crt.2021.1121

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Purpose
This study aimed to investigate the methylation status of major histone modification sites in primary central nervous system lymphoma (PCNSL) samples and examine their prognostic roles in patients with PCNSL.
Materials and Method
Between 2007 and 2020, 87 patients were histopathologically diagnosed with PCNSL. We performed immunohistochemical staining of the formalin-fixed paraffin-embedded samples of PCNSL for major histone modification sites, such as H3K4, H3K9, H3K27, H3K14, and H3K36. After detection of meaningful methylation sites, we examined histone modification enzymes that induce methylation or demethylation at each site using immunohistochemical staining. The meaningful immunoreactivity was validated by western blotting using fresh tissue of PCNSL.
Results
More frequent recurrences were found in hypomethylation of H3K4me3 (p=0.004) and hypermethylation of H3K27me2 (p<0.001) and H3K27me3 (p=0.002). These factors were also statistically related to short PFS and overall survival in the univariate and multivariate analyses. Next, histone modification enzymes inducing the demethylation of H3K4 (lysine-specific demethylase-1/2 and Jumonji AT-rich interactive domain [JARID] 1A-D]) and methylation of H3K27 (enhancer of zeste homolog [EZH]-1/2) were immu- nohistochemically stained. Among them, the immunoreactivity of JARID1A inversely associated with the methylation status of H3K4me3 (R²=-1.431), and immunoreactivity of EZH2 was directly associated with the methylation status of H3K27me2 (R²=0.667) and H3K27me3 (R²=0.604). These results were validated by western blotting in fresh PCNSL samples.
Conclusion
Our study suggests that hypomethylation of H3K4me3 and hypermethylation of H3K27me2 and H3K27me3 could be associated with poor outcomes in patients with PCNSL and that these relationships are modified by JARID1A and EZH2.

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Updates of primary central nervous system lymphoma
Jiaying Wu, Delian Zhou, Xiaojian Zhu, Yicheng Zhang, Yi Xiao
Therapeutic Advances in Hematology.2024;[Epub] CrossRef
3-deazaneplanocin A, a histone methyltransferase inhibitor, improved the chemoresistance induced under hypoxia in melanoma cells
Mika Hosokawa, Sekai Tetsumoto, Mirano Yasui, Yusuke Kono, Ken-ichi Ogawara
Biochemical and Biophysical Research Communications.2023; 677: 26. CrossRef
Extranodal lymphoma: pathogenesis, diagnosis and treatment
Hua Yang, Yang Xun, Chao Ke, Kensuke Tateishi, Hua You
Molecular Biomedicine.2023;[Epub] CrossRef
Diagnostic and Therapeutic Perspectives Associated to Cobalamin-Dependent Metabolism and Transcobalamins’ Synthesis in Solid Cancers
Valentin Lacombe, Guy Lenaers, Geoffrey Urbanski
Nutrients.2022; 14(10): 2058. CrossRef
Primary central nervous system lymphoma: advances in its pathogenesis, molecular markers and targeted therapies
Isaias Hernández-Verdin, Andrea Morales-Martínez, Khê Hoang-Xuan, Agustí Alentorn
Current Opinion in Neurology.2022; 35(6): 779. CrossRef

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Gastric Mucosal Atrophy Impedes Housekeeping Gene Methylation in Gastric Cancer Patients: Jung-Hwan Oh, Mun-Gan Rhyu, Suk-Il Kim, Mi-Ri Yun, Jung-Ha Shin, Seung-Jin Hong; Cancer Res Treat. 2019;51(1):267-279. Published online April 30, 2018; DOI: https://doi.org/10.4143/crt.2018.085

