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Liu T, Conesa A. Profiling the epigenome using long-read sequencing. Nat Genet 2025; 57:27-41. [PMID: 39779955 DOI: 10.1038/s41588-024-02038-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 11/19/2024] [Indexed: 01/11/2025]
Abstract
The advent of single-molecule, long-read sequencing (LRS) technologies by Oxford Nanopore Technologies and Pacific Biosciences has revolutionized genomics, transcriptomics and, more recently, epigenomics research. These technologies offer distinct advantages, including the direct detection of methylated DNA and simultaneous assessment of DNA sequences spanning multiple kilobases along with their modifications at the single-molecule level. This has enabled the development of new assays for analyzing chromatin states and made it possible to integrate data for DNA methylation, chromatin accessibility, transcription factor binding and histone modifications, thereby facilitating comprehensive epigenomic profiling. Owing to recent advancements, alternative, nascent and translating transcripts can be detected using LRS approaches. This Review discusses LRS-based experimental and computational strategies for characterizing chromatin states and highlights their advantages over short-read sequencing methods. Furthermore, we demonstrate how various long-read methods can be integrated to design multi-omics studies to investigate the relationship between chromatin states and transcriptional dynamics.
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Affiliation(s)
- Tianyuan Liu
- Institute for Integrative Systems Biology, Spanish National Research Council, Paterna, Spain
| | - Ana Conesa
- Institute for Integrative Systems Biology, Spanish National Research Council, Paterna, Spain.
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2
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Han S, Wang M, Wang Y, Wu J, Guo Z, Wang H, Liu R, Qiu X, Hu L, Bi J, Yan W, An H, Zhang G, Zhi Y, Chen Z, Chen L, Liu L, Cheng H, Zhu S, Wang M, Zhang Y, Liu X, Lou F, Cao S, Ye D, Niu Y, Xing N. Development and validation of the utLIFE-PC algorithm for noninvasive detection of prostate cancer in urine: A prospective, observational study. Cell Rep Med 2024; 5:101870. [PMID: 39657665 PMCID: PMC11722088 DOI: 10.1016/j.xcrm.2024.101870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 03/20/2024] [Accepted: 11/18/2024] [Indexed: 12/12/2024]
Abstract
Overbiopsy is a serious health issue in prostate cancer (PCa) diagnostics. We have developed a urine tumor DNA multidimensional bioinformatic algorithm, utLIFE, to avoid unnecessary biopsy. The objective is to recognize all or clinically significant PCa. Of the 801 participants recruited in our study, 630 are selected for subsequent analysis. In the training cohort (n = 237), utLIFE-PC gets an area under the receiver operating characteristic curve (AUC) of 0.967 and a sensitivity of 85.57% at 95% specificity. In the independent prospective validation cohort (n = 343), utLIFE-PC has an AUC of 0.929, sensitivity of 84.24%, and specificity of 93.26%. Notably, in patients with ≥grade group (GG)2 and ≥GG3, the assay's sensitivity is still excellent (85.33% and 87.10%, respectively). The model shows better performance than prostate-specific antigen (PSA) (p < 0.001) or the single-dimensional biomarkers (methylation, p < 0.001; copy-number variations [CNVs], p < 0.001; mutation, p < 0.001). The utLIFE-PC model can potentially optimize the PCa diagnostic process and avoid unnecessary biopsies. This study was registered at Chinese Clinical Trial Registry: ChiCTR2300071837.
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Affiliation(s)
- Sujun Han
- Department of Urology and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mingshuai Wang
- Department of Urology and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yong Wang
- Department of Urology, The Second Affiliated Hospital of Tianjin Medical University, Tianjin, China
| | - Junlong Wu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhaoxia Guo
- Department of Research and Development, Acornmed Biotechnology Co., Ltd., Beijing, China
| | - Huina Wang
- Department of Research and Development, Acornmed Biotechnology Co., Ltd., Beijing, China
| | - Ranlu Liu
- Department of Urology, The Second Affiliated Hospital of Tianjin Medical University, Tianjin, China
| | - Xiaofu Qiu
- Department of Urology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Linjun Hu
- Department of Urology, Cancer Hospital of HuanXing, Chaoyang District Beijing, Beijing, China
| | - Jianbin Bi
- Department of Urology, China Medical University, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Weigang Yan
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Hengqing An
- Department of Urology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China
| | - Gejun Zhang
- Department of Urology, China Medical University, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yi Zhi
- Department of Urology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhiyuan Chen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Libin Chen
- Department of Research and Development, Acornmed Biotechnology Co., Ltd., Beijing, China
| | - Lei Liu
- Department of Research and Development, Acornmed Biotechnology Co., Ltd., Beijing, China
| | - Huanqing Cheng
- Department of Research and Development, Acornmed Biotechnology Co., Ltd., Beijing, China
| | - Shuaipeng Zhu
- Department of Research and Development, Acornmed Biotechnology Co., Ltd., Beijing, China
| | - Meng Wang
- Department of Research and Development, Acornmed Biotechnology Co., Ltd., Beijing, China
| | - Yanrui Zhang
- Department of Research and Development, Acornmed Biotechnology Co., Ltd., Beijing, China
| | - Xiao Liu
- Department of Research and Development, Acornmed Biotechnology Co., Ltd., Beijing, China
| | - Feng Lou
- Department of Research and Development, Acornmed Biotechnology Co., Ltd., Beijing, China.
| | - Shanbo Cao
- Department of Research and Development, Acornmed Biotechnology Co., Ltd., Beijing, China.
| | - Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
| | - Yuanjie Niu
- Department of Urology, The Second Affiliated Hospital of Tianjin Medical University, Tianjin, China.
| | - Nianzeng Xing
- Department of Urology and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Urology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China.
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Lucchini S, Constantinou M, Marino S. Unravelling the mosaic: Epigenetic diversity in glioblastoma. Mol Oncol 2024; 18:2871-2889. [PMID: 39148319 PMCID: PMC11619803 DOI: 10.1002/1878-0261.13706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 06/21/2024] [Accepted: 07/23/2024] [Indexed: 08/17/2024] Open
Abstract
Glioblastoma is the most common primary malignant brain tumour. Despite decades of intensive research in the disease, its prognosis remains poor, with an average survival of only 14 months after diagnosis. The remarkable level of intra- and interpatient heterogeneity is certainly contributing to the lack of progress in tackling this tumour. Epigenetic dysregulation plays an important role in glioblastoma biology and significantly contributes to intratumour heterogeneity. However, it is becoming increasingly clear that it also contributes to intertumour heterogeneity, which historically had mainly been linked to diverse genetic events occurring in different patients. In this review, we explore how DNA methylation, chromatin remodelling, microRNA (miRNA) dysregulation, and long noncoding RNA (lncRNA) alterations contribute to intertumour heterogeneity in glioblastoma, including its implications for advanced tumour stratification, which is the essential first step for developing more effective patient-specific therapeutic approaches.
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Affiliation(s)
- Sara Lucchini
- Brain Tumour Research Centre, Blizard Institute, Faculty of Medicine and DentistryQueen Mary University of LondonUK
| | - Myrianni Constantinou
- Brain Tumour Research Centre, Blizard Institute, Faculty of Medicine and DentistryQueen Mary University of LondonUK
| | - Silvia Marino
- Brain Tumour Research Centre, Blizard Institute, Faculty of Medicine and DentistryQueen Mary University of LondonUK
- Barts Brain Tumour Centre, Faculty of Medicine and DentistryQueen Mary University of LondonUK
- Barts Health NHS TrustLondonUK
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4
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Li L, Fei X, Wang H, Chen S, Xu X, Ke H, Zhou Y, Hu Y, He C, Xie C, Lu N, Liu J, Zhu Y, Li N. Genome-wide DNA methylation profiling reveals a novel hypermethylated biomarker PRKCB in gastric cancer. Sci Rep 2024; 14:26605. [PMID: 39496833 PMCID: PMC11535215 DOI: 10.1038/s41598-024-78135-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 10/29/2024] [Indexed: 11/06/2024] Open
Abstract
Globally, gastric cancer (GC) ranks among the most prevalent forms of malignancy, posing a significant health burden. Epigenetic modifications, predominantly characterized by alterations in DNA methylation patterns, have been linked to a diverse array of neoplastic processes. Here, we undertake a comprehensive analysis of the DNA methylation signature in GC, with the aim to discover the potential diagnostic epigenetic biomarkers. Utilizing the Illumina 935 K BeadChip, we conducted a genome-wide exploration of DNA methylation patterns in four paired samples of GC tissues and adjacent non-cancerous counterparts. The bisulfite-pyrosequencing (n = 7) was employed to the quantification for methylated gene. The pubic databases including GWAS Catalog, TCGA and GEO were used. The immunohistochemistry and qRT-PCR analysis were performed. In contrast to adjacent tissues, GC tissues manifested pronounced hypermethylation patterns specifically within the promoter cytosine-phosphate-guanine (CpG) islands, indicating localized epigenetic alterations. DNA methylome analysis further revealed 4432 differentially-methylated probes (DMPs), with the gene PRKCB exhibited the most prominent average DNA methylation disparity (mean Δβ = 0.353). Pyrosequencing validation confirmed three DMPs within the PRKCB promoter (cg08406370, cg00735962, and cg18526361). Notably, the mean methylation levels of PRKCB were inversely correlated with mRNA expression levels in the GWAS Catalog. Furthermore, both mRNA and protein expression levels of PRKCB were significantly reduced in GCs when compared to their adjacent non-cancerous counterparts, verified by TCGA and GEO database. Our study reveals significant DNA methylation alterations in GC and emphasizes the pivotal role of PRKCB gene hypermethylation in conferring GC risk, which offers fresh perspectives for advancing diagnostic approaches and therapeutic strategies for GC.
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Affiliation(s)
- Leyan Li
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xiao Fei
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Huan Wang
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Postdoctoral Innovation Practice Base, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Sihai Chen
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xinbo Xu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Huajing Ke
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yanan Zhou
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yi Hu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Cong He
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Chuan Xie
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Nonghua Lu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Jianping Liu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yin Zhu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
| | - Nianshuang Li
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
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Esteller M, Dawson MA, Kadoch C, Rassool FV, Jones PA, Baylin SB. The Epigenetic Hallmarks of Cancer. Cancer Discov 2024; 14:1783-1809. [PMID: 39363741 DOI: 10.1158/2159-8290.cd-24-0296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/08/2024] [Accepted: 06/24/2024] [Indexed: 10/05/2024]
Abstract
Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, in the latest iteration of the cancer hallmarks, "nonmutational epigenetic reprogramming" was newly added. However, epigenetics, much like genetics, is a broad scientific area that deserves further attention due to its multiple roles in cancer initiation, progression, and adaptive nature. Herein, we present a detailed examination of the epigenetic hallmarks affected in human cancer, elucidating the pathways and genes involved, and dissecting the disrupted landscapes for DNA methylation, histone modifications, and chromatin architecture that define the disease. Significance: Cancer is a disease characterized by constant evolution, spanning from its initial premalignant stages to the advanced invasive and disseminated stages. It is a pathology that is able to adapt and survive amidst hostile cellular microenvironments and diverse treatments implemented by medical professionals. The more fixed setup of the genetic structure cannot fully provide transformed cells with the tools to survive but the rapid and plastic nature of epigenetic changes is ready for the task. This review summarizes the epigenetic hallmarks that define the ecological success of cancer cells in our bodies.
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Affiliation(s)
- Manel Esteller
- Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
- Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
- Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
| | - Mark A Dawson
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Centre for Cancer Research, University of Melbourne, Melbourne, Australia
| | - Cigall Kadoch
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Howard Hughes Medical Institute, Chevy Chase, Maryland
| | - Feyruz V Rassool
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Peter A Jones
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
| | - Stephen B Baylin
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
- Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
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Xu S, Chen T, Yu J, Wan L, Zhang J, Chen J, Wei W, Li X. Insights into the regulatory role of epigenetics in moyamoya disease: Current advances and future prospectives. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102281. [PMID: 39188306 PMCID: PMC11345382 DOI: 10.1016/j.omtn.2024.102281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/28/2024]
Abstract
Moyamoya disease (MMD) is a progressive steno-occlusive cerebrovascular disorder that predominantly affecting East Asian populations. The intricate interplay of distinct and overlapping mechanisms, including genetic associations such as the RNF213-p.R4810K variant, contributes to the steno-occlusive lesions and moyamoya vessels. However, genetic mutations alone do not fully elucidate the occurrence of MMD, suggesting a potential role for epigenetic factors. Accruing evidence has unveiled the regulatory role of epigenetic markers, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), in regulating pivotal cellular and molecular processes implicated in the pathogenesis of MMD by modulating endothelial cells and smooth muscle cells. The profile of these epigenetic markers in cerebral vasculatures and circulation has been determined to identify potential diagnostic biomarkers and therapeutic targets. Furthermore, in vitro studies have demonstrated the multifaceted effects of modulating specific epigenetic markers on MMD pathogenesis. These findings hold great potential for the discovery of novel therapeutic targets, translational studies, and clinical applications. In this review, we comprehensively summarize the current understanding of epigenetic mechanisms, including DNA methylation, histone modifications, and ncRNAs, in the context of MMD. Furthermore, we discuss the potential challenges and opportunities that lie ahead in this rapidly evolving field.
