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Newell ME, Babbrah A, Aravindan A, Rathnam R, Halden RU. DNA Methylation in Urine and Feces Indicative of Eight Major Human Cancer Types Globally. Life (Basel) 2025; 15:482. [PMID: 40141826 PMCID: PMC11943902 DOI: 10.3390/life15030482] [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: 12/24/2024] [Revised: 03/05/2025] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
Toxic chemicals and epigenetic biomarkers associated with cancer have been used successfully in clinical diagnostic screening of feces and urine from individuals, but they have been underutilized in a global setting. We analyzed peer-reviewed literature to achieve the following: (i) compile epigenetic biomarkers of disease, (ii) explore whether research locations are geographically aligned with disease hotspots, and (iii) determine the potential for tracking disease-associated epigenetic biomarkers. Studies (n = 1145) of epigenetic biomarkers (n = 146) in urine and feces from individuals have established notable diagnostic potential for detecting and tracking primarily gastric and urinary cancers. Panels with the highest sensitivity and specificity reported more than once were SEPT9 (78% and 93%, respectively) and the binary biomarker combinations GDF15, TMEFF2, and VIM (93% and 95%), NDRG4 and BMP3 (98% and 90%), and TWIST1 and NID2 (76% and 79%). Screening for epigenetic biomarkers has focused on biospecimens from the U.S., Europe, and East Asia, whereas data are limited in regions with similar/higher disease incidence rates (i.e., data for New Zealand, Japan, and Australia for colorectal cancer). The epigenetic markers discussed here may aid in the future monitoring of multiple cancers from individual- to population-level scales by leveraging the emerging science of wastewater-based epidemiology (WBE).
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Affiliation(s)
- Melanie Engstrom Newell
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ 85281, USA
| | - Ayesha Babbrah
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
| | - Anumitha Aravindan
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
| | - Raj Rathnam
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
| | - Rolf U. Halden
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
- School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ 85281, USA
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Sun JX, Yao Y, Li WX, Su X, Yang H, Lu Z, Liu C, Xu XH, Jin L. Upregulation of GPR133 expression impaired the phagocytosis of macrophages in recurrent spontaneous miscarriage. Epigenetics 2024; 19:2337087. [PMID: 38564758 PMCID: PMC10989699 DOI: 10.1080/15592294.2024.2337087] [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: 09/05/2023] [Accepted: 03/26/2024] [Indexed: 04/04/2024] Open
Abstract
Decidual macrophages are the second-largest immune cell group at the maternal-foetal interface. They participate in apoptotic cell removal, and protect the foetus from microorganisms or pathogens. Dysfunction of decidual macrophages gives rise to pregnancy complications such as preeclampsia and recurrent spontaneous miscarriage (RSM). However, the mechanisms by which decidual macrophages are involved in the occurrence of adverse pregnancy outcomes have not been elucidated. Here we integrated DNA methylation and gene expression data from decidua macrophages to identify potential risk factors related to RSM. GPR133 was significantly hypomethylated and upregulated in decidual macrophages from RSM patients. Further demethylation analysis demonstrated that GPR133 expression in decidual macrophages was significantly increased by 5-Aza-dC treatment. In addition, the influence of GPR133 on the phagocytic ability of macrophages was explored. Phagocytosis was impaired in the decidual macrophages of RSM patients with increased GPR133 expression. Increased GPR133 expression induced by demethylation treatment in the decidual macrophages of healthy control patients led to a significant decrease in phagocytic function. Importantly, knockdown of GPR133 resulted in a significant improvement in the phagocytic function of THP-1 macrophages. In conclusion, the existing studies have shown the influence of GPR133 on the phagocytic function of decidual macrophages and pregnancy outcomes, providing new data and ideas for future research on the role of decidual macrophages in RSM.