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Purpose
Helicobacter pylori infection induces phenotype-stabilizing methylation and promotes gastric mucosal atrophy that can inhibit CpG-island methylation. Relationship between the progression of gastric mucosal atrophy and the initiation of CpG-island methylation was analyzed to delineate epigenetic period for neoplastic transformation.
Materials and Methods
Normal-appearing gastric mucosa was biopsied from 110 H. pylori–positive controls, 95 H. pylori–negative controls, 99 gastric cancer patients, and 118 gastric dysplasia patients. Gastric atrophy was assessed using endoscopic-atrophic-border score. Methylation-variable sites of eight CpG-island genes adjacent to Alu (CDH1, ARRDC4, PPARG, and TRAPPC2L) or LTR (MMP2, CDKN2A, RUNX2, and RUNX3) retroelements and stomach-specific TFF3 gene were analyzed using radioisotope-labeled methylation-specific polymerase chain reaction.
Results
Mean ages of H. pylori–positive controls with mild, moderate, and severe atrophy were 51, 54, and 65 years and those of H. pylori–associated TFF3 overmethylation at the three atrophic levels (51, 58, and 63 years) tended to be periodic. Alu-adjacent overmethylation (50 years) was earlier than TFF3 overmethylation (58 years) in H. pylori–positive controls with moderate atrophy. Cancer patients with moderate atrophy showed late Alu-adjacent (58 years) overmethylation and frequent LTR-adjacent overmethylation. LTR-adjacent overmethylation was frequent in cancer (66 years) and dysplasia (68 years) patients with severe atrophy.
Conclusion
Atrophic progression is associated with gastric cancer at moderate level by impeding the initiation of Alu-adjacent methylation. LTR-adjacent methylation is increased in cancer patients and subsequently in dysplasia patients.

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The global prevalence of gastric cancer in Helicobacter pylori-infected individuals: a systematic review and meta-analysis
Maryam Shirani, Reza Pakzad, Mohammad Hossein Haddadi, Sousan Akrami, Arezoo Asadi, Hossein Kazemian, Melika Moradi, Vahab Hassan Kaviar, Abolfazl Rafati Zomorodi, Saeed Khoshnood, Mahnaz Shafieian, Ronia Tavasolian, Mohsen Heidary, Morteza Saki
BMC Infectious Diseases.2023;[Epub] CrossRef
Periodic Fluctuations in the Incidence of Gastrointestinal Cancer
Mun-Gan Rhyu, Jung-Hwan Oh, Tae Ho Kim, Joon-Sung Kim, Young A Rhyu, Seung-Jin Hong
Frontiers in Oncology.2021;[Epub] CrossRef
Fluoride exposure and CALCA methylation is associated with the bone mineral density of Chinese women
Renjie Sun, Guoyu Zhou, Lihua Liu, Lijun Ren, Yu Xi, Jingyuan Zhu, Hui Huang, Zhiyuan Li, Yan Li, Xuemin Cheng, Yue Ba
Chemosphere.2020; 253: 126616. CrossRef
Periodic Methylation Patterns in the Background Mucosa of Gastric Cancer
Sang-Woong Kim, Jung-Hwan Oh, Tae Ho Kim, Joon-Sung Kim, Seung-Jin Hong
The Korean Journal of Helicobacter and Upper Gastrointestinal Research.2019; 19(1): 48. CrossRef

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p15^Ink4b Loss of Expression by Promoter Hypermethylation Adds to Leukemogenesis and Confers a Poor Prognosis in Acute Promyelocytic Leukemia Patients: Shahid M. Baba, Niyaz A. Azad, Zafar A. Shah, Dil-Afroze , Arshad A. Pandith, Aleem Jan, Sheikh A. Aziz; Cancer Res Treat. 2017;49(3):790-797. Published online December 5, 2016; DOI: https://doi.org/10.4143/crt.2016.108

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Purpose
The p15^Ink4b gene exerts its influence as an inhibitor of cyclin-dependent kinases and is frequently associated with hematological malignancies. Inactivation of this gene through DNA methylation has been found to be the most prevalent epigenetic alteration reported, with a high frequency in all French-American-British subtypes of acute myeloid leukemias, including acute promyelocytic leukemia (APL). In this study,we investigated the prognostic significance of p15 gene promoter hypermethylation and its expression in APL patients of Kashmir(North India).
Materials and Methods
p15 gene promoter hypermethylation was conducted by methylation-specific polymerase chain reaction,while its subsequent expression analysiswas carried out by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR).
Results
Of the 37 patients, 16 (43.2%) were found to have methylated p15 genes. Of these 16 cases, seven (43.8%) were methylated partially and nine (56.2%) were found to have complete methylation. Moreover, nine of the 37 patients (24.3%) who presented with leukocytosis at their baseline had complete p15 gene methylation as well (p < 0.05). Semiquantitative RT-PCR showed a complete loss of p15 expression in nine patients with complete methylation coupled with leukocytosis (p=0.031), while seven patients with partial methylation showed decreased p15 expression. Six patients relapsed during the maintenance phase of treatment and were found to have a completely methylated p15 gene and no p15 mRNA.
Conclusion
Complete methylation and loss of p15 gene expression causes susceptibility to relapse and decreased survival in APL patients. Thus, p15 promoter hypermethylation is a prospective prognostic indicator and a reliable clinical aid in assessment of patients with APL.