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Affiliation(s)
- Shuangxiang Xu
- Brain Research Center, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Tongyu Chen
- Brain Research Center, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Jin Yu
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Lei Wan
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Jianjian Zhang
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Jincao Chen
- Brain Research Center, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Wei Wei
- Brain Research Center, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Xiang Li
- Brain Research Center, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, China
- Medical Research Institute, Wuhan University, Wuhan 430071, China
- Sino-Italian Ascula Brain Science Joint Laboratory, Wuhan University, Wuhan 430071, China
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Chen XP, He SX, Chen MY, Chen FB, Wu P, Shi P, Zhao SC, Zhao LY, Xiong XM, Zeng J. Meta-analysis of the accuracy for RASSF1A methylation in bronchial aspirates for the diagnosis of lung cancer. PLoS One 2024; 19:e0299447. [PMID: 39052646 PMCID: PMC11271935 DOI: 10.1371/journal.pone.0299447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 02/10/2024] [Indexed: 07/27/2024] Open
Abstract
OBJECTIVE To establish the diagnostic accuracy of RASSF1A (Ras association domain family 1 isoform) methylation using bronchial aspirates as an auxiliary method for diagnosing lung cancer through a systematic review and meta-analysis. METHODS Studies published prior to October 30, 2022, were retrieved from the Embase, PubMed, Web of Science, and Wan Fang databases using the keywords "lung cancer", "RASSF1A", "methylation", and "bronchial aspirates". A fixed or random effect model was used to calculate the combined sensitivity, specificity, positive likelihood ratios (LR), negative LR, diagnostic odds ratio (DOR), along with the respective 95% confidence intervals (CIs) and the area under the curve (AUC) with Q index. The threshold effect was defined by using the Spearman correlation coefficient, and the Deeks funnel plot was generated to evaluate publication bias. RESULTS Among the 12 trials that met the inclusion criteria, a total of 2388 participants were involved. The pooled results for the diagnosis of lung cancer were as follows, when compared to the pathological diagnosis: sensitivity of 0.47 (95% CI: 0.45-0.50), specificity of 0.96 (95% CI: 0.95-0.97), positive LR of 12.18 (95% CI: 8.96-16.55), negative LR of 0.56 (95% CI: 0.52-0.61), DOR of 24.05 (95% CI: 17.29-33.47), and AUC of 0.78 (Q index = 0.72), respectively. The sensitivity of the RASSF1A methylation assay was relatively low in a detailed subgroup analysis, fluctuating between 0.39 and 0.90, indicating a limitation in its diagnostic value for lung cancer. The RASSF1A methylation assay, on the other hand, demonstrated excellent specificity, suggesting a high exclusion value. Of note, the diagnostic sensitivity, specificity, DOR, and AUC for small cell lung cancer were 0.90 (0.84-0.94), 0.95 (0.94-0.97), 249.5 (103.94-598.8), and 0.98, respectively, showing that RASSF1A methylation was a promising biomarker for diagnosing small cell lung cancer with both high diagnostic and exclusion value. Furthermore, RASSF1A methylation using bronchial washings and bronchial aspirates showed a high AUC of 0.998 and 0.93, respectively, indicating excellent diagnostic performance. CONCLUSIONS The methylation of RASSF1A in bronchial aspirates demonstrated a high level of diagnostic accuracy and has the potential to be a valuable supplementary diagnostic method, especially for identifying small cell lung cancer.
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Affiliation(s)
- Xu-ping Chen
- Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, Sichuan Province, China
| | - Shi-xu He
- Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, Sichuan Province, China
| | - Meng-you Chen
- Intern, Qiqihar Medical University, Qiqihar, Heilongjiang Province, China
| | - Fu-bin Chen
- Department of General Internal Medicine, Qianwei Xuefu Community Health Service Center, Leshan, SiChuan Province, China
| | - Peng Wu
- Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, Sichuan Province, China
| | - Ping Shi
- Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, Sichuan Province, China
| | - Shi-cai Zhao
- Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, Sichuan Province, China
| | - Ling-yan Zhao
- Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, Sichuan Province, China
| | - Xiao-min Xiong
- Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, Sichuan Province, China
| | - Jia Zeng
- Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, Sichuan Province, China
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Rendek T, Pos O, Duranova T, Saade R, Budis J, Repiska V, Szemes T. Current Challenges of Methylation-Based Liquid Biopsies in Cancer Diagnostics. Cancers (Basel) 2024; 16:2001. [PMID: 38893121 PMCID: PMC11171112 DOI: 10.3390/cancers16112001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 05/13/2024] [Accepted: 05/16/2024] [Indexed: 06/21/2024] Open
Abstract
In current clinical practice, effective cancer testing and screening paradigms are limited to specific types of cancer, exhibiting varying efficiency, acceptance, and adherence. Cell-free DNA (cfDNA) methylation profiling holds promise in providing information about the presence of malignity regardless of its type and location while leveraging blood-based liquid biopsies as a method to obtain analytical samples. However, technical difficulties, costs and challenges resulting from biological variations, tumor heterogeneity, and exogenous factors persist. This method exploits the mechanisms behind cfDNA release but faces issues like fragmentation, low concentrations, and high background noise. This review explores cfDNA methylation's origins, means of detection, and profiling for cancer diagnostics. The critical evaluation of currently available multi-cancer early detection methods (MCEDs) as well as tests targeting single genes, emphasizing their potential and limits to refine strategies for early cancer detection, are explained. The current methodology limitations, workflows, comparisons of clinically approved liquid biopsy-based methylation tests for cancer, their utilization in companion diagnostics as well as the biological limitations of the epigenetics approach are discussed, aiming to help healthcare providers as well as researchers to orient themselves in this increasingly complex and evolving field of diagnostics.
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Affiliation(s)
- Tomas Rendek
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Ondrej Pos
- Geneton Ltd., 841 04 Bratislava, Slovakia; (O.P.); (J.B.); (T.S.)
- Comenius University Science Park, 841 04 Bratislava, Slovakia;
| | | | - Rami Saade
- 2nd Department of Gynaecology and Obstetrics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Jaroslav Budis
- Geneton Ltd., 841 04 Bratislava, Slovakia; (O.P.); (J.B.); (T.S.)
- Comenius University Science Park, 841 04 Bratislava, Slovakia;
| | - Vanda Repiska
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Tomas Szemes
- Geneton Ltd., 841 04 Bratislava, Slovakia; (O.P.); (J.B.); (T.S.)
- Comenius University Science Park, 841 04 Bratislava, Slovakia;
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Zhu C, Hao Z, Liu D. Reshaping the Landscape of the Genome: Toolkits for Precise DNA Methylation Manipulation and Beyond. JACS AU 2024; 4:40-57. [PMID: 38274248 PMCID: PMC10806789 DOI: 10.1021/jacsau.3c00671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/26/2023] [Accepted: 12/01/2023] [Indexed: 01/27/2024]
Abstract
DNA methylation plays a pivotal role in various biological processes and is highly related to multiple diseases. The exact functions of DNA methylation are still puzzling due to its uneven distribution, dynamic conversion, and complex interactions with other substances. Current methods such as chemical- and enzyme-based sequencing techniques have enabled us to pinpoint DNA methylation at single-base resolution, which necessitated the manipulation of DNA methylation at comparable resolution to precisely illustrate the correlations and causal relationships between the functions of DNA methylation and its spatiotemporal patterns. Here a perspective on the past, recent process, and future of precise DNA methylation tools is provided. Specifically, genome-wide and site-specific manipulation of DNA methylation methods is discussed, with an emphasis on their principles, limitations, applications, and future developmental directions.
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Affiliation(s)
- Chenyou Zhu
- Engineering
Research Center of Advanced Rare Earth Materials, Ministry of Education,
Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Ziyang Hao
- School
of Pharmaceutical Sciences, Capital Medical
University, Beijing, 100069, PR China
| | - Dongsheng Liu
- Engineering
Research Center of Advanced Rare Earth Materials, Ministry of Education,
Department of Chemistry, Tsinghua University, Beijing 100084, China
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10
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Sharma S, Sarkar O, Ghosh R. Exploring the Role of Unconventional Post-Translational Modifications in Cancer Diagnostics and Therapy. Curr Protein Pept Sci 2024; 25:780-796. [PMID: 38910429 DOI: 10.2174/0113892037274615240528113148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 04/22/2024] [Accepted: 04/29/2024] [Indexed: 06/25/2024]
Abstract
Unconventional Post-Translational Modifications (PTMs) have gained increasing attention as crucial players in cancer development and progression. Understanding the role of unconventional PTMs in cancer has the potential to revolutionize cancer diagnosis, prognosis, and therapeutic interventions. These modifications, which include O-GlcNAcylation, glutathionylation, crotonylation, including hundreds of others, have been implicated in the dysregulation of critical cellular processes and signaling pathways in cancer cells. This review paper aims to provide a comprehensive analysis of unconventional PTMs in cancer as diagnostic markers and therapeutic targets. The paper includes reviewing the current knowledge on the functional significance of various conventional and unconventional PTMs in cancer biology. Furthermore, the paper highlights the advancements in analytical techniques, such as biochemical analyses, mass spectrometry and bioinformatic tools etc., that have enabled the detection and characterization of unconventional PTMs in cancer. These techniques have contributed to the identification of specific PTMs associated with cancer subtypes. The potential use of Unconventional PTMs as biomarkers will further help in better diagnosis and aid in discovering potent therapeutics. The knowledge about the role of Unconventional PTMs in a vast and rapidly expanding field will help in detection and targeted therapy of cancer.
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Affiliation(s)
- Sayan Sharma
- Department of Biotechnology, Amity University Kolkata, AIBNK, Kolkata, West Bengal, India
| | - Oindrila Sarkar
- Department of Biotechnology, Amity University Kolkata, AIBNK, Kolkata, West Bengal, India
| | - Rajgourab Ghosh
- Department of Biotechnology, Amity University Kolkata, AIBNK, Kolkata, West Bengal, India
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11
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Papakonstantinou E, Pappa I, Androutsopoulos G, Adonakis G, Maroulis I, Tzelepi V. Comprehensive Analysis of DNA Methyltransferases Expression in Primary and Relapsed Ovarian Carcinoma. Cancers (Basel) 2023; 15:4950. [PMID: 37894317 PMCID: PMC10605797 DOI: 10.3390/cancers15204950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/21/2023] [Accepted: 10/02/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Despite recent advances in epithelial ovarian carcinoma (EOC) treatment, its recurrence and mortality rates have not improved significantly. DNA hypermethylation has generally been associated with an ominous prognosis and chemotherapy resistance, but the role of DNA methyltransferases (DNMTs) in EOC remains to be investigated. METHODS In the current study, we systematically retrieved gene expression data from patients with EOC and studied the immunohistochemical expression of DNMTs in 108 primary and 26 relapsed tumors. RESULTS Our results showed that the DNMT1, DNMT3A, DNMT3B and DNMT3L RNA levels were higher and the DNMT2 level was lower in tumors compared to non-neoplastic tissue, and DNMT3A and DNMT2 expression decreased from Stage-II to Stage-IV carcinomas. The proteomic data also suggested that the DNMT1 and DNMT3A levels were increased in the tumors. Similarly, the DNMT1, DNMT3A and DNMT3L protein levels were overexpressed and DNMT2 expression was reduced in high-grade carcinomas compared to non-neoplastic tissue and low-grade tumors. Moreover, DNMT1 and DNMT3L were increased in relapsed tumors compared to their primaries. The DNMT3A, DNMT1 and DNMT3B mRNA levels were correlated with overall survival. CONCLUSIONS Our study demonstrates that DNMT1 and DNMT3L are upregulated in primary high-grade EOC and further increase in relapses, whereas DNMT3A is upregulated only in the earlier stages of cancer progression. DNMT2 downregulation highlights the presumed tumor-suppressor activity of this gene in ovarian carcinoma.
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Affiliation(s)
- Efthymia Papakonstantinou
- Department of Obstetrics and Gynecology, School of Medicine, University of Patras, 26504 Patras, Greece; (E.P.); (G.A.)
| | - Ioanna Pappa
- Multidimensional Data Analysis and Knowledge Management Laboratory, Computer Engineering and Informatics Department, School of Engineering, University of Patras, 26504 Patras, Greece;
| | - Georgios Androutsopoulos
- Gynecological Oncology Unit, Department of Obstetrics and Gynecology, Medical School, University of Patras, 26504 Patras, Greece;
| | - Georgios Adonakis
- Department of Obstetrics and Gynecology, School of Medicine, University of Patras, 26504 Patras, Greece; (E.P.); (G.A.)
| | - Ioannis Maroulis
- Department of General Surgery, School of Medicine, University of Patras, 26504 Patras, Greece;
| | - Vasiliki Tzelepi
- Department of Pathology, School of Medicine, University of Patras, 26504 Patras, Greece
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12
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Yabushita T, Chinen T, Nishiyama A, Asada S, Shimura R, Isobe T, Yamamoto K, Sato N, Enomoto Y, Tanaka Y, Fukuyama T, Satoh H, Kato K, Saitoh K, Ishikawa T, Soga T, Nannya Y, Fukagawa T, Nakanishi M, Kitagawa D, Kitamura T, Goyama S. Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment. Cell Rep 2023; 42:113098. [PMID: 37714156 DOI: 10.1016/j.celrep.2023.113098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 06/22/2023] [Accepted: 08/21/2023] [Indexed: 09/17/2023] Open
Abstract
Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.