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Affiliation(s)
- Jia-Xue Sun
- Department of Biobank, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, P.R, China
| | - Yongli Yao
- Department of Biobank, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, P.R, China
| | - Wen-Xuan Li
- Department of Biobank, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, P.R, China
| | - Xin Su
- Department of Biobank, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, P.R, China
| | - Haoyu Yang
- Department of Biobank, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, P.R, China
| | - Zhouping Lu
- Department of Biobank, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, P.R, China
| | - Chenfei Liu
- Department of Biobank, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, P.R, China
| | - Xiang-Hong Xu
- Department of Biobank, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, P.R, China
| | - Liping Jin
- Department of Biobank, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, P.R, China
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Silva-Ferreira M, Carvalho JA, Salta S, Henriques TS, Pereira Rodrigues P, Monteiro-Reis S, Henrique R, Jerónimo C. Diagnostic Test Accuracy of Urinary DNA Methylation-based Biomarkers for the Detection of Primary and Recurrent Bladder Cancer: A Systematic Review and Meta-analysis. Eur Urol Focus 2024; 10:922-934. [PMID: 38897871 DOI: 10.1016/j.euf.2024.05.024] [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: 03/21/2024] [Revised: 05/13/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND AND OBJECTIVE Diagnosis of primary and relapsed bladder carcinomas is accomplished by urethrocystoscopy, an invasive procedure, combined with urinary cytology, with limited sensitivity, resulting in a substantial burden. Thus, noninvasive biomarkers have been investigated, among which DNA methylation has shown promise. This systematic review and meta-analysis sought to assess the diagnostic accuracy of DNA methylation biomarkers reported in the literature for bladder cancer detection, pinpointing the most informative one. METHODS The search for this systematic review and meta-analysis was conducted on PubMed, Scopus, and Cochrane Library for relevant studies published until December 31, 2022. A meta-analysis was performed using a random-effect model, to compute the pooled sensitivity and specificity of the markers. PROSPERO's registration ID for the study is CRD42023397703. KEY FINDINGS AND LIMITATIONS Out of the 2297 studies retrieved, 68 were included in the final analysis, despite considerable heterogeneity. These involved 12 696 participants, of whom 5557 were diagnosed with bladder cancer. Using diagnostic odds ratio (DOR) as a comparative measure, the five most promising markers (pooled sensitivity, specificity, and DOR) were SALL3 (61%, 97%, and 55.67, respectively), PENK (77%, 93%, and 47.90, respectively), ZNF154 (87%, 90%, and 45.07, respectively), VIM (82%, 90%, and 44.81, respectively), and POU4F2 (81%, 89%, and 34.89, respectively). Urinary cytology identified bladder cancer with 55% sensitivity, 92% specificity, and 14.37 DOR. CONCLUSIONS AND CLINICAL IMPLICATIONS DNA methylation biomarkers disclose high accuracy for bladder cancer detection in urine. Nonetheless, validation studies in different clinical settings are scarce, hampering clinical use. The identified biomarkers should be prioritized in future validation studies. PATIENT SUMMARY In this meta-analysis, we include previously published studies that used urine samples of bladder cancer patients' from all around the globe. We were able to compare the diagnostic accuracy of noninvasive markers across different populations. We were able to conclude on the most promising DNA methylation markers to detect bladder cancer using urine.
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Affiliation(s)
- Mariana Silva-Ferreira
- Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center - Raquel Seruca (Porto.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal; Master Program in Oncology, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
| | - João A Carvalho
- Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center - Raquel Seruca (Porto.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal; Doctoral Program in Medical Science, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal; Department of Urology & Urology Clinics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Sofia Salta
- Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center - Raquel Seruca (Porto.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal; Doctoral Program in Pathology and Molecular Genetics, ICBAS - School of Medicine and Biomedical Sciences - University of Porto, Porto, Portugal
| | - Teresa S Henriques
- CINTESIS@RISE - Health Research Network & MEDCIDS, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Pedro Pereira Rodrigues
- CINTESIS@RISE - Health Research Network & MEDCIDS, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Sara Monteiro-Reis
- Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center - Raquel Seruca (Porto.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal; Institute of Science and Innovation in Mechanical and Industrial Engineering (INEGI), Porto, Portugal
| | - Rui Henrique
- Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center - Raquel Seruca (Porto.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal; Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; Department of Pathology and Molecular Immunology, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.
| | - Carmen Jerónimo
- Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center - Raquel Seruca (Porto.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal; Department of Pathology and Molecular Immunology, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.