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Realgar (α-As4S4) Treats Myelodysplastic Syndromes through Reducing DNA Hypermethylation
Miao Zhang, Jia-yi Zhang, Ming-qian Sun, Peng Lu, Jian-xun Liu
Chinese Journal of Integrative Medicine.2022; 28(3): 281. CrossRef
A study on DNA methylation status in promoter region of p15 gene in patients of acute myeloid leukemia and myelodysplastic syndrome
Sangeetha Sampath, Pratibha Misra, Sandeep Kumar Yadav, Sanjeevan Sharma, Venkatesan Somasundaram
Medical Journal Armed Forces India.2021; 77(3): 337. CrossRef
Gene regulations and delivery vectors for treatment of cancer
Ming Chen, Yu-Xin Ren, Ying Xie, Wan-Liang Lu
Journal of Pharmaceutical Investigation.2020; 50(3): 309. CrossRef
SERS-Based Assessment of MRD in Acute Promyelocytic Leukemia?
Cristina Turcas, Vlad Moisoiu, Andrei Stefancu, Ancuta Jurj, Stefania D. Iancu, Patric Teodorescu, Sergiu Pasca, Anca Bojan, Adrian Trifa, Sabina Iluta, Alina-Andreea Zimta, Bobe Petrushev, Mihnea Zdrenghea, Horia Bumbea, Daniel Coriu, Delia Dima, Nicolae
Frontiers in Oncology.2020;[Epub] CrossRef
Clinical and prognostic effects ofCDKN2A,CDKN2BandCDH13promoter methylation in ovarian cancer: a study using meta-analysis and TCGA data
Liang Xia, Wenzhu Zhang, Li Gao
Biomarkers.2019; 24(7): 700. CrossRef
Higher satisfaction with an alternative collection device for stool sampling in colorectal cancer screening with fecal immunochemical test: a cross-sectional study
Hye Young Shin, Mina Suh, Kui Son Choi, Sang-Hyun Hwang, Jae Kwan Jun, Dong Soo Han, You Kyoung Lee, Jae Hwan Oh, Chan Wha Lee, Do-Hoon Lee
BMC Cancer.2018;[Epub] CrossRef
Aging- and Senescence-associated Changes of Mesenchymal Stromal Cells in Myelodysplastic Syndromes
Domenico Mattiucci, Giulia Maurizi, Pietro Leoni, Antonella Poloni
Cell Transplantation.2018; 27(5): 754. CrossRef
The interaction between DNA methylation and long non‐coding RNA during the onset of puberty in goats
Chen Yang, Xiaoxiao Gao, Jing Ye, Jianping Ding, Ya Liu, Hongyu Liu, Xiumei Li, Yunhai Zhang, Jie Zhou, Weiping Huang, Fugui Fang, Yinghui Ling
Reproduction in Domestic Animals.2018; 53(6): 1287. CrossRef

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AKAP12α is Associated with Promoter Methylation in Lung Cancer: Ukhyun Jo, Young Mi Whang, Han Kyeom Kim, Yeul Hong Kim; Cancer Res Treat. 2006;38(3):144-151. Published online June 30, 2006; DOI: https://doi.org/10.4143/crt.2006.38.3.144

Abstract PDF PubReader ePub

Purpose

Promoter methylation is an important mechanism for silencing tumor-suppressor genes in cancer and it is a promising tool for the development of molecular biomarkers. The purpose of the present study was to investigate whether inactivation of the A Kinase Anchoring Protein 12 (AKAP12) gene is assoCiated with promoter methylation in lung cancer.