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Affiliation(s)
- Tomohiro Yabushita
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takumi Chinen
- Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Atsuya Nishiyama
- Division of Cancer Cell Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Shuhei Asada
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; The Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, Japan
| | - Ruka Shimura
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Tomoya Isobe
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Keita Yamamoto
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Naru Sato
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yutaka Enomoto
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yosuke Tanaka
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tomofusa Fukuyama
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Hematology, International University of Health and Welfare Hospital, Tochigi, Japan
| | - Hitoshi Satoh
- Division of Medical Genome Sciences, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Keiko Kato
- Infinity Lab, INC, Yamagata, Japan; Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Kaori Saitoh
- Infinity Lab, INC, Yamagata, Japan; Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Takamasa Ishikawa
- Infinity Lab, INC, Yamagata, Japan; Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Yasuhito Nannya
- Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tatsuo Fukagawa
- Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
| | - Makoto Nakanishi
- Division of Cancer Cell Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Daiju Kitagawa
- Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Toshio Kitamura
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan
| | - Susumu Goyama
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
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13
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Steers GJ, O’Leary BR, Du J, Wagner BA, Carroll RS, Domann FE, Goswami PC, Buettner GR, Cullen JJ. Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer. Antioxidants (Basel) 2023; 12:1683. [PMID: 37759986 PMCID: PMC10525653 DOI: 10.3390/antiox12091683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/23/2023] [Accepted: 08/25/2023] [Indexed: 09/29/2023] Open
Abstract
Recent studies have demonstrated an important role for vitamin C in the epigenetic regulation of cancer-related genes via DNA demethylation by the ten-eleven translocation (TET) methylcytosine dioxygenase enzymes. DNA methyltransferase (DNMT) reverses this, increasing DNA methylation and decreasing gene expression. Dual oxidase (DUOX) enzymes produce hydrogen peroxide (H2O2) in normal pancreatic tissue but are silenced in pancreatic cancer (PDAC). Treatment of PDAC with pharmacologic ascorbate (P-AscH-, intravenous, high dose vitamin C) increases DUOX expression. We hypothesized that inhibiting DNMT may act synergistically with P-AscH- to further increase DUOX expression and cytotoxicity of PDAC. PDAC cells demonstrated dose-dependent increases in DUOX mRNA and protein expression when treated with DNMT inhibitors. PDAC cells treated with P-AscH- + DNMT inhibitors demonstrated increased DUOX expression, increased intracellular oxidation, and increased cytotoxicity in vitro and in vivo compared to either treatment alone. These findings suggest a potential therapeutic, epigenetic mechanism to treat PDAC.
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Affiliation(s)
- Garett J. Steers
- Free Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USA; (G.J.S.); (B.R.O.); (J.D.); (B.A.W.); (R.S.C.); (F.E.D.); (P.C.G.); (G.R.B.)
- The Department of Surgery, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Brianne R. O’Leary
- Free Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USA; (G.J.S.); (B.R.O.); (J.D.); (B.A.W.); (R.S.C.); (F.E.D.); (P.C.G.); (G.R.B.)
- The Department of Surgery, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Juan Du
- Free Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USA; (G.J.S.); (B.R.O.); (J.D.); (B.A.W.); (R.S.C.); (F.E.D.); (P.C.G.); (G.R.B.)
- The Department of Surgery, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Brett A. Wagner
- Free Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USA; (G.J.S.); (B.R.O.); (J.D.); (B.A.W.); (R.S.C.); (F.E.D.); (P.C.G.); (G.R.B.)
| | - Rory S. Carroll
- Free Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USA; (G.J.S.); (B.R.O.); (J.D.); (B.A.W.); (R.S.C.); (F.E.D.); (P.C.G.); (G.R.B.)
- The Department of Surgery, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Frederick E. Domann
- Free Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USA; (G.J.S.); (B.R.O.); (J.D.); (B.A.W.); (R.S.C.); (F.E.D.); (P.C.G.); (G.R.B.)
| | - Prabhat C. Goswami
- Free Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USA; (G.J.S.); (B.R.O.); (J.D.); (B.A.W.); (R.S.C.); (F.E.D.); (P.C.G.); (G.R.B.)
| | - Garry R. Buettner
- Free Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USA; (G.J.S.); (B.R.O.); (J.D.); (B.A.W.); (R.S.C.); (F.E.D.); (P.C.G.); (G.R.B.)
| | - Joseph J. Cullen
- Free Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USA; (G.J.S.); (B.R.O.); (J.D.); (B.A.W.); (R.S.C.); (F.E.D.); (P.C.G.); (G.R.B.)
- The Department of Surgery, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
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14
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Shahraki K, Shahraki K, Ghasemi Boroumand P, Sheervalilou R. Promotor methylation in ocular surface squamous neoplasia development: epigenetics implications in molecular diagnosis. Expert Rev Mol Diagn 2023; 23:753-769. [PMID: 37493058 DOI: 10.1080/14737159.2023.2240238] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 07/20/2023] [Indexed: 07/27/2023]
Abstract
INTRODUCTION Cancer is heavily influenced by epigenetic mechanisms that include DNA methylation, histone modifications, and non-coding RNA. A considerable proportion of human malignancies are believed to be associated with global DNA hypomethylation, with localized hypermethylation at promoters of certain genes. AREA COVERED The present review aims to emphasize on recent investigations on the epigenetic landscape of ocular surface squamous neoplasia, that could be targeted/explored using novel approaches such as personalized medicine. EXPERT OPINION While the former is thought to contribute to genomic instability, promoter-specific hypermethylation might facilitate tumorigenesis by silencing tumor suppressor genes. Ocular surface squamous neoplasia, the most prevalent type of ocular surface malignancy, is suggested to be affected by epigenetic mechanisms, as well. Although the exact role of epigenetics in ocular surface squamous neoplasia has mostly been unexplored, recent findings have greatly contributed to our understanding regarding this pathology of the eye.
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Affiliation(s)
- Kourosh Shahraki
- Ocular Tissue Engineering Research Center, Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Ophthalmology, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Kianoush Shahraki
- Department of Ophthalmology, Zahedan University of Medical Sciences, Zahedan, Iran
- Cornea Department, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Paria Ghasemi Boroumand
- ENT, Head and Neck Research Center and Department, Iran University of Medical Science, Tehran, Iran
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15
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Fangyu Zhou, Chen H, Fan T, Guo Z, Liu F. Fluorescence turn-off strategy for sensitive detection of DNA methyltransferase activity based on DNA-templated gold nanoclusters. Heliyon 2023; 9:e17724. [PMID: 37449164 PMCID: PMC10336507 DOI: 10.1016/j.heliyon.2023.e17724] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 06/07/2023] [Accepted: 06/26/2023] [Indexed: 07/18/2023] Open
Abstract
DNA methylation results in a variety of human diseases and the DNA methylation process is mediated by DNA methyltransferases, which have therefore become potential targets for disease treatment. In this study, a turn-off nanogold biological probe system was successfully created for determining the activity of DNA methyltransferases (M.SssI MTase). A dumbbell-shaped DNA probe with a site-recognizable region of M. SssI MTase and a fluorescent signal probe based on a DNA-templated gold nanocluster (DNA-AuNC) probe combined for the quantitative detection of M. SssI MTase. This dumbbell-shaped DNA probe was methylated by M. SssI MTase, and the dumbbell-shaped DNA probe with a methyl group was recognized by an endonuclease (GlaI) and cleaved into hairpin DNA. The dGTP was added to the 3'-OH terminus of hairpin DNA fragments in the presence of terminal deoxynucleotidyl transferase (TdT), and the hairpin DNA was extended with a G-rich sequence that can be used as an inactivation probe. When the inactivation probe was combined with the signal probe, the fluorescent signal disappeared due to the photoinduced electron transfer effect. Methyltransferase activity was then detected based on the turn-off principle of the fluorescence signal from the DNA-AuNCs. The bioprobe enabled sensitive detection of M. SssI MTase with a detection limit of 0.178 U mL-1 and good specificity. The bioprobe demonstrated good detection efficiency in both human serum and cell lysates, and its unique fluorescence turn-off mechanism provided good resistance to interference, thus increasing its potential application in complex biological samples. Moreover, it is suitable for screening and assessing the inhibitory activity of M. SssI MTase inhibitors, and therefore has significant potential for disease diagnosis and drug discovery.
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Affiliation(s)
- Fangyu Zhou
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China
| | - Hui Chen
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China
| | - Tingting Fan
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China
| | - Zixia Guo
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China
| | - Feng Liu
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China
- National & Local United Engineering Lab for Personalized Anti-Tumor Drugs, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, PR China
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16
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Fujita M, Goto M, Tanaka M, Yoshida W. Detection of CpG methylation level using methyl-CpG-binding domain-fused fluorescent protein. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2023; 15:2294-2299. [PMID: 37010025 DOI: 10.1039/d3ay00227f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Methylation of cytosine to 5-methylcytosine on CpG dinucleotides is the most frequently studied epigenetic modification involved in the regulation of gene expression. In normal tissues, tissue-specific CpG methylation patterns are established during development. In contrast, alterations in methylation patterns have been observed in abnormal cells, such as cancer cells. Cancer type-specific CpG methylation patterns have been identified and used as biomarkers for cancer diagnosis. In this study, we developed a hybridization-based CpG methylation level sensing system using a methyl-CpG-binding domain (MBD)-fused fluorescent protein. In this system, the target DNA is captured by a complementary methylated probe DNA. When the target DNA is methylated, a symmetrically methylated CpG is formed in the double-stranded DNA. MBD specifically recognizes symmetrical methyl-CpG on double-stranded DNA; therefore, the methylation level is quantified by measuring the fluorescence intensity of the bound MBD-fused fluorescent protein. We prepared MBD-fused AcGFP1 and quantified the CpG methylation levels of the target DNA against SEPT9, BRCA1, and long interspersed nuclear element-1 (LINE-1) using MBD-AcGFP1. This detection principle can be applied to the simultaneous and genome-wide modified base detection systems using microarrays coupled with modified base binding proteins fused to fluorescent proteins.
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Affiliation(s)
- Marika Fujita
- Graduate School of Bionics, Tokyo University of Technology, 1404-1 Katakuramachi, Hachioji, Tokyo, 192-0982, Japan.
| | - Masanori Goto
- Graduate School of Bionics, Tokyo University of Technology, 1404-1 Katakuramachi, Hachioji, Tokyo, 192-0982, Japan.
| | - Masayoshi Tanaka
- Department of Chemical Science and Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8503, Japan.
| | - Wataru Yoshida
- Graduate School of Bionics, Tokyo University of Technology, 1404-1 Katakuramachi, Hachioji, Tokyo, 192-0982, Japan.
- School of Bioscience and Biotechnology, Tokyo University of Technology, 1404-1 Katakuramachi, Hachioji, Tokyo, 192-0982, Japan
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Lu Y, Cao Q, Yu Y, Sun Y, Jiang X, Li X. Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications. BMC Genomics 2023; 24:235. [PMID: 37138231 PMCID: PMC10157937 DOI: 10.1186/s12864-023-09341-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 04/27/2023] [Indexed: 05/05/2023] Open
Abstract
BACKGROUND DNA hypermethylation at promoter CpG islands (CGIs) is a hallmark of cancers and could lead to dysregulation of gene expression in the development of cancers, however, its dynamics and regulatory mechanisms remain elusive. Bivalent genes, that direct development and differentiation of stem cells, are found to be frequent targets of hypermethylation in cancers. RESULTS Here we performed comprehensive analysis across multiple cancer types and identified that the decrease in H3K4me1 levels coincides with DNA hypermethylation at the bivalent promoter CGIs during tumorigenesis. Removal of DNA hypermethylation leads to increment of H3K4me1 at promoter CGIs with preference for bivalent genes. Nevertheless, the alteration of H3K4me1 by overexpressing or knockout LSD1, the demethylase of H3K4, doesn't change the level or pattern of DNA methylation. Moreover, LSD1 was found to regulate the expression of a bivalent gene OVOL2 to promote tumorigenesis. Knockdown of OVOL2 in LSD1 knockout HCT116 cells restored the cancer cell phenotype. CONCLUSION In summary, our work identified a universal indicator that can pre-mark DNA hypermethylation in cancer cells, and dissected the interplay between H3K4me1 and DNA hypermethylation in detail. Current study also reveals a novel mechanism underlying the oncogenic role of LSD1, providing clues for cancer therapies.
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Affiliation(s)
- Yang Lu
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China
| | - Qiang Cao
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China
| | - Yue Yu
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China
| | - Yazhou Sun
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Xuan Jiang
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China.
| | - Xin Li
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China.