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Griñán-Ferré C, Bellver-Sanchis A, Guerrero A, Pallàs M. Advancing personalized medicine in neurodegenerative diseases: The role of epigenetics and pharmacoepigenomics in pharmacotherapy. Pharmacol Res 2024; 205:107247. [PMID: 38834164 DOI: 10.1016/j.phrs.2024.107247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 04/23/2024] [Accepted: 05/30/2024] [Indexed: 06/06/2024]
Abstract
About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. The emergence of new sequencing technologies and tools to study the epigenome has led to identifying predictive biomarkers for earlier diagnosis, opening up the possibility of prophylactical interventions. As a result, advances in pharmacogenetics and pharmacoepigenomics now allow for personalized treatments based on the profile of each patient and the specific genetic and epigenetic mechanisms involved. This Review highlights the complexity of neurodegenerative diseases and the variability in patient responses to pharmacotherapy, emphasizing the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of drugs used to treat those conditions. We specifically discuss the potential modulatory effect of several genetic polymorphisms associated with an increased risk of developing different neurodegenerative diseases. We explore genetic and genomic technologies and the potential of analyzing individual-specific drug metabolism to predict and influence drug response and associated clinical outcomes. We also provide insights into the mechanism of action of the drugs under investigation and their potential impact on disease-modifying pathways. Finally, the Review underscores the great potential of this field to enhance the effectiveness and safety of drug treatments through personalized medicine.
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Affiliation(s)
- Christian Griñán-Ferré
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Avda. Joan XXIII, 27, Barcelona 08028, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
| | - Aina Bellver-Sanchis
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Avda. Joan XXIII, 27, Barcelona 08028, Spain
| | - Ana Guerrero
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Avda. Joan XXIII, 27, Barcelona 08028, Spain
| | - Mercè Pallàs
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Avda. Joan XXIII, 27, Barcelona 08028, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
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Rismanbaf A. Improving targeted small molecule drugs to overcome chemotherapy resistance. Cancer Rep (Hoboken) 2024; 7:e1945. [PMID: 37994401 PMCID: PMC10809209 DOI: 10.1002/cnr2.1945] [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: 07/15/2023] [Revised: 10/25/2023] [Accepted: 11/12/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Conventional cancer treatments face the challenge of therapeutic resistance, which causes poor treatment outcomes. The use of combination therapies can improve treatment results in patients and is one of the solutions to overcome this challenge. Chemotherapy is one of the conventional treatments that, due to the non-targeted and lack of specificity in targeting cancer cells, can cause serious complications in the short and long-term for patients by damaging healthy cells. Also, the employment of a wide range of strategies for chemotherapy resistance by cancer cells, metastasis, and cancer recurrence create serious problems to achieve the desired results of chemotherapy. Accordingly, targeted therapies can be used as a combination treatment with chemotherapy to both cause less damage to healthy cells, which as a result, they reduce the side effects of chemotherapy, and by targeting the factors that cause therapeutic challenges, can improve the results of chemotherapy in patients. RECENT FINDINGS Small molecules are one of the main targeted therapies that can be used for diverse targets in cancer treatment due to their penetration ability and characteristics. However, small molecules in cancer treatment are facing obstacles that a better understanding of cancer biology, as well as the mechanisms and factors involved in chemotherapy resistance, can lead to the improvement of this type of major targeted therapy. CONCLUSION In this review article, at first, the challenges that lead to not achieving the desired results in chemotherapy and how cancer cells can be resistant to chemotherapy are examined, and at the end, research areas are suggested that more focusing on them, can lead to the improvement of the results of using targeted small molecules as an adjunctive treatment for chemotherapy in the conditions of chemotherapy resistance and metastasis of cancer cells.
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Affiliation(s)
- Amirhossein Rismanbaf
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical SciencesIslamic Azad UniversityTehranIran
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Chin FW, Chan SC, Veerakumarasivam A. Homeobox Gene Expression Dysregulation as Potential Diagnostic and Prognostic Biomarkers in Bladder Cancer. Diagnostics (Basel) 2023; 13:2641. [PMID: 37627900 PMCID: PMC10453580 DOI: 10.3390/diagnostics13162641] [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: 05/30/2023] [Revised: 07/07/2023] [Accepted: 07/10/2023] [Indexed: 08/27/2023] Open
Abstract
Homeobox genes serve as master regulatory transcription factors that regulate gene expression during embryogenesis. A homeobox gene may have either tumor-promoting or tumor-suppressive properties depending on the specific organ or cell lineage where it is expressed. The dysregulation of homeobox genes has been reported in various human cancers, including bladder cancer. The dysregulated expression of homeobox genes has been associated with bladder cancer clinical outcomes. Although bladder cancer has high risk of tumor recurrence and progression, it is highly challenging for clinicians to accurately predict the risk of tumor recurrence and progression at the initial point of diagnosis. Cystoscopy is the routine surveillance method used to detect tumor recurrence. However, the procedure causes significant discomfort and pain that results in poor surveillance follow-up amongst patients. Therefore, the development of reliable non-invasive biomarkers for the early detection and monitoring of bladder cancer is crucial. This review provides a comprehensive overview of the diagnostic and prognostic potential of homeobox gene expression dysregulation in bladder cancer.