Materials and Methods

The AKAP12 expression was examined by reverse transcription-polymerase chain reaction (RT-PCR) in ten lung cancer cell lines. The methylation status of the AKAP12α promoter was analyzed by performing bisulfite sequencing analysis in ten lung cancer cell lines, twenty four lung tissues and matched normal tissues.

Results

The AKAP12α expression was reduced in 6 of 10 (60%) lung cancer cell lines, whereas the AKAP12β expression was absent in 1 of 10 (10%) lung cancer cell lines. The AKAP12α expression was restored after treatment with the demethylating agent 5-aza-2'-deoxycytidine in three lung cancer cell lines. Methylation of CpG island 1 in the AKAP12α promoter was detected in 30% of the lung cancer cell lines, whereas methylation of CpG island 2 in the AKAP12α promoter was observed in the immortalized bronchial cell line and in all the lung cancer cell lines. In lung tumors, the CpG island 1 in the AKAP12α promoter was infrequently methylated. However, CpG island 2 in the AKAP12α promoter was highly methylated in lung tumors compared with the surrounding normal tissues, and this was statistically significant (p=0.0001).

Conclusion

Our results suggest that inactivation of the AKAP12α expression is assoCiated with DNA methylation of the promoter region in lung cancer, and that AKAP12α may play an important role in lung cancer carcinogenesis.

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AKAP12 promotes cancer stem cell-like phenotypes and activates STAT3 in colorectal cancer
Ke Li, Xuan Wu, Yuan Li, Ting-Ting Hu, Weifeng Wang, Frank J. Gonzalez, Weiwei Liu
Clinical and Translational Oncology.2023; 25(11): 3263. CrossRef
Metastasis suppressor genes in clinical practice: are they druggable?
Irwin H. Gelman
Cancer and Metastasis Reviews.2023; 42(4): 1169. CrossRef
FGF10 Triggers De Novo Alveologenesis in a Bronchopulmonary Dysplasia Model: Impact on Resident Mesenchymal Niche Cells
Sara Taghizadeh, Cho-Ming Chao, Stefan Guenther, Lea Glaser, Luisa Gersmann, Gabriela Michel, Simone Kraut, Kerstin Goth, Janine Koepke, Monika Heiner, Ana Ivonne Vazquez-Armendariz, Susanne Herold, Christos Samakovlis, Norbert Weissmann, Francesca Ricci,
Stem Cells.2022; 40(6): 605. CrossRef
Identifying General Tumor and Specific Lung Cancer Biomarkers by Transcriptomic Analysis
Beatriz Andrea Otálora-Otálora, Daniel Alejandro Osuna-Garzón, Michael Steven Carvajal-Parra, Alejandra Cañas, Martín Montecino, Liliana López-Kleine, Adriana Rojas
Biology.2022; 11(7): 1082. CrossRef
Gene expression changes in cervical squamous cancers following neoadjuvant interventional chemoembolization
Yonghua Chen, Yuanyuan Hou, Ying Yang, Meixia Pan, Jing Wang, Wenshuang Wang, Ying Zuo, Jianglin Cong, Xiaojie Wang, Nan Mu, Chenglin Zhang, Benjiao Gong, Jianqing Hou, Shaoguang Wang, Liping Xu
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Cellular Signalling.2017; 40: 143. CrossRef
Elevated AKAP12 in Paclitaxel-Resistant Serous Ovarian Cancer Cells Is Prognostic and Predictive of Poor Survival in Patients
Nicholas W. Bateman, Elizabeth Jaworski, Wei Ao, Guisong Wang, Tracy Litzi, Elizabeth Dubil, Charlotte Marcus, Kelly A. Conrads, Pang-ning Teng, Brian L. Hood, Neil T. Phippen, Lisa A. Vasicek, William P. McGuire, Keren Paz, David Sidransky, Chad A. Hamil
Journal of Proteome Research.2015; 14(4): 1900. CrossRef
Suppression of tumor and metastasis progression through the scaffolding functions of SSeCKS/Gravin/AKAP12
Irwin H. Gelman
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CancerMA: a web-based tool for automatic meta-analysis of public cancer microarray data
Julia Feichtinger, Ramsay J. McFarlane, Lee D. Larcombe
Database.2012;[Epub] CrossRef
The angiogenesis suppressor gene AKAP12 is under the epigenetic control of HDAC7 in endothelial cells
Andrei Turtoi, Denis Mottet, Nicolas Matheus, Bruno Dumont, Paul Peixoto, Vincent Hennequière, Christophe Deroanne, Alain Colige, Edwin De Pauw, Akeila Bellahcène, Vincent Castronovo
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Nicole P. Chappell, Pang-ning Teng, Brian L. Hood, Guisong Wang, Kathleen M. Darcy, Chad A. Hamilton, G. Larry Maxwell, Thomas P. Conrads
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Akap12
Irwin Gelman
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Jeffrey W. Streb, Xiaochun Long, Ting-Hein Lee, Qiang Sun, Chad M. Kitchen, Mary A. Georger, Orazio J. Slivano, William S. Blaner, Daniel W. Carr, Irwin H. Gelman, Joseph M. Miano, Gian Paolo Fadini
PLoS ONE.2011; 6(4): e18538. CrossRef