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18
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Deng L, Zeng S, Yi Q, Song L. High expression of six-transmembrane epithelial antigen of prostate 3 promotes the migration and invasion and predicts unfavorable prognosis in glioma. PeerJ 2023; 11:e15136. [PMID: 37009153 PMCID: PMC10065001 DOI: 10.7717/peerj.15136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
Recent studies have suggested that ferroptosis, a form of iron-dependent regulated cell death, might play essential roles in tumor initiation and progression. Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is a ferrireductase involved in the regulation of intracellular iron homeostasis. However, the clinical significance and biological function of STEAP3 in human cancers remain poorly understood. Through a comprehensive bioinformatics analysis, we found that STEAP3 mRNA and protein expression were up-regulated in GBM, LUAD, and UCEC, and down-regulated in LIHC. Survival analysis indicated that STEAP3 had prognostic significance only in glioma. Multivariate Cox regression analysis revealed that high STEPA3 expression was correlated with poor prognosis. STEAP3 expression was significantly negatively correlated with promoter methylation level, and patients with lower STEAP3 methylation level had worse prognosis than those with higher STEAP3 methylation level. Single-cell functional state atlas showed that STEAP3 regulated epithelial-to-mesenchymal transition (EMT) in GBM. Furthermore, the results of wound healing and transwell invasion assays demonstrated that knocking down STEAP3 inhibited the migration and invasion of T98G and U251 cells. Functional enrichment analysis suggested that genes co-expressed with STEAP3 mainly participated in inflammation and immune-related pathways. Immunological analysis revealed that STEAP3 expression was significantly correlated with immune infiltration cells, including macrophages and neutrophils, especially the M2 macrophages. Individuals with low STEAP3 expression were more likely to respond to immunotherapy than those with high STEAP3 expression. These results suggest that STEAP3 promotes glioma progression and highlight its pivotal role in regulating immune microenvironment.
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Affiliation(s)
- Langmei Deng
- Department of Emergency, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shuangshuang Zeng
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiaoli Yi
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Liying Song
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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Agarwal A, Kansal V, Farooqi H, Prasad R, Singh VK. Epigallocatechin Gallate (EGCG), an Active Phenolic Compound of Green Tea, Inhibits Tumor Growth of Head and Neck Cancer Cells by Targeting DNA Hypermethylation. Biomedicines 2023; 11:biomedicines11030789. [PMID: 36979768 PMCID: PMC10045148 DOI: 10.3390/biomedicines11030789] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 02/24/2023] [Accepted: 03/03/2023] [Indexed: 03/08/2023] Open
Abstract
Head and neck cancers are among the deadliest cancers, ranked sixth globally in rates of high mortality and poor patient prognoses. The prevalence of head and neck squamous cell carcinoma (HNSCC) is associated with smoking and excessive alcohol consumption. Despite several advances in diagnostic and interventional methods, the morbidity of subjects with HNSCC has remained unchanged over the last 30 years. Epigenetic alterations, such as DNA hypermethylation, are commonly associated with several cancers, including HNSCC. Thus, epigenetic changes are considered promising therapeutic targets for chemoprevention. Here, we investigated the effect of EGCG on DNA hypermethylation and the growth of HNSCC. First, we assessed the expression levels of global DNA methylation in HNSCC cells (FaDu and SCC-1) and observed enhanced methylation levels compared with normal human bronchial epithelial cells (NHBE). Treatment of EGCG to HNSCC cells significantly inhibited global DNA hypermethylation by up to 70–80% after 6 days. Inhibition of DNA hypermethylation in HNSCC cells was confirmed by the conversion of 5-methylcytosine (5-mc) into 5-hydroxy methylcytosine (5hmC). DNA methyltransferases regulate DNA methylation. Next, we checked the effect of EGCG on the expression levels of DNA methyltransferases (DNMTs) and DNMT activity. Treatment of EGCG to HNSCC cells significantly reduced DNMT activity to 60% in SCC-1 and 80% in FaDu cells. The protein levels of DNMT3a and DNMT3b were downregulated in both cell lines after EGCG treatment. EGCG treatment to HNSCC cells reactivated tumor suppressors and caused decreased cell proliferation. Our in vivo study demonstrated that administration of EGCG (0.5%, w/w) as a supplement within an AIN76A diet resulted in inhibition of tumor growth in FaDu xenografts in nude mice (80%; p < 0.01) compared with non-EGCG-treated controls. The growth inhibitory effect of dietary EGCG on the HNSCC xenograft tumors was associated with the inhibition of DNMTs and reactivation of silenced tumor suppressors. Together, our study provides evidence that EGCG acts as a DNA demethylating agent and can reactivate epigenetically silenced tumor suppressors to inhibit the growth of HNSCC cells.
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Affiliation(s)
- Anshu Agarwal
- Department of Zoology, Agra College, Dr. Bhimrao Ambedkar University, Agra 282004, India
| | - Vikash Kansal
- Department of Otolaryngology, Emory University, Atlanta, GA 30322, USA
| | - Humaira Farooqi
- Department of Biochemistry, Hamdard University, New Delhi 110062, India
| | - Ram Prasad
- Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence: (R.P.); (V.K.S.); Tel.: +1-205-996-8685 (R.P.); +91-9412137516 (V.K.S.); Fax: +1-205-996-8653 (R.P.)
| | - Vijay Kumar Singh
- Department of Zoology, Agra College, Dr. Bhimrao Ambedkar University, Agra 282004, India
- Narain PG Degree College, Shikohabad, Dr. Bhimrao Ambedkar University, Agra 282004, India
- Correspondence: (R.P.); (V.K.S.); Tel.: +1-205-996-8685 (R.P.); +91-9412137516 (V.K.S.); Fax: +1-205-996-8653 (R.P.)
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20
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Asif H, Foley G, Simon M, Roque D, Kim JJ. Analysis of endometrial carcinoma TCGA reveals differences in DNA methylation in tumors from Black and White women. Gynecol Oncol 2023; 170:1-10. [PMID: 36580834 PMCID: PMC10023328 DOI: 10.1016/j.ygyno.2022.12.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022]
Abstract
OBJECTIVE Racial disparities exist in cancer patients both in incidence and death rates. In endometrial cancer, Black patients are reported to have higher incidence of aggressive endometrial cancer subtypes and higher death rates than White women. To date, diagnostic and prognostic biomarkers associated with race-specific methylation driven genes have yet to be identified. The objective of this study was to explore DNA methylation patterns in endometrial tumor samples from White and Black women. METHODS Differentially methylated CpGs (DMCs) and differentially methylated regions (DMRs) were identified in White tumor samples compared to Black tumor samples using Endometrial Carcinoma (EC) methylation and clinical data from The Cancer Genome Atlas (TCGA). Survival analysis was performed using survival R package and results were visualized using Kaplan-Meier plots. To access the correlation between changes in methylation and gene expression, we downloaded raw RNA-sequencing by Expectation-Maximization (RSEM) counts data from The Cancer Genome Atlas (TCGA) using TCGABiolinks package (v2.18.0). RESULTS Our analysis revealed 704 differentially methylated CpGs in tumors from Black and White women. These differentially methylated genes showed strong negative correlation with gene expression and statistically significant enrichment in regulatory regions such as DNase I hypersensitivity sites (DHSs) and transcription factor binding sites (TFBSs). Increased variability in methylation occurred in genes such as the insulin signaling pathway in Black tumor samples. CONCLUSION By using two independent statistical method based on means (DMR, DMCs) and variances (DVCs) on the endometrial carcinoma TCGA data, we showed that endometrial tumors from Black women are hypomethylated and more hypervariable than tumors from White women. In-depth investigation of these methylation driven markers can aid in successful management of endometrial cancer disparities and improved overall survival in Black and White populations.
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Affiliation(s)
- Huma Asif
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, USA
| | - Grace Foley
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, USA
| | - Melissa Simon
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, USA
| | - Dario Roque
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, USA
| | - J Julie Kim
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, USA.
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21
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Sahinyan K, Lazure F, Blackburn DM, Soleimani VD. Decline of regenerative potential of old muscle stem cells: contribution to muscle aging. FEBS J 2023; 290:1267-1289. [PMID: 35029021 DOI: 10.1111/febs.16352] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 12/23/2021] [Accepted: 01/11/2022] [Indexed: 01/01/2023]
Abstract
Muscle stem cells (MuSCs) are required for life-long muscle regeneration. In general, aging has been linked to a decline in the numbers and the regenerative potential of MuSCs. Muscle regeneration depends on the proper functioning of MuSCs, which is itself dependent on intricate interactions with its niche components. Aging is associated with both cell-intrinsic and niche-mediated changes, which can be the result of transcriptional, posttranscriptional, or posttranslational alterations in MuSCs or in the components of their niche. The interplay between cell intrinsic alterations in MuSCs and changes in the stem cell niche environment during aging and its impact on the number and the function of MuSCs is an important emerging area of research. In this review, we discuss whether the decline in the regenerative potential of MuSCs with age is the cause or the consequence of aging skeletal muscle. Understanding the effect of aging on MuSCs and the individual components of their niche is critical to develop effective therapeutic approaches to diminish or reverse the age-related defects in muscle regeneration.
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Affiliation(s)
- Korin Sahinyan
- Department of Human Genetics, McGill University, Montréal, QC, Canada.,Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada
| | - Felicia Lazure
- Department of Human Genetics, McGill University, Montréal, QC, Canada.,Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada
| | - Darren M Blackburn
- Department of Human Genetics, McGill University, Montréal, QC, Canada.,Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada
| | - Vahab D Soleimani
- Department of Human Genetics, McGill University, Montréal, QC, Canada.,Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada
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22
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Shi Y, Wu J, Wu W, Luo N, Huang H, Chen Y, Sun J, Yu Q, Ao H, Xu Q, Wu X, Xia Q, Ju H. AuNPs@MoSe 2 heterostructure as a highly efficient coreaction accelerator of electrocheluminescence for amplified immunosensing of DNA methylation. Biosens Bioelectron 2023; 222:114976. [PMID: 36516632 DOI: 10.1016/j.bios.2022.114976] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/26/2022] [Accepted: 11/29/2022] [Indexed: 12/02/2022]
Abstract
Electrocheluminescence analysis amplified by coreaction accelerators has experienced breakthrough in ultrasensitive detection of biomarkers. Herein, a highly efficient coreaction accelerator, two-dimensional layered MoSe2 nanosheets loaded with gold nanoparticles (AuNPs@MoSe2 heterostructure), is proposed to enhance the ECL efficiency of Ru(bpy)32+/tripropylamine (TPrA) system. The presence of AuNPs avoids the aggregation of MoSe2 nanosheets, and improves the electrical conductivity of modified surface. The AuNPs@MoSe2 modified electrode also provides a large area for loading of abundant capture probe. MoSe2 as an electroactive substrate can remarkably accelerate the generation of TPrA•+ radicals to react with electrooxidized Ru(bpy)32+, which achieves about 3.4-fold stronger ECL intensity. Thus, an enhanced ECL immunoassay method can be achieved after Ru(bpy)32+-doped silica nanoparticle labeled antibody (Ab2-Ru@SiO2) is captured to the modified electrode via immunological recognition. Using methylated DNA as a target, the immunosensor was prepared by binding capture DNA on AuNPs@MoSe2 modified electrode to successively capture the target, anti-5-methylcytosine antibody (anti-5mC) and Ab2-Ru@SiO2. The proposed strategy could detect 0.26 fM 5 mC (3σ) with a detectable concentration range of 1.0 fM - 10 nM at methylated DNA. This immunosensor showed excellent selectivity, good stability and reproducibility, and acceptable recovery, indicating the broad prospects of the novel coreaction accelerator in clinical diagnosis.
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Affiliation(s)
- Yao Shi
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, NHC Key Laboratory of Tropical Disease Control, School of Tropical Medicine and the Second Affiliated Hospital, Hainan Medical University, Haikou, Hainan, 571199, China
| | - Jie Wu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
| | - Wenxin Wu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, NHC Key Laboratory of Tropical Disease Control, School of Tropical Medicine and the Second Affiliated Hospital, Hainan Medical University, Haikou, Hainan, 571199, China
| | - Nini Luo
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, NHC Key Laboratory of Tropical Disease Control, School of Tropical Medicine and the Second Affiliated Hospital, Hainan Medical University, Haikou, Hainan, 571199, China
| | - Hao Huang
- Research & Development Center, Canon Medical Systems (China) Co., LTD, Beijing, 100015, China
| | - Yuhui Chen
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
| | - Jun Sun
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
| | - Qian Yu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
| | - Hang Ao
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China
| | - Qiqi Xu
- Research & Development Center, Canon Medical Systems (China) Co., LTD, Beijing, 100015, China
| | - Xiaotian Wu
- Research & Development Center, Canon Medical Systems (China) Co., LTD, Beijing, 100015, China
| | - Qianfeng Xia
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, NHC Key Laboratory of Tropical Disease Control, School of Tropical Medicine and the Second Affiliated Hospital, Hainan Medical University, Haikou, Hainan, 571199, China.
| | - Huangxian Ju
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China.