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Affiliation(s)
- Fee-Wai Chin
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia;
| | - Soon-Choy Chan
- School of Liberal Arts, Science and Technology, Perdana University, Kuala Lumpur 50490, Malaysia
| | - Abhi Veerakumarasivam
- School of Medical and Life Sciences, Sunway University, Bandar Sunway 47500, Selangor, Malaysia
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DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities. Int J Mol Sci 2022; 23:ijms232314672. [PMID: 36499000 PMCID: PMC9735783 DOI: 10.3390/ijms232314672] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/20/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022] Open
Abstract
Resistance to chemo- and radiotherapy is a common event among cancer patients and a reason why new cancer therapies and therapeutic strategies need to be in continuous investigation and development. DNA damage response (DDR) comprises several pathways that eliminate DNA damage to maintain genomic stability and integrity, but different types of cancers are associated with DDR machinery defects. Many improvements have been made in recent years, providing several drugs and therapeutic strategies for cancer patients, including those targeting the DDR pathways. Currently, poly (ADP-ribose) polymerase inhibitors (PARP inhibitors) are the DDR inhibitors (DDRi) approved for several cancers, including breast, ovarian, pancreatic, and prostate cancer. However, PARPi resistance is a growing issue in clinical settings that increases disease relapse and aggravate patients' prognosis. Additionally, resistance to other DDRi is also being found and investigated. The resistance mechanisms to DDRi include reversion mutations, epigenetic modification, stabilization of the replication fork, and increased drug efflux. This review highlights the DDR pathways in cancer therapy, its role in the resistance to conventional treatments, and its exploitation for anticancer treatment. Biomarkers of treatment response, combination strategies with other anticancer agents, resistance mechanisms, and liabilities of treatment with DDR inhibitors are also discussed.
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Xiao Y, Ju L, Qian K, Jin W, Wang G, Zhao Y, Jiang W, Liu N, Wu K, Peng M, Cao R, Li S, Shi H, Gong Y, Zheng H, Liu T, Luo Y, Ma H, Chang L, Li G, Cao X, Tian Y, Xu Z, Yang Z, Shan L, Guo Z, Yao D, Zhou X, Chen X, Guo Z, Liu D, Xu S, Ji C, Yu F, Hong X, Luo J, Cao H, Zhang Y, Wang X. Non-invasive diagnosis and surveillance of bladder cancer with driver and passenger DNA methylation in a prospective cohort study. Clin Transl Med 2022; 12:e1008. [PMID: 35968916 PMCID: PMC9377153 DOI: 10.1002/ctm2.1008] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 07/18/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND State-of-art non-invasive diagnosis processes for bladder cancer (BLCA) harbour shortcomings such as low sensitivity and specificity, unable to distinguish between high- (HG) and low-grade (LG) tumours, as well as inability to differentiate muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). This study investigates a comprehensive characterization of the entire DNA methylation (DNAm) landscape of BLCA to determine the relevant biomarkers for the non-invasive diagnosis of BLCA. METHODS A total of 304 samples from 224 donors were enrolled in this multi-centre, prospective cohort study. BLCA-specific DNAm signature discovery was carried out with genome-wide bisulfite sequencing in 32 tumour tissues and 12 normal urine samples. A targeted sequencing assay for BLCA-specific DNAm signatures was developed to categorize tumour tissue against normal urine, or MIBC against NMIBC. Independent validation was performed with targeted sequencing of 259 urine samples in a double-blinded manner to determine the clinical diagnosis and prognosis value of DNAm-based classification models. Functions of genomic region harbouring BLCA-specific DNAm signature were validated with biological assays. Concordances of pathology to urine tumour DNA (circulating tumour DNA [ctDNA]) methylation, genomic mutations or other state-of-the-art diagnosis methods were measured. RESULTS Genome-wide DNAm profile could accurately classify LG tumour from HG tumour (LG NMIBC vs. HG NMIBC: p = .038; LG NMIBC vs. HG MIBC, p = .00032; HG NMIBC vs. HG MIBC: p = .82; Student's t-test). Overall, the DNAm profile distinguishes MIBC from NMIBC and normal urine. Targeted-sequencing-based DNAm signature classifiers accurately classify LG NMIBC tissues from HG MIBC and could detect tumours in urine at a limit of detection of less than .5%. In tumour tissues, DNAm accurately classifies pathology, thus outperforming genomic mutation or RNA expression profiles. In the independent validation cohort, pre-surgery urine ctDNA methylation outperforms fluorescence in situ hybridization (FISH) assay to detect HG BLCA (n = 54) with 100% sensitivity (95% CI: 82.5%-100%) and LG BLCA (n = 26) with 62% sensitivity (95% CI: 51.3%-72.7%), both at 100% specificity (non-BLCA: n = 72; 95% CI: 84.1%-100%). Pre-surgery urine ctDNA methylation signature correlates with pathology and predicts recurrence and metastasis. Post-surgery urine ctDNA methylation (n = 61) accurately predicts recurrence-free survival within 180 days, with 100% accuracy. CONCLUSION With the discovery of BLCA-specific DNAm signatures, targeted sequencing of ctDNA methylation outperforms FISH and DNA mutation to detect tumours, predict recurrence and make prognoses.