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Gene Promoter Hypermethylation in Tumors and Plasma of Breast Cancer Patients: Young Kyung Bae, Young Ran Shim, Joon Hyuk Choi, Mi Jin Kim, Edward Gabrielson, Soo Jung Lee, Tae Yoon Hwang, Sei One Shin; Cancer Res Treat. 2005;37(4):233-240. Published online August 31, 2005; DOI: https://doi.org/10.4143/crt.2005.37.4.233

Abstract PDF PubReader ePub

Purpose

To measure the hypermethylation of four genes in primary tumors and paired plasma samples to determine the feasibility of gene promoter hypermethylation markers for detecting breast cancer in the plasma.

Materials and Methods

DNA was extracted from the tumor tissues and peripheral blood plasma of 34 patients with invasive breast cancer, and the samples examined for aberrant hypermethylation in cyclin D2, retinoic acid receptor β (RARβ), twist and high in normal-1 (HIN-1) genes using methylation-specific PCR (MSP), and the results correlated with the clinicopathological parameters.

Results

Promoter hypermethylation was detected at high frequency in the primary tumors for cyclin D2 (53%), RARβ (56%), twist (41%) and HIN-1 (77%). Thirty-three of the 34 (97%) primary tumors displayed promoter hypermethylation in at least one of the genes examined. The corresponding plasma samples showed hyperme thylation of the same genes, although at lower frequencies (6% for cyclin D2, 16% for RARβ, 36% for twist, and 54% for HIN-1). Overall, 22 of the 33 (67%) primary tumors with hypermethylation of at least one of the four genes also had abnormally hypermethylated DNA in their matched plasma samples. No significant relationship was recognized between any of the clinical or pathological parameters (tumor size, axillary lymph node metastasis, stage, or Ki-67 labeling index) with the frequency of hypermethylated DNA in the primary tumor or plasma.

Conclusion

The detection of aberrant promoter hypermethylation of cancer-related genes in the plasma may be a useful tool for the detection of breast cancer.

Citations

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Aberrantly Methylated cfDNA in Body Fluids as a Promising Diagnostic Tool for Early Detection of Breast Cancer
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Epigenetic Modifications as Biomarkers of Tumor Development, Therapy Response, and Recurrence across the Cancer Care Continuum
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Cancers.2018; 10(4): 101. CrossRef
Promoter Hypermethylation Analysis of the Tumor Suppressor Genes RASSF1A and RASSF2A in Iranian Endometrial Carcinoma Patients
Neda Jabbara, Golnaz Asaadi Tehrani, Fatemeh Lalooha, Seyed Amir Farzam, Khadijeh Elmizadeh
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Fatima Zahra Mouh, Mohammed El Mzibri, Meriem Slaoui, Mariam Amrani
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Menha Swellam, Mohamed D.E. Abdelmaksoud, Magda Sayed Mahmoud, Amal Ramadan, Walid Abdel‐Moneem, Mona M. Hefny
IUBMB Life.2015; 67(1): 61. CrossRef
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Mohamed M. Hafez, Othman A. Al-Shabanah, Salim S. Al-Rejaie, Naif O. Al-Harbi, Zeinab K. Hassan, Abdulmalik Alsheikh, Abdurrahman I. Al Theyab, Meshan L. Aldelemy, Mohamed M. Sayed-Ahmed
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Yanjie You, Wenjun Yang, Zhizhong Wang, Huimin Zhu, Haijun Li, Canfeng Lin, Yonggang Ran
Cellular Oncology.2013; 36(4): 323. CrossRef
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David S. Guttery, Kevin Blighe, Karen Page, Stephanie D. Marchese, Allison Hills, R. Charles Coombes, Justin Stebbing, Jacqueline A. Shaw
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K.P.M. Suijkerbuijk, P.J. van Diest, E. van der Wall
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Alterations of p15INK4B, p16INK4A and Methylthioadenosine Phosphorylase Gene in Korean Hepatdegrees Cellular Carcinoma: Ho Young Pyun, Jae We Cho, Won Ki Baik, Jong Wook Park, Jae Pok Park, Min Ho Suh, Seong Il Suh; J Korean Cancer Assoc. 2000;32(3):553-562.