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23
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Lee DY, Salahuddin T, Iqbal J. Lysine-Specific Demethylase 1 (LSD1)-Mediated Epigenetic Modification of Immunogenicity and Immunomodulatory Effects in Breast Cancers. Curr Oncol 2023; 30:2127-2143. [PMID: 36826125 PMCID: PMC9955398 DOI: 10.3390/curroncol30020164] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/05/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
Tumor evolution to evade immune surveillance is a hallmark of carcinogenesis, and the modulation of tumor immunogenicity has been a challenge to present therapeutic responses in immunotherapies alone for numerous cancers. By altering the cell phenotype and reshaping the tumor microenvironment, epigenetic modifications enable tumor cells to overcome immune surveillance as a mechanism of cancer progression and immunotherapy resistance. Demethylase enzymatic activity of lysine-specific demethylase 1 (LSD1), a histone demethylase first identified in 2004, plays a pivotal role in the vast cellular processes of cancer. While FDA-approved indications for epigenetic therapies are limited to hematological malignancies, it is imperative to understand how epigenetic machinery can be targeted to prime immunotherapy responses in breast cancers. In this review, we discuss the potential roles of epigenetics and demethylating agent LSD1 as a potent new cancer management strategy to combat the current challenges of breast cancers, which have presented modest efficacy to immune checkpoint inhibitors till date. Additionally, we describe the combined use of LSD1-specific inhibitors and immune checkpoint inhibitors in existing breast cancer preclinical and clinical trials that elicits a robust immune response and benefit. Overall, the promising results observed in LSD1-targeting therapies signify the central role of epigenetics as a potential novel strategy to overcome resistance commonly seen in immunotherapies.
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Affiliation(s)
- Dong Yeul Lee
- Department of Anatomical Pathology, Singapore General Hospital, 20 College Road, Academia, Level 10, Diagnostics Tower, Singapore 169856, Singapore
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
- Correspondence: (D.Y.L.); (J.I.)
| | - Talha Salahuddin
- Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Grattan Street, Parkville, VIC 3010, Australia
| | - Jabed Iqbal
- Department of Anatomical Pathology, Singapore General Hospital, 20 College Road, Academia, Level 10, Diagnostics Tower, Singapore 169856, Singapore
- Correspondence: (D.Y.L.); (J.I.)
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24
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Biological and Genetic Mechanisms of COPD, Its Diagnosis, Treatment, and Relationship with Lung Cancer. Biomedicines 2023; 11:biomedicines11020448. [PMID: 36830984 PMCID: PMC9953173 DOI: 10.3390/biomedicines11020448] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/26/2023] [Accepted: 01/31/2023] [Indexed: 02/09/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic adult diseases, with significant worldwide morbidity and mortality. Although long-term tobacco smoking is a critical risk factor for this global health problem, its molecular mechanisms remain unclear. Several phenomena are thought to be involved in the evolution of emphysema, including airway inflammation, proteinase/anti-proteinase imbalance, oxidative stress, and genetic/epigenetic modifications. Furthermore, COPD is one main risk for lung cancer (LC), the deadliest form of human tumor; formation and chronic inflammation accompanying COPD can be a potential driver of malignancy maturation (0.8-1.7% of COPD cases develop cancer/per year). Recently, the development of more research based on COPD and lung cancer molecular analysis has provided new light for understanding their pathogenesis, improving the diagnosis and treatments, and elucidating many connections between these diseases. Our review emphasizes the biological factors involved in COPD and lung cancer, the advances in their molecular mechanisms' research, and the state of the art of diagnosis and treatments. This work combines many biological and genetic elements into a single whole and strongly links COPD with lung tumor features.
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25
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Chen G, Zhang J, Fu Q, Taly V, Tan F. Integrative analysis of multi-omics data for liquid biopsy. Br J Cancer 2023; 128:505-518. [PMID: 36357703 PMCID: PMC9938261 DOI: 10.1038/s41416-022-02048-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 10/22/2022] [Accepted: 10/24/2022] [Indexed: 11/12/2022] Open
Abstract
The innovation of liquid biopsy holds great potential to revolutionise cancer management through early diagnosis and timely treatment of cancer. Integrative analysis of different tumour-derived omics data (such as genomics, epigenetics, fragmentomics, and proteomics) from body fluids for cancer detection and monitoring could outperform the analysis of single modality data alone. In this review, we focussed on the discussion of early cancer detection and molecular residual disease surveillance based on multi-omics data of blood. We summarised diverse types of tumour-derived components, current popular platforms for profiling cancer-associated signals, machine learning approaches for joint analysis of liquid biopsy data, as well as multi-omics-based early detection of cancers, molecular residual disease monitoring, and treatment response surveillance. We also discussed the challenges and future directions of multi-omics-based liquid biopsy. With the development of both experimental protocols and computational methods dedicated to liquid biopsy, the implementation of multi-omics strategies into the clinical workflow will likely benefit the clinical management of cancers including decision-making guidance and patient outcome improvement.
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Affiliation(s)
- Geng Chen
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 200443, Shanghai, China.
- Center for Bioinformatics and Computational Biology, School of Life Sciences, East China Normal University, 200241, Shanghai, China.
| | - Jing Zhang
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 200443, Shanghai, China
| | - Qiaoting Fu
- Shanghai Skin Disease Clinical College, The Fifth Clinical Medical College, Anhui Medical University, 200443, Shanghai, China
| | - Valerie Taly
- Université de Paris, UMR-S1138, CNRS SNC5096, Équipe labélisée Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers, Paris, France.
| | - Fei Tan
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 200443, Shanghai, China.
- Shanghai Skin Disease Clinical College, The Fifth Clinical Medical College, Anhui Medical University, 200443, Shanghai, China.
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26
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Sehgal P, Chaturvedi P. Chromatin and Cancer: Implications of Disrupted Chromatin Organization in Tumorigenesis and Its Diversification. Cancers (Basel) 2023; 15:cancers15020466. [PMID: 36672415 PMCID: PMC9856863 DOI: 10.3390/cancers15020466] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/04/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
A hallmark of cancers is uncontrolled cell proliferation, frequently associated with an underlying imbalance in gene expression. This transcriptional dysregulation observed in cancers is multifaceted and involves chromosomal rearrangements, chimeric transcription factors, or altered epigenetic marks. Traditionally, chromatin dysregulation in cancers has been considered a downstream effect of driver mutations. However, here we present a broader perspective on the alteration of chromatin organization in the establishment, diversification, and therapeutic resistance of cancers. We hypothesize that the chromatin organization controls the accessibility of the transcriptional machinery to regulate gene expression in cancerous cells and preserves the structural integrity of the nucleus by regulating nuclear volume. Disruption of this large-scale chromatin in proliferating cancerous cells in conventional chemotherapies induces DNA damage and provides a positive feedback loop for chromatin rearrangements and tumor diversification. Consequently, the surviving cells from these chemotherapies become tolerant to higher doses of the therapeutic reagents, which are significantly toxic to normal cells. Furthermore, the disorganization of chromatin induced by these therapies accentuates nuclear fragility, thereby increasing the invasive potential of these tumors. Therefore, we believe that understanding the changes in chromatin organization in cancerous cells is expected to deliver more effective pharmacological interventions with minimal effects on non-cancerous cells.
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27
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Loaeza-Loaeza J, Cerecedo-Castillo AJ, Rodríguez-Ruiz HA, Castro-Coronel Y, Del Moral-Hernández O, Recillas-Targa F, Hernández-Sotelo D. DNMT3B overexpression downregulates genes with CpG islands, common motifs, and transcription factor binding sites that interact with DNMT3B. Sci Rep 2022; 12:20839. [PMID: 36460706 PMCID: PMC9718745 DOI: 10.1038/s41598-022-24186-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 11/11/2022] [Indexed: 12/04/2022] Open
Abstract
DNA methylation is a key epigenetic modification to regulate gene expression in mammalian cells. Abnormal DNA methylation in gene promoters is common across human cancer types. DNMT3B is the main de novo methyltransferase enhanced in several primary tumors. How de novo methylation is established in genes related to cancer is poorly understood. CpG islands (CGIs), common sequences, and transcription factors (TFs) that interact with DNMT3B have been associated with abnormal de novo methylation. We initially identified cis elements associated with DNA methylation to investigate the contribution of DNMT3B overexpression to the deregulation of its possible target genes in an epithelial cell model. In a set of downregulated genes (n = 146) from HaCaT cells with DNMT3B overexpression, we found CGI, common sequences, and TFs Binding Sites that interact with DNMT3B (we called them P-down-3B). PPL1, VAV3, IRF1, and BRAF are P-down-3B genes that are downregulated and increased their methylation in DNMT3B presence. Together these findings suggest that methylated promoters aberrantly have some cis elements that could conduce de novo methylation by DNMT3B.
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Affiliation(s)
- Jaqueline Loaeza-Loaeza
- grid.412856.c0000 0001 0699 2934Laboratorio de Epigenética del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N Col. Haciendita, 39070 Chilpancingo, Guerrero Mexico
| | - Angel Josué Cerecedo-Castillo
- grid.9486.30000 0001 2159 0001Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 Ciudad de México, Mexico
| | - Hugo Alberto Rodríguez-Ruiz
- grid.412856.c0000 0001 0699 2934Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N Col. Haciendita, 39070 Chilpancingo, Guerrero Mexico
| | - Yaneth Castro-Coronel
- grid.412856.c0000 0001 0699 2934Laboratorio de Citopatología e Inmunohistoquímica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N Col. Haciendita, 39070 Chilpancingo, Guerrero Mexico
| | - Oscar Del Moral-Hernández
- grid.412856.c0000 0001 0699 2934Laboratorio de Virus y Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N Col. Haciendita, 39070 Chilpancingo, Guerrero Mexico
| | - Félix Recillas-Targa
- grid.9486.30000 0001 2159 0001Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 Ciudad de México, Mexico
| | - Daniel Hernández-Sotelo
- grid.412856.c0000 0001 0699 2934Laboratorio de Epigenética del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N Col. Haciendita, 39070 Chilpancingo, Guerrero Mexico
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Comprehensive Analysis of GDF10 Methylation Site-Associated Genes as Prognostic Markers for Endometrial Cancer. JOURNAL OF ONCOLOGY 2022; 2022:7117083. [PMID: 36262352 PMCID: PMC9576415 DOI: 10.1155/2022/7117083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/16/2022] [Accepted: 09/21/2022] [Indexed: 11/29/2022]
Abstract
Growth differentiation factor-10 (GDF10) with its methylation trait has recently been found to play a crucial regulatory and communication role in cancers. This investigation aims to identify GDF10 methylation site-associated genes that are closely associated with endometrial cancer (EC) patients' survival based on normal and UCEC samples from the UCSC Xena database. Our study revealed for the first time that EC exhibited significantly higher levels of GDF10 promoter methylation in comparison with normal tissues. Multiple differentiated methylation sites, which have prognostic value due to their apparent survival differences, were found in the GDF10 promoter region. We performed weighted gene coexpression network analysis (WGCNA) on EC tissues and paraneoplastic tissues while using these differentially methylated sites as phenotypes for selecting the most correlated key modules and their internal genes. To obtain a gene set, the key module genes and differentially expressed genes (DEGs) of EC were intersected. The least absolute shrinkage and selection operator (LASSO) regression along with multivariate Cox regression were performed from the gene set and we screened out the key genes B4GALNT3, DNAJC22, and GREB1. Finally, a prognostic model was validated for effectiveness based on these genes. Additionally, Kaplan-Meier analysis and time-dependent receiver operating characteristics (ROC) were applied to assess and verify the model, and they showed good prognosis prediction. Moreover, the differences in risk scores were statistically significant with age, tumor stage, and grade. They may be related to the immune infiltration of tumors as well. In conclusion, based on the methylation-related genes associated with GDF10, we developed a prognosis model for EC patients. It might provide a fresh view for further research and treatment of EC.
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Maki M, JeongMin H, Nakagawa T, Kawai H, Sakamoto N, Sato Y, Noguchi M. Aberrant OCIAD2 demethylation in lung adenocarcinoma is associated with outcome. Pathol Int 2022; 72:496-505. [PMID: 35920378 DOI: 10.1111/pin.13262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/13/2022] [Indexed: 12/24/2022]
Abstract
Overexpression of OCIAD2 in lung adenocarcinoma has already been reported in several research articles, but the molecular mechanism involved remains unknown. Promoter CpG methylation is a representative form of epigenetic gene regulation, and a considerable number of tumor suppressor genes show hypermethylation in many cancers. In contrast, promoter CpG hypomethylation causes oncogene overexpression, resulting in carcinogenesis and malignant progression. In the present study, we investigated the CpG methylation and expression status of OCIAD2 using tumor tissues and adjacent normal tissues from seven cases of lung adenocarcinoma. We also examined the relationship between CpG methylation status and outcome in 58 patients with adenocarcinoma. Pyrosequencing showed that CpG sites in OCIAD2 promoter regions were more frequently demethylated in tumor tissues than in adjacent normal tissues, and reverse transcription-quantitative polymerase chain reaction revealed overexpression of OCIAD2 in lung adenocarcinoma. There was a correlation between OCIAD2 CpG demethylation and the level of mRNA expression, and statistical analysis showed that CpG hypomethylation of OCIAD2 was associated with poor outcomes. Our results suggest that overexpression of OCIAD2 might be caused mainly by CpG hypomethylation and that OCIAD2 methylation status might be a useful prognostic indicator in lung adenocarcinoma.