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Parisi GF, Mòllica F, Giallongo A, Papale M, Manti S, Leonardi S. Cystic fibrosis transmembrane conductance regulator (CFTR): beyond cystic fibrosis. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00308-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The cystic fibrosis transmembrane conductance regulator (CFTR) gene has been traditionally linked to cystic fibrosis (CF) inheritance in an autosomal recessive manner. Advances in molecular biology and genetics have expanded our understanding of the CFTR gene and its encoding products expressed in different tissues.
Aim
The study’s aim consists of reviewing the different pathological CF phenotypes using the existing literature. We know that alterations of the CFTR protein’s structure may result in different pathological phenotypes.
Methods
Open sources such as PubMed and Science Direct databases have been used for this review. We focused our selection on articles published within the last 15 years. Critical terms related to the CFTR protein have been used: “CFTR AND cancer,” “CFTR AND celiac disease,” “CFTR AND pancreatitis,” “children,” “adults,” “genotype,” “phenotype,” “correlation,” “mutation,” “CFTR,” “diseases,” “disorders,” and “no cystic fibrosis.”
Results
We analyzed 1,115 abstracts in total. Moreover, only 189 were suitable for the topic. We focused on the role of CFTR in cancer, gastrointestinal disorders, respiratory diseases, reproductive system, and systemic hypertension.
Conclusions
Mutations in CFTR gene are often associated with CF. In this review, we highlighted the broad spectrum of alterations reported for this gene, which may be involved in the pathogenesis of other diseases. The importance of these new insights in the role of CFTR relies on the possibility of considering this protein/gene as a novel therapeutic target for CF- and CFTR-related diseases.
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Karaglani M, Panagopoulou M, Baltsavia I, Apalaki P, Theodosiou T, Iliopoulos I, Tsamardinos I, Chatzaki E. Tissue-Specific Methylation Biosignatures for Monitoring Diseases: An In Silico Approach. Int J Mol Sci 2022; 23:2959. [PMID: 35328380 PMCID: PMC8952417 DOI: 10.3390/ijms23062959] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/01/2022] [Accepted: 03/03/2022] [Indexed: 02/06/2023] Open
Abstract
Tissue-specific gene methylation events are key to the pathogenesis of several diseases and can be utilized for diagnosis and monitoring. Here, we established an in silico pipeline to analyze high-throughput methylome datasets to identify specific methylation fingerprints in three pathological entities of major burden, i.e., breast cancer (BrCa), osteoarthritis (OA) and diabetes mellitus (DM). Differential methylation analysis was conducted to compare tissues/cells related to the pathology and different types of healthy tissues, revealing Differentially Methylated Genes (DMGs). Highly performing and low feature number biosignatures were built with automated machine learning, including: (1) a five-gene biosignature discriminating BrCa tissue from healthy tissues (AUC 0.987 and precision 0.987), (2) three equivalent OA cartilage-specific biosignatures containing four genes each (AUC 0.978 and precision 0.986) and (3) a four-gene pancreatic β-cell-specific biosignature (AUC 0.984 and precision 0.995). Next, the BrCa biosignature was validated using an independent ccfDNA dataset showing an AUC and precision of 1.000, verifying the biosignature's applicability in liquid biopsy. Functional and protein interaction prediction analysis revealed that most DMGs identified are involved in pathways known to be related to the studied diseases or pointed to new ones. Overall, our data-driven approach contributes to the maximum exploitation of high-throughput methylome readings, helping to establish specific disease profiles to be applied in clinical practice and to understand human pathology.