Abstract PDF: PURPOSE
We analyzed the gene status of p16INK4A, p15INK4B and MTAP (methylthio adenosine phophorylase) in Korean hepatdegrees Cellular carcinoma (HCC) to investigate whether the inactivation of these genes participated in hepatdegrees Carcinogenesis, and evaluated MTAP-targeted chemotherapy in MTAP-deficient cell lines. MATERIAL AND METHODS: We examined eleven primary HCC and 8 SNU cell lines using PCR, Southern blot analysis, PCR-SSCP, DNA sequencing, methylation-specific PCR, Western blot analysis, MTT assay, and crystal violet staining.
RESULTS
Mutations or deletion of the p16INK4A, 15INK4B, and MTAP genes were rare, but methylation of the p16INK4A promoter region was common in HCC. The base alterations of 3' untranslated region of p16INK4A exon 3 were also detected in 3 samples. In SNU cells, p16INK4A was not detectable, when treated with demethylating agent, high levels of re-expressed p16INK4A protein were detected. In MTAP-targeted chemotherapy experiment, methylthioadeno sine (MTA) was able to rescue MTAP positive cell lines but not MTAP negative cell lines from growth inhibition by depletion of methionine and MTX treatment.
CONCLUSION
These results suggest that de novo methylation of the p16INK4A promoter region seems to play an important role in the pathogenesis of HCC. And treatment of MTX, combined with methionine depletion in the presence of MTA, may be a high selective treatment for MTAP negative HCC.

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Genetic Alterations of p16Ink4A and p15Ink4B in Gastric Carcinomas: Kwon Hur, Han Kwang Yang, Ja June Jang, Jin Pok Kim, Dae Young Kim; J Korean Cancer Assoc. 1999;31(5):887-897.

Abstract PDF: PURPOSE
p16Ink4A and p15lnk4B, encoded by the genes located on chromosome 9p21, are cyclin-dependent kinase 4 inhibitors and are the upstream regulators of pRB (retinoblastoma protein) function and are involved in the regulation of cell cycle in mammalian cells. It has been demonstrated that p16 and p15 genes are frequently deleted, mutated, and hypermethylated in many malignancies and cancer cell lines. This study was performed to investigate the genetic alteration and immunohistochemical profile of p16 and p15 in gastric carcinomas.
MATERIALS AND METHODS
We examined 30 primary gastric cancer samples using PCR- SSCP (Polymerase chain reaction-single strand conformation polymorphism), DNA sequencing, PCR-based hypermethylation assay, and immunohistochemistry.
RESULTS
No homozygous deletion was detected in either pl6 or p15 gene, and only one gastric carcinoma sample showed mutation of p16 gene and p15 gene. However, hyper-methylation of 5' CpG islands was observed in 53.6% of exon1 of p16 gene and in 46.4% of exon 1 of pl5 gene. By immunohistochemistry of p16, nuclear under-expression was observed in 58.6%, whereas nuclear over-expression was detected in 31% of formalin-fixed, paraffin-embedded gastric cancer tissues.
CONCLUSIONS
Our results suggest that the p16 and p15 tumor suppressor genes may play an important role in gastric carcinogenesis and may be inactivated not by deletions or mutations but mainly by hypermethylation of their 5' CpG islands. There was a good correlation between methylation study and immunohistochemical results in p16 genes.

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