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Affiliation(s)
- Masahiro Maki
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hong JeongMin
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Tomoki Nakagawa
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hitomi Kawai
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Noriaki Sakamoto
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yukio Sato
- Department of Thoracic Surgery, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Masayuki Noguchi
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.,Center for Clinical and Translational Science, Shonan Kamakura General Hospital, Kanagawa, Japan
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30
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Zhang X, Li A, Wu J, Wu Y, Ma X, Liu Y, Chen Q, Zhang Y. Promoter methylation analysis of DKK2 may be a potential biomarker for early detection of cervical cancer. ASIAN BIOMED 2022; 16:181-189. [PMID: 37551167 PMCID: PMC10321177 DOI: 10.2478/abm-2022-0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Background Dickkopf 2 (DKK2) plays an important role in multiple cancers. Its potential value in the clinical diagnosis of cervical cancer has remained unclear. Objectives To investigate the expression and promoter methylation levels of DKK2 in cervical cancer and their clinicopathological associations. Methods We used the Gene Expression Omnibus, Oncomine, Cancer Genome Atlas, and University of ALabama at Birmingham CANcer data analysis databases, reverse transcription-PCR, and methylation-specific PCR analysis to predict and examine the expression of DKK2 mRNA and DKK2 methylation levels in cell lines and cervical cancer tissues from 79 patients with cervical cancer and 63 with cervical precancerous lesions including 25 with low-grade squamous intraepithelial lesions (LSIL) and 38 patients with high-grade squamous intraepithelial lesions (HSIL). Results DKK2 mRNA expression was downregulated in all cancer cell lines and cervical cancer tissues, whereas hypermethylation of DKK2 was higher in cervical cancer tissue samples. DKK2 methylation in cervical cancer was significantly higher than that in HSIL (χ2 = 8.346, P = 0.004), whereas DKK2 methylation in HSIL was significantly higher than that in normal cervical samples (χ2 = 7.934, P = 0.005) and in LSIL samples (χ2 = 4.375, P = 0.037). DKK2 silencing caused by its promoter hypermethylation was confirmed by treatment with the methyltransferase inhibitor 5-Aza-dC in cell lines. Patients with lymph node metastasis exhibited increased promoter methylation frequency (χ2 = 5.239, P = 0.022) and low DKK2 mRNA expression (χ2 = 3.958, P = 0.047) compared with patients with no lymph node metastasis. Patients with high-risk human papillomavirus infection exhibited increased promoter methylation frequency (χ2 = 6.279, P = 0.015). Conclusions DKK2 epigenetic changes of DKK2 may play a key role in the development of cervical cancer, suggesting that DKK2 hypermethylation could be used as a triage test for screening, early diagnosis, or risk prediction of cervical cancer.
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Affiliation(s)
- Xian Zhang
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
| | - Aihua Li
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
| | - Jie Wu
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, Shandong266000, China
| | - Yu Wu
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
| | - Xiaoping Ma
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
| | - Yanjun Liu
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
| | - Qingfa Chen
- Institute of Tissue Engineering and Regenerative Medicine, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
| | - Yan Zhang
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong252000, China
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Bai H, Li QZ, Qi YC, Zhai YY, Jin W. The prediction of tumor and normal tissues based on the DNA methylation values of ten key sites. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2022; 1865:194841. [PMID: 35798200 DOI: 10.1016/j.bbagrm.2022.194841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 05/28/2022] [Accepted: 06/28/2022] [Indexed: 06/15/2023]
Abstract
Abnormal DNA methylation can alter the gene expression to promote or inhibit tumorigenesis in colon adenocarcinoma (COAD). However, the finding important genes and key sites of abnormal DNA methylation which result in the occurrence of COAD is still an eventful task. Here, we studied the effects of DNA methylation in the 12 types of genomic features on the changes of gene expression in COAD, the 10 important COAD-related genes and the key abnormal DNA methylation sites were identified. The effects of important genes on the prognosis were verified by survival analysis. Moreover, it was shown that the important genes were participated in cancer pathways and were hub genes in a co-expression network. Based on the DNA methylation levels in the ten sites, the least diversity increment algorithm for predicting tumor tissues and normal tissues in seventeen cancer types are proposed. The better results are obtained in jackknife test. For example, the predictive accuracies are 94.17 %, 91.28 %, 89.04 % and 88.89 %, respectively, for COAD, rectum adenocarcinoma, pancreatic adenocarcinoma and cholangiocarcinoma. Finally, by computing enrichment score of infiltrating immunocytes and the activity of immune pathways, we found that the genes are highly correlated with immune microenvironment.
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Affiliation(s)
- Hui Bai
- Laboratory of Theoretical Biophysics, School of Physical Science and Technology, Inner Mongolia University, Hohhot 010021, China
| | - Qian-Zhong Li
- Laboratory of Theoretical Biophysics, School of Physical Science and Technology, Inner Mongolia University, Hohhot 010021, China; The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010070, China.
| | - Ye-Chen Qi
- Laboratory of Theoretical Biophysics, School of Physical Science and Technology, Inner Mongolia University, Hohhot 010021, China
| | - Yuan-Yuan Zhai
- Laboratory of Theoretical Biophysics, School of Physical Science and Technology, Inner Mongolia University, Hohhot 010021, China
| | - Wen Jin
- Inner Mongolia key laboratory of gene regulation of the metabolic disease, Department of Clinical Medical Research Center, Inner Mongolia People's Hospital, Hohhot 010010, China
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32
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Lin RK, Su CM, Lin SY, Thi Anh Thu L, Liew PL, Chen JY, Tzeng HE, Liu YR, Chang TH, Lee CY, Hung CS. Hypermethylation of TMEM240 predicts poor hormone therapy response and disease progression in breast cancer. Mol Med 2022; 28:67. [PMID: 35715741 PMCID: PMC9204905 DOI: 10.1186/s10020-022-00474-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 04/13/2022] [Indexed: 12/16/2022] Open
Abstract
Background Approximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in TMEM240 in breast cancer were identified and investigated to monitor treatment response and disease progression. Methods Circulating methylated TMEM240 in the plasma of breast cancer patients was used to monitor treatment response and disease progression. The Cancer Genome Atlas (TCGA) data in Western countries and Illumina methylation arrays in Taiwanese breast cancer patients were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific PCR (QMSP), real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation and mRNA and protein expression levels in 394 samples from Taiwanese and Korean breast cancer patients. TMEM240 gene manipulation, viability, migration assays, RNA-seq, and MetaCore were performed to determine its biological functions and relationship to hormone drug treatment response in breast cancer cells. Results Aberrant methylated TMEM240 was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and migration and regulates the expression levels of enzymes involved in estrone and estradiol metabolism. TMEM240 protein expression was observed in normal breast tissues but was not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of TMEM240 was at least twofold higher in tumor tissues than in matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival (p = 0.003) and poor treatment response, especially hormone therapy response (p < 0.001). Circulating methylated TMEM240 dramatically and gradually decreased and then diminished in patients without disease progression, whereas it returned and its levels in plasma rose again in patients with disease progression. Prediction of disease progression based on circulating methylated TMEM240 was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy. Conclusions Hypermethylation of TMEM240 is a potential biomarker for treatment response and disease progression monitoring in breast cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-022-00474-9.
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Affiliation(s)
- Ruo-Kai Lin
- Program in Drug Discovery and Development Industry, Program in Clinical Drug Development of Herbal Medicine, Master Program in Clinical Genomics and Proteomics, College of Pharmacy, Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan.,Clinical Trial Center, Taipei Medical University Hospital, 252 Wu-Hsing Street, Taipei, Taiwan
| | - Chih-Ming Su
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.,Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shih-Yun Lin
- Program in Drug Discovery and Development Industry, Program in Clinical Drug Development of Herbal Medicine, Master Program in Clinical Genomics and Proteomics, College of Pharmacy, Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan
| | - Le Thi Anh Thu
- Quang Tri Medical College, Dien Bien Phu Str., Dong Luong District, Dong Ha City, Quang Tri, Vietnam
| | - Phui-Ly Liew
- Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jian-Yu Chen
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Huey-En Tzeng
- Division of Hematology and Oncology, Department of Medicine, Taipei Medical University Hospital, Taipei, Taiwan.,Department of Medical Research, Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung City, Taiwan.,Program for Cancer Molecular Biology and Drug Discovery, and Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Yun-Ru Liu
- Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan
| | - Tzu-Hao Chang
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Cheng-Yang Lee
- Bioinformatics Center, Office of Data Science, Taipei Medical University, Taipei, Taiwan
| | - Chin-Sheng Hung
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan. .,Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. .,Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan.
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Methylation Status of Gene Bodies of Selected microRNA Genes Associated with Neoplastic Transformation in Equine Sarcoids. Cells 2022; 11:cells11121917. [PMID: 35741046 PMCID: PMC9221590 DOI: 10.3390/cells11121917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/06/2022] [Accepted: 06/09/2022] [Indexed: 02/04/2023] Open
Abstract
Horses are of great importance in recreation, livestock production, as working animals in poorly developed countries, and for equine-assisted therapy. Equine sarcoids belong to the most commonly diagnosed tumors in this species. They may cause discomfort, pain, and can lead to the permanent impairment of motor function. The molecular bases of their formation are still under investigation. Our previous studies revealed altered microRNA (miRNA) expression and DNA methylation levels in sarcoid tumors. Abnormal patterns of methylation may be responsible for changes in gene expression levels, including microRNAs. Recently, the DNA methylation of gene bodies has also been shown to have an impact on gene expression. Thus, the aim of the study was to investigate the methylation pattern of gene bodies of chosen miRNAs identified in sarcoid tissue (miR-101, miR-10b, miR-200a, and miR-338-3p), which have also been established to play roles in neoplastic transformation. To this end, we applied qRT-PCR, Bisulfite Sequencing PCR (BSP), and Mquant methods. As a result, we identified the statistically significant downregulation of pri-mir-101-1, pri-mir-10b, and pri-mir-200a in the sarcoid samples in comparison to the control. The DNA methylation analysis revealed their hypermethylation. This suggests that DNA methylation may be one mechanism responsible for the downregulation of theses miRNAs. However, the identified differences in the methylation levels are not very high, which implies that other mechanisms may also underlie the downregulation of the expression of these miRNAs in equine sarcoids. For the first time, the results obtained shed light on microRNA expression regulation by gene body methylation in equine sarcoids and provide bases for further deeper studies on other mechanisms influencing the miRNA repertoire.
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High-throughput sample processing for methylation analysis in an automated, enclosed environment. SLAS Technol 2022; 27:172-179. [DOI: 10.1016/j.slast.2021.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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35
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Yang S, Huang Y, Zhao Q. Epigenetic Alterations and Inflammation as Emerging Use for the Advancement of Treatment in Non-Small Cell Lung Cancer. Front Immunol 2022; 13:878740. [PMID: 35514980 PMCID: PMC9066637 DOI: 10.3389/fimmu.2022.878740] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 03/21/2022] [Indexed: 12/26/2022] Open
Abstract
Lung cancer remains one of the most common malignancies in the world. Nowadays, the most common lung cancer is non-small cell lung cancer (NSCLC), namely, adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Epigenetic alterations that refer to DNA methylation, histone modifications, and noncoding RNA expression, are now suggested to drive the genesis and development of NSCLC. Additionally, inflammation-related tumorigenesis also plays a vital role in cancer research and efforts have been attempted to reverse such condition. During the occurrence and development of inflammatory diseases, the immune component of inflammation may cause epigenetic changes, but it is not always certain whether the immune component itself or the stimulated host cells cause epigenetic changes. Moreover, the links between epigenetic alterations and cancer-related inflammation and their influences on the human cancer are not clear so far. Therefore, the connection between epigenetic drivers, inflammation, and NSCLC will be summarized. Investigation on such topic is most likely to shed light on the molecular and immunological mechanisms of epigenetic and inflammatory factors and promote the application of epigenetics in the innovative diagnostic and therapeutic strategies for NSCLC.
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Affiliation(s)
- Shuo Yang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- *Correspondence: Shuo Yang, ; Yang Huang, ; Qi Zhao,
| | - Yang Huang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- *Correspondence: Shuo Yang, ; Yang Huang, ; Qi Zhao,
| | - Qi Zhao
- Cancer Centre, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, Macau SAR, China
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau, Macau SAR, China
- *Correspondence: Shuo Yang, ; Yang Huang, ; Qi Zhao,
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36
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Lemma RB, Fleischer T, Martinsen E, Ledsaak M, Kristensen V, Eskeland R, Gabrielsen OS, Mathelier A. Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers. Epigenetics Chromatin 2022; 15:13. [PMID: 35440061 PMCID: PMC9016969 DOI: 10.1186/s13072-022-00444-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 03/14/2022] [Indexed: 12/15/2022] Open
Abstract
Methylation of cytosines on DNA is a prominent modification associated with gene expression regulation. Aberrant DNA methylation patterns have recurrently been linked to dysregulation of the regulatory program in cancer cells. To shed light on the underlying molecular mechanism driving this process, we hypothesised that aberrant methylation patterns could be controlled by the binding of specific transcription factors (TFs) across cancer types. By combining DNA methylation arrays and gene expression data with TF binding sites (TFBSs), we explored the interplay between TF binding and DNA methylation in 19 cancer types. We performed emQTL (expression-methylation quantitative trait loci) analyses independently in each cancer type and identified 13 TFs whose expression levels are correlated with local DNA methylation patterns around their binding sites in at least 2 cancer types. The 13 TFs are mainly associated with local demethylation and are enriched for pioneer function, suggesting a specific role for these TFs in modulating chromatin structure and transcription in cancer patients. Furthermore, we confirmed that de novo methylation is precluded across cancers at CpGs lying in genomic regions enriched for TF binding signatures associated with SP1, CTCF, NRF1, GABPA, KLF9, and/or YY1. The modulation of DNA methylation associated with TF binding was observed at cis-regulatory regions controlling immune- and cancer-associated pathways, corroborating that the emQTL signals were derived from both cancer and tumor-infiltrating cells. As a case example, we experimentally confirmed that FOXA1 knock-down is associated with higher methylation in regions bound by FOXA1 in breast cancer MCF-7 cells. Finally, we reported physical interactions between FOXA1 with TET1 and TET2 both in an in vitro setup and in vivo at physiological levels in MCF-7 cells, adding further support for FOXA1 attracting TET1 and TET2 to induce local demethylation in cancer cells.