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Affiliation(s)
- Makrina Karaglani
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, GR-68100 Alexandroupolis, Greece; (M.K.); (M.P.); (P.A.); (T.T.)
| | - Maria Panagopoulou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, GR-68100 Alexandroupolis, Greece; (M.K.); (M.P.); (P.A.); (T.T.)
| | - Ismini Baltsavia
- Department of Basic Sciences, School of Medicine, University of Crete, GR-71003 Heraklion, Greece; (I.B.); (I.I.)
| | - Paraskevi Apalaki
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, GR-68100 Alexandroupolis, Greece; (M.K.); (M.P.); (P.A.); (T.T.)
| | - Theodosis Theodosiou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, GR-68100 Alexandroupolis, Greece; (M.K.); (M.P.); (P.A.); (T.T.)
| | - Ioannis Iliopoulos
- Department of Basic Sciences, School of Medicine, University of Crete, GR-71003 Heraklion, Greece; (I.B.); (I.I.)
| | - Ioannis Tsamardinos
- JADBio Gnosis DA S.A., Science and Technology Park of Crete, GR-70013 Heraklion, Greece;
- Department of Computer Science, University of Crete, GR-70013 Heraklion, Greece
- Institute of Applied and Computational Mathematics, Foundation for Research and Technology—Hellas, GR-70013 Heraklion, Greece
| | - Ekaterini Chatzaki
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, GR-68100 Alexandroupolis, Greece; (M.K.); (M.P.); (P.A.); (T.T.)
- Institute of Agri-Food and Life Sciences, Hellenic Mediterranean University Research Centre, GR-71410 Heraklion, Greece
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11
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Fang Q, Zhang X, Nie Q, Hu J, Zhou S, Wang C. Improved urine DNA methylation panel for early bladder cancer detection. BMC Cancer 2022; 22:237. [PMID: 35241014 PMCID: PMC8895640 DOI: 10.1186/s12885-022-09268-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 02/02/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Bladder cancer is one of the most common malignancies but the corresponding diagnostic methods are either invasive or limited in specificity and/or sensitivity. This study aimed to develop a urine-based methylation panel for bladder cancer detection by improving published panels and validate performance of the new panel with clinical samples. METHODS Related researches were reviewed and 19 potential panels were selected. RRBS was performed on a cohort with 45 samples to reassess these panels and a new panel inherited best markers was developed. The new panel was applied with qMSP platform to 33 samples from the RRBS cohort and the results were compared to those of RRBS. Lastly, another larger cohort with 207 samples was used to validate new panel performance with qMSP. RESULTS Three biomarkers (PCDH17, POU4F2 and PENK) were selected to construct a new panel P3. P3 panel achieved 100% specificity and 71% sensitivity with RRBS in corresponding cohort and then showed a better performance of 100% specificity and 84% sensitivity with qMSP platforms in a balanced cohort. When validated with 207-sample cohort, P3 with qMSP showed a performance of 97% specificity and 87% sensitivity which was modestly improved compared to the panels it derided from. CONCLUSIONS Overall, the P3 panel achieved relatively high sensitivity and accuracy in bladder cancer detection.
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Affiliation(s)
- Qixun Fang
- Yaneng Bioscience, Co., Ltd, Shenzhen, 518100, China.,South China University of Technology, Guangzhou, 510641, China
| | - Xu Zhang
- Department of Urology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Qing Nie
- Yaneng Bioscience, Co., Ltd, Shenzhen, 518100, China
| | - Jianqiang Hu
- South China University of Technology, Guangzhou, 510641, China
| | - Shujun Zhou
- Yaneng Bioscience, Co., Ltd, Shenzhen, 518100, China. .,South China University of Technology, Guangzhou, 510641, China.