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Affiliation(s)
- Roza Berhanu Lemma
- Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway
| | - Thomas Fleischer
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Emily Martinsen
- Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway
- Institute of Basic Medical Sciences, Department of Molecular Medicine, and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Marit Ledsaak
- Institute of Basic Medical Sciences, Department of Molecular Medicine, and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Vessela Kristensen
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Ragnhild Eskeland
- Institute of Basic Medical Sciences, Department of Molecular Medicine, and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | | | - Anthony Mathelier
- Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
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Contreras-Romero C, Pérez-Yépez EA, Martinez-Gutierrez AD, Campos-Parra A, Zentella-Dehesa A, Jacobo-Herrera N, López-Camarillo C, Corredor-Alonso G, Martínez-Coronel J, Rodríguez-Dorantes M, de León DC, Pérez-Plasencia C. Gene Promoter-Methylation Signature as Biomarker to Predict Cisplatin-Radiotherapy Sensitivity in Locally Advanced Cervical Cancer. Front Oncol 2022; 12:773438. [PMID: 35359376 PMCID: PMC8963763 DOI: 10.3389/fonc.2022.773438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 01/25/2022] [Indexed: 11/13/2022] Open
Abstract
Despite efforts to promote health policies focused on screening and early detection, cervical cancer continues to be one of the leading causes of mortality in women; in 2020, estimated 30,000 deaths in Latin America were reported for this type of tumor. While the therapies used to treat cervical cancer have excellent results in tumors identified in early stages, those women who are diagnosed in locally advanced and advanced stages show survival rates at 5 years of <50%. Molecular patterns associated with clinical response have been studied in patients who present resistance to treatment; none of them have reached clinical practice. It is therefore necessary to continue analyzing molecular patterns that allow us to identify patients at risk of developing resistance to conventional therapy. In this study, we analyzed the global methylation profile of 22 patients diagnosed with locally advanced cervical cancer and validated the genomic results in an independent cohort of 70 patients. We showed that BRD9 promoter region methylation and CTU1 demethylation were associated with a higher overall survival (p = 0.06) and progression-free survival (p = 0.0001), whereas DOCK8 demethylation was associated with therapy-resistant patients and a lower overall survival and progression-free survival (p = 0.025 and p = 0.0001, respectively). Our results suggest that methylation of promoter regions in specific genes may provide molecular markers associated with response to treatment in cancer; further investigation is needed.
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Affiliation(s)
| | - Eloy-Andrés Pérez-Yépez
- Laboratorio de Genómica, Insituto Nacional de Cancerología, Ciudad de México, Mexico.,Cátedra CONACYT, Dirección de cátedras, Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico City, Mexico
| | | | - Alma Campos-Parra
- Laboratorio de Genómica, Insituto Nacional de Cancerología, Ciudad de México, Mexico
| | - Alejandro Zentella-Dehesa
- Programa Institucional de Cáncer de Mama, Dpto Medicina Genómica y Toxicología Ambiental, IIB, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Nadia Jacobo-Herrera
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Ciudad de México, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México (UACM), Mexico City, Mexico
| | | | | | | | - David Cantu de León
- Laboratorio de Genómica, Insituto Nacional de Cancerología, Ciudad de México, Mexico
| | - Carlos Pérez-Plasencia
- Laboratorio de Genómica, Insituto Nacional de Cancerología, Ciudad de México, Mexico.,Laboratorio de Genómica, Unidad de Biomedicina, FES-Iztacala, UNAM, Tlalnepantla, Mexico
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38
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Stability and context of intercalated motifs (i-motifs) for biological applications. Biochimie 2022; 198:33-47. [PMID: 35259471 DOI: 10.1016/j.biochi.2022.03.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/21/2022] [Accepted: 03/03/2022] [Indexed: 11/24/2022]
Abstract
DNA is naturally dynamic and can self-assemble into alternative secondary structures including the intercalated motif (i-motif), a four-stranded structure formed in cytosine-rich DNA sequences. Until recently, i-motifs were thought to be unstable in physiological cellular environments. Studies demonstrating their existence in the human genome and role in gene regulation are now shining light on their biological relevance. Herein, we review the effects of epigenetic modifications on i-motif structure and stability, and biological factors that affect i-motif formation within cells. Furthermore, we highlight recent progress in targeting i-motifs with structure-specific ligands for biotechnology and therapeutic purposes.
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Simon T, Riemer P, Jarosch A, Detjen K, Di Domenico A, Bormann F, Menne A, Khouja S, Monjé N, Childs LH, Lenze D, Leser U, Rossner F, Morkel M, Blüthgen N, Pavel M, Horst D, Capper D, Marinoni I, Perren A, Mamlouk S, Sers C. DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas and pancreatic neuroendocrine tumors. Genome Med 2022; 14:24. [PMID: 35227293 PMCID: PMC8886788 DOI: 10.1186/s13073-022-01018-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 01/28/2022] [Indexed: 02/07/2023] Open
Abstract
Background Pancreatic neuroendocrine neoplasms (PanNENs) fall into two subclasses: the well-differentiated, low- to high-grade pancreatic neuroendocrine tumors (PanNETs), and the poorly-differentiated, high-grade pancreatic neuroendocrine carcinomas (PanNECs). While recent studies suggest an endocrine descent of PanNETs, the origin of PanNECs remains unknown. Methods We performed DNA methylation analysis for 57 PanNEN samples and found that distinct methylation profiles separated PanNENs into two major groups, clearly distinguishing high-grade PanNECs from other PanNETs including high-grade NETG3. DNA alterations and immunohistochemistry of cell-type markers PDX1, ARX, and SOX9 were utilized to further characterize PanNECs and their cell of origin in the pancreas. Results Phylo-epigenetic and cell-type signature features derived from alpha, beta, acinar, and ductal adult cells suggest an exocrine cell of origin for PanNECs, thus separating them in cell lineage from other PanNENs of endocrine origin. Conclusions Our study provides a robust and clinically applicable method to clearly distinguish PanNECs from G3 PanNETs, improving patient stratification. Supplementary Information The online version contains supplementary material available at 10.1186/s13073-022-01018-w.
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Affiliation(s)
- Tincy Simon
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany
| | - Pamela Riemer
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany
| | - Armin Jarosch
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany
| | - Katharina Detjen
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hepatology and Gastroenterology, Berlin, Germany
| | | | | | - Andrea Menne
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany
| | - Slim Khouja
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany
| | - Nanna Monjé
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany
| | - Liam H Childs
- Humboldt-Universität zu Berlin, Knowledge Management in Bioinformatics, Berlin, Germany
| | - Dido Lenze
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany
| | - Ulf Leser
- Humboldt-Universität zu Berlin, Knowledge Management in Bioinformatics, Berlin, Germany
| | - Florian Rossner
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany
| | - Markus Morkel
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany
| | - Nils Blüthgen
- Integrative Research Institute (IRI) Life Sciences, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Marianne Pavel
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hepatology and Gastroenterology, Berlin, Germany
| | - David Horst
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany
| | - David Capper
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Neuropathology, Berlin, Germany.,German Cancer Consortium (DKTK); Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ilaria Marinoni
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland
| | - Aurel Perren
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland
| | - Soulafa Mamlouk
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany. .,German Cancer Consortium (DKTK); Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Christine Sers
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany. .,German Cancer Consortium (DKTK); Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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40
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Muthamilselvan S, Raghavendran A, Palaniappan A. Stage-differentiated ensemble modeling of DNA methylation landscapes uncovers salient biomarkers and prognostic signatures in colorectal cancer progression. PLoS One 2022; 17:e0249151. [PMID: 35202405 PMCID: PMC8870460 DOI: 10.1371/journal.pone.0249151] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 02/01/2022] [Indexed: 12/15/2022] Open
Abstract
Background Aberrant DNA methylation acts epigenetically to skew the gene transcription rate up or down, contributing to cancer etiology. A gap in our understanding concerns the epigenomics of stagewise cancer progression. In this study, we have developed a comprehensive computational framework for the stage-differentiated modelling of DNA methylation landscapes in colorectal cancer (CRC). Methods The methylation β-matrix was derived from the public-domain TCGA data, converted into M-value matrix, annotated with AJCC stages, and analysed for stage-salient genes using an ensemble of approaches involving stage-differentiated modelling of methylation patterns and/or expression patterns. Differentially methylated genes (DMGs) were identified using a contrast against controls (adjusted p-value <0.001 and |log fold-change of M-value| >2), and then filtered using a series of all possible pairwise stage contrasts (p-value <0.05) to obtain stage-salient DMGs. These were then subjected to a consensus analysis, followed by matching with clinical data and performing Kaplan–Meier survival analysis to evaluate the impact of methylation patterns of consensus stage-salient biomarkers on disease prognosis. Results We found significant genome-wide changes in methylation patterns in cancer cases relative to controls agnostic of stage. The stage-differentiated models yielded the following consensus salient genes: one stage-I gene (FBN1), one stage-II gene (FOXG1), one stage-III gene (HCN1) and four stage-IV genes (NELL1, ZNF135, FAM123A, LAMA1). All the biomarkers were significantly hypermethylated in the promoter regions, indicating down-regulation of expression and implying a putative CpG island Methylator Phenotype (CIMP) manifestation. A prognostic signature consisting of FBN1 and FOXG1 survived all the analytical filters, and represents a novel early-stage epigenetic biomarker / target. Conclusions We have designed and executed a workflow for stage-differentiated epigenomic analysis of colorectal cancer progression, and identified several stage-salient diagnostic biomarkers, and an early-stage prognostic biomarker panel. The study has led to the discovery of an alternative CIMP-like signature in colorectal cancer, reinforcing the role of CIMP drivers in tumor pathophysiology.
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Affiliation(s)
- Sangeetha Muthamilselvan
- Department of Bioinformatics, School of Chemical and BioTechnology, SASTRA Deemed University, Thanjavur, India
| | - Abirami Raghavendran
- Department of Bioinformatics, School of Chemical and BioTechnology, SASTRA Deemed University, Thanjavur, India
| | - Ashok Palaniappan
- Department of Bioinformatics, School of Chemical and BioTechnology, SASTRA Deemed University, Thanjavur, India
- * E-mail:
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41
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Ketkar M, Dutt S. Epigenetic Regulation Towards Acquired Drug Resistance in Cancer. Subcell Biochem 2022; 100:473-502. [PMID: 36301503 DOI: 10.1007/978-3-031-07634-3_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Therapy resistance remains the most challenging obstacle in cancer treatment. Substantial efforts and evidences have accumulated over decades suggesting not only genetic but non-genomic mechanisms underlying this adaptation of tumor cells. Alterations in epigenome can have a fundamental effect on cellular functions and response to stresses like anticancer therapy. This chapter discusses the principal mechanisms by which epigenetic modifications in the genome and transcriptome aid tumor cells toward acquisition of resistance to chemotherapy.
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Affiliation(s)
- Madhura Ketkar
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Shilpee Dutt
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India.
- Homi Bhabha National Institute, Mumbai, India.
- ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.
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42
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Verma A, Sinha A, Datta D. Modulation of DNA/RNA Methylation by Small-Molecule Modulators and Their Implications in Cancer. Subcell Biochem 2022; 100:557-579. [PMID: 36301506 DOI: 10.1007/978-3-031-07634-3_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Chromatin is an organized complex of DNA, histone proteins, and RNA. Chromatin modifications include DNA methylation, RNA methylation, and histone acetylation and methylation. The methylation of chromatin complexes predominantly alters the regulation of gene expression, and its deregulation is associated with several human diseases including cancer. Cancer is a disease characterized by dynamic changes in the genetic and epigenetic architecture of a cell. Altered DNA methylation by DNA methyltransferases (DNMTs) and m6A RNA methylation facilitate tumor initiation and progression and thus serve as critical targets for cancer therapy. Small-molecule modulators of these epigenetic targets are at the hotspots of current cancer drug discovery research. Indeed, recent studies have led to the discovery of several chemical modulators against these targets, some of which have already gained approval for cancer therapy while others are undergoing clinical trials. In this chapter, we will focus on the role of small-molecule modulators in regulating DNA/RNA methylation and their implications in cancer.
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Affiliation(s)
- Ayushi Verma
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, India
| | - Abhipsa Sinha
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, India
| | - Dipak Datta
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, India.
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43
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Xu M, Ma T, Shi S, Xing J, Xi Y. Development and Validation of a Mutational Burden-Associated LncRNA Signature for Improving the Clinical Outcome of Hepatocellular Carcinoma. Life (Basel) 2021; 11:life11121312. [PMID: 34947843 PMCID: PMC8706720 DOI: 10.3390/life11121312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 11/21/2021] [Indexed: 02/06/2023] Open
Abstract
Background: Long non-coding RNAs (lncRNAs) modulate numerous cellular processes, including DNA damage repair. Here, we investigated the clinical importance of lncRNAs associated with mutational burden in hepatocellular carcinoma (HCC). Methods: Prognosis-related lncRNAs associated with mutational burden were screened and determined to score the mutational burden-associated lncRNA signature (MbLncSig) from TCGA. Prognostic values and predictive performance of the MbLncSig score were analysed. Results: Four mutational burden-associated lncRNAs (AC010643.1, AC116351.1, LUCAT1 and MIR210HG) were identified for establishing the MbLncSig score. The MbLncSig score served as an independent risk factor for HCC prognosis in different subgroup patients. The predictive performance of one-year and three-year OS was 0.739 and 0.689 in the entire cohort, respectively. Moreover, the MbLncSig score can further stratify the patient survival in those with TP53 wild type or mutation. Conclusions: This study identified a four-lncRNA signature (the MbLncSig score) which could predict survival in HCC patient with/without TP53 mutation.
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Affiliation(s)
| | | | | | | | - Yang Xi
- Correspondence: ; Tel.: +86-574-87600754
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44
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Papanicolau-Sengos A, Aldape K. DNA Methylation Profiling: An Emerging Paradigm for Cancer Diagnosis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2021; 17:295-321. [PMID: 34736341 DOI: 10.1146/annurev-pathol-042220-022304] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Histomorphology has been a mainstay of cancer diagnosis in anatomic pathology for many years. DNA methylation profiling is an additional emerging tool that will serve as an adjunct to increase accuracy of pathological diagnosis. Genome-wide interrogation of DNA methylation signatures, in conjunction with machine learning methods, has allowed for the creation of clinical-grade classifiers, most prominently in central nervous system and soft tissue tumors. Tumor DNA methylation profiling has led to the identification of new entities and the consolidation of morphologically disparate cancers into biologically coherent entities, and it will progressively become mainstream in the future. In addition, DNA methylation patterns in circulating tumor DNA hold great promise for minimally invasive cancer detection and classification. Despite practical challenges that accompany any new technology, methylation profiling is here to stay and will become increasingly utilized as a cancer diagnostic tool across a range of tumor types. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
| | - Kenneth Aldape
- Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892, USA; ,
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45
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Malapelle U, Pisapia P, Addeo A, Arrieta O, Bellosillo B, Cardona AF, Cristofanilli M, De Miguel-Perez D, Denninghoff V, Durán I, Jantus-Lewintre E, Nuzzo PV, O'Byrne K, Pauwels P, Pickering EM, Raez LE, Russo A, Serrano MJ, Gandara DR, Troncone G, Rolfo C. Liquid biopsy from research to clinical practice: focus on non-small cell lung cancer. Expert Rev Mol Diagn 2021; 21:1165-1178. [PMID: 34570988 DOI: 10.1080/14737159.2021.1985468] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
INTRODUCTION In the current era of personalized medicine, liquid biopsy has acquired a relevant importance in patient management of advanced stage non-small cell lung cancer (NSCLC). As a matter of fact, liquid biopsy may supplant the problem of inadequate tissue for molecular testing. The term 'liquid biopsy' refers to a number of different biological fluids, but is most clearly associated with plasma-related platforms. It must be taken into account that pre-analytical processing and the selection of the appropriate technology according to the clinical context may condition the results obtained. In addition, novel clinical applications beyond the evaluation of the molecular status of predictive biomarkers are currently under investigation. AREAS COVERED This review summarizes the available evidence on pre-analytical issues and different clinical applications of liquid biopsies in NSCLC patients. EXPERT OPINION Liquid biopsy should be considered not only as a valid alternative but as complementary to tissue-based molecular approaches. Careful attention should be paid to the optimization and standardization of all phases of liquid biopsy samples management in order to determine a significant improvement in either sensitivity or specificity, while significant reducing the number of 'false negative' or 'false positive' molecular results.
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Affiliation(s)
- Umberto Malapelle
- Department of Public Health, University of Naples Federico Ii, Naples, Italy
| | - Pasquale Pisapia
- Department of Public Health, University of Naples Federico Ii, Naples, Italy
| | - Alfredo Addeo
- Oncology Department, University Hospital Geneva, Geneva, Switzerland
| | - Oscar Arrieta
- Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), México City, México
| | - Beatriz Bellosillo
- Department of Pathology, Hospital Del Mar, Barcelona, Spain.,Department of Pathology, Ciberonc, Madrid, Spain
| | - Andres F Cardona
- Department of Oncology, Clinical and Translational Oncology Group, Clínica Del Country, Bogotá, Colombia.,Department of Oncology, Foundation for Clinical and Applied Cancer Research (Ficmac), Bogotá, Colombia.,Molecular Oncology and Biology Systems Research Group (Fox-g/oncolgroup), Universidad el Bosque, Bogotá, Colombia
| | - Massimo Cristofanilli
- Division of Hematology and Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Diego De Miguel-Perez
- GENyO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Liquid Biopsy and Cancer Interception Group, Granada, Spain.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Valeria Denninghoff
- Department of Pathology, University of Buenos Aires - National Council for Scientific and Technical Research (Conicet), Buenos Aires, Argentina
| | - Ignacio Durán
- Department of Oncology, Hospital Universitario Marques de Valdecilla, IDIVAL, Santander, Spain
| | - Eloísa Jantus-Lewintre
- Department of Pathology, Ciberonc, Madrid, Spain.,Molecular Oncology Laboratory, Fundación Para La Investigación Del Hospital General Universitario De Valencia, Valencia, Spain.,Mixed Unit TRIAL, (Príncipe Felipe Research Centre & Fundación Para La Investigación Del Hospital General Universitario De Valencia), Valencia, Spain.,Department of Biotechnology, Universitat Politècnica De València, Valencia, Spain
| | - Pier Vitale Nuzzo
- Department of Medical Oncology, The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ken O'Byrne
- Medical Oncology, Princess Alexandra Hospital, Queensland University of Technology, Brisbane City, Australia
| | - Patrick Pauwels
- Center for Oncological Research Antwerp (Core), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp (Uantwerp), Wilrijk, Belgium.,Laboratory of Pathological Anatomy, Antwerp University Hospital (UZA), Edegem, Belgium
| | - Edward M Pickering
- Divison of Pulmonary and Critical Care Medicine, Section of Interventional Pulmonology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Luis E Raez
- Thoracic Oncology Program, Memorial Cancer Institute/Memorial Health Care System, Florida International University, Miami, FL, USA
| | - Alessandro Russo
- Department of Oncology, Medical Oncology Unit, A.O. Papardo, Messina, Italy
| | - Maria José Serrano
- GENyO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Liquid Biopsy and Cancer Interception Group, Granada, Spain
| | - David R Gandara
- Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - Giancarlo Troncone
- Department of Public Health, University of Naples Federico Ii, Naples, Italy
| | - Christian Rolfo
- Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Medical System & Icahn School of Medicine, New York, NY, USA
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46
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Thompson JK, Bednar F. Clinical Utility of Epigenetic Changes in Pancreatic Adenocarcinoma. EPIGENOMES 2021; 5:20. [PMID: 34968245 PMCID: PMC8715475 DOI: 10.3390/epigenomes5040020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 09/22/2021] [Accepted: 09/22/2021] [Indexed: 12/17/2022] Open
Abstract
Pancreatic cancer is a molecularly heterogeneous disease. Epigenetic changes and epigenetic regulatory mechanisms underlie at least some of this heterogeneity and contribute to the evolution of aggressive tumor biology in patients and the tumor's intrinsic resistance to therapy. Here we review our current understanding of epigenetic dysregulation in pancreatic cancer and how it is contributing to our efforts in early diagnosis, predictive and prognostic biomarker development and new therapeutic approaches in this deadly cancer.
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Affiliation(s)
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA;
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47
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Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer. Sci Rep 2021; 11:17346. [PMID: 34462486 PMCID: PMC8405634 DOI: 10.1038/s41598-021-96844-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/17/2021] [Indexed: 12/15/2022] Open
Abstract
Tumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human MAGEA6/GABRA3 gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript (CT-GABRA3) that overlaps downstream promoters (GABRQ and GABRA3) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark deposited during transcriptional elongation and known to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the CT-GABRA3 overlapping transcript. Importantly, experimental induction of CT-GABRA3 by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of regional DNA hypermethylation. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo/hypermethylation, and some of these included tumor suppressor genes, e.g. RERG and PTPRO. Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.
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48
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Wu J, Gupta R, Barreto J, Doo P, Joseph NM, Lee JC, Perry A, Chang SM, Berger MS, Solomon DA. Tumor DNA requirements for accurate epigenetic-based classification of CNS neoplasia. Neuro Oncol 2021; 23:1798-1800. [PMID: 34351421 DOI: 10.1093/neuonc/noab157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
- Jasper Wu
- Department of Pathology, University of California, San Francisco, San Francisco, California, USA
| | - Rohit Gupta
- Department of Pathology, University of California, San Francisco, San Francisco, California, USA
| | - Jairo Barreto
- Department of Pathology, University of California, San Francisco, San Francisco, California, USA
| | - Pamela Doo
- Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA
| | - Nancy M Joseph
- Department of Pathology, University of California, San Francisco, San Francisco, California, USA
| | - Julieann C Lee
- Department of Pathology, University of California, San Francisco, San Francisco, California, USA
| | - Arie Perry
- Department of Pathology, University of California, San Francisco, San Francisco, California, USA.,Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Susan M Chang
- Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Mitchel S Berger
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA
| | - David A Solomon
- Department of Pathology, University of California, San Francisco, San Francisco, California, USA
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49
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Tran NH, Kisiel J, Roberts LR. Using cell-free DNA for HCC surveillance and prognosis. JHEP Rep 2021; 3:100304. [PMID: 34136776 PMCID: PMC8182265 DOI: 10.1016/j.jhepr.2021.100304] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/22/2021] [Accepted: 04/24/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Its incidence is rising faster than any other cancer in the United States and it remains one of the leading causes of cancer-related deaths worldwide. While advances in massive parallel sequencing and integration of 'omics information have transformed the field of oncology, tissue access is often limited in HCC and a single biopsy is poorly representative of the known genetic heterogeneity of tumours. Liquid biopsy has emerged as a promising strategy for analysing circulating tumour components including circulating tumour DNA. Cell-free DNA and tumour DNA are derived from necrotic, apoptotic and living eukaryotic cells. The profiling of genetic and epigenetic alterations in circulating cell-free DNA has potential clinical applications including early disease detection, prediction of treatment response and prognostication in real time. Novel biomarker candidates for disease detection and monitoring are under study. Of these, methylation analyses of circulating tumour DNA have shown promising performance for early HCC detection in at-risk patients. Assessments of assay performance in longitudinal validation cohorts are ongoing. Implementation of liquid biopsy for HCC will likely improve upon the current surveillance strategy. This review summarises the most recent developments on the role and utility of circulating cell-free DNA in the detection and management of HCC.
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Affiliation(s)
- Nguyen H Tran
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, United States
| | - John Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States
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50
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Schwalbe EC, H L, Lafta F, Barrow TM, Strathdee G. Integration of genome-level data to allow identification of subtype-specific vulnerability genes as novel therapeutic targets. Oncogene 2021; 40:5213-5223. [PMID: 34230614 PMCID: PMC8376645 DOI: 10.1038/s41388-021-01923-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 06/16/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023]
Abstract
The identification of cancer-specific vulnerability genes is one of the most promising approaches for developing more effective and less toxic cancer treatments. Cancer genomes exhibit thousands of changes in DNA methylation and gene expression, with the vast majority likely to be passenger changes. We hypothesised that, through integration of genome-wide DNA methylation/expression data, we could exploit this inherent variability to identify cancer subtype-specific vulnerability genes that would represent novel therapeutic targets that could allow cancer-specific cell killing. We developed a bioinformatics pipeline integrating genome-wide DNA methylation/gene expression data to identify candidate subtype-specific vulnerability partner genes for the genetic drivers of individual genetic/molecular subtypes. Using acute lymphoblastic leukaemia as an initial model, 21 candidate subtype-specific vulnerability genes were identified across the five common genetic subtypes, with at least one per subtype. To confirm the approach was applicable across cancer types, we also assessed medulloblastoma, identifying 15 candidate subtype-specific vulnerability genes across three of four established subtypes. Almost all identified genes had not previously been implicated in these diseases. Functional analysis of seven candidate subtype-specific vulnerability genes across the two tumour types confirmed that siRNA-mediated knockdown induced significant inhibition of proliferation/induction of apoptosis, which was specific to the cancer subtype in which the gene was predicted to be specifically lethal. Thus, we present a novel approach that integrates genome-wide DNA methylation/expression data to identify cancer subtype-specific vulnerability genes as novel therapeutic targets. We demonstrate this approach is applicable to multiple cancer types and identifies true functional subtype-specific vulnerability genes with high efficiency.
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Affiliation(s)
- Edward C Schwalbe
- Biosciences Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle, UK
- Department of Applied Sciences, Northumbria University, Newcastle, UK
| | - Lalchungnunga H
- Biosciences Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle, UK
| | - Fadhel Lafta
- Biosciences Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle, UK
- Department of Biology, College of Science, University of Baghdad, Baghdad, Iraq
| | - Timothy M Barrow
- Biosciences Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle, UK
- Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland, UK
| | - Gordon Strathdee
- Biosciences Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle, UK.
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