| | - Chaojun Wang
- Department of Urology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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12
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SALL Proteins; Common and Antagonistic Roles in Cancer. Cancers (Basel) 2021; 13:cancers13246292. [PMID: 34944911 PMCID: PMC8699250 DOI: 10.3390/cancers13246292] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/06/2021] [Accepted: 12/09/2021] [Indexed: 01/02/2023] Open
Abstract
Simple Summary Transcription factors play essential roles in regulating gene expression, impacting the cell phenotype and function, and in the response of cells to environmental conditions. Alterations in transcription factors, including gene amplification or deletion, point mutations, and expression changes, are implicated in carcinogenesis, cancer progression, metastases, and resistance to cancer treatments. Not surprisingly, transcription factor activity is altered in numerous cancers, representing a unique class of cancer drug targets. This review updates and integrates information on the SALL family of transcription factors, highlighting the synergistic and/or antagonistic functions they perform in various cancer types. Abstract SALL proteins are a family of four conserved C2H2 zinc finger transcription factors that play critical roles in organogenesis during embryonic development. They regulate cell proliferation, survival, migration, and stemness; consequently, they are involved in various human genetic disorders and cancer. SALL4 is a well-recognized oncogene; however, SALL1–3 play dual roles depending on the cancer context and stage of the disease. Current reviews of SALLs have focused only on SALL2 or SALL4, lacking an integrated view of the SALL family members in cancer. Here, we update the recent advances of the SALL members in tumor development, cancer progression, and therapy, highlighting the synergistic and/or antagonistic functions they perform in similar cancer contexts. We identified common regulatory mechanisms, targets, and signaling pathways in breast, brain, liver, colon, blood, and HPV-related cancers. In addition, we discuss the potential of the SALL family members as cancer biomarkers and in the cancer cells’ response to therapies. Understanding SALL proteins’ function and relationship will open new cancer biology, clinical research, and therapy perspectives.
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13
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Li M, Yue W, Li Q, Yu W, Li Y, Cao X. Circular RNA Circ_0000098 Elevates ALX4 Expression via Adsorbing miR-1204 to Inhibit the Progression of Hepatocellular Carcinoma. Front Oncol 2021; 11:696078. [PMID: 34900665 PMCID: PMC8662564 DOI: 10.3389/fonc.2021.696078] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 10/21/2021] [Indexed: 11/21/2022] Open
Abstract
Background Circular RNAs (CircRNAs) feature prominently in the progression of various cancers. However, the biological functions of many circRNAs in hepatocellular carcinoma (HCC) are far from fully clarified. This work is performed to decipher the function of circ_0000098 (circSLC30A7) in modulating the progression of HCC and its molecular mechanism. Methods Microarray data (GSE97332) were available from the Gene Expression Omnibus (GEO) database, and circRNA differentially expressed in HCC tissues was screened out by GEO2R tool. Circ_0000098, microRNA-1204 (miR-1204), and aristaless-like homeobox-4 (ALX4) mRNA expressions were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell counting kit-8 (CCK-8), scratch wound healing, and Transwell assays were adopted to determine proliferation, migration, and invasion of HCC cells. ALX4 protein, E-cadherin, N-cadherin, and Vimentin expressions were evaluated by Western blot. In addition, the targeting relationship between miR-1204 and circ_0000098 or ALX4 was studied with dual-luciferase reporter assay and RIP assay. Results Circ_0000098 expression level was markedly declined in HCC tissues and cells, and its underexpression was associated with larger tumor size of HCC patients. Knocking down circ_0000098 observably promoted the multiplication, migration, invasion, and epithelial-mesenchymal transition (EMT) of Huh7 and SMMC-7721 cells. Additionally, circ_0000098 was mainly distributed in the cytoplasm of HCC cells, and up-regulated ALX4 expression through competitively decoying miR-1204. Conclusion Circ_0000098, as a competitive endogenous RNA (ceRNA) of miR-1204, upregulates ALX4 expression and suppresses the growth, migration, invasion, and EMT of HCC cells.
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Affiliation(s)
- Ming Li
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Wenjing Yue
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Qiankun Li
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Wenyu Yu
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Yao Li
- Medical Office, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Xiaoling Cao
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
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14
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Xiao X, Sun H, Liu X, Guo Z, Zheng S, Xu J, Sun J, Lan Y, Shao C, Sun W. Qualitative and quantitative proteomic and metaproteomic analyses of healthy human urine sediment. Proteomics Clin Appl 2021; 16:e2100007. [PMID: 34687263 DOI: 10.1002/prca.202100007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 09/30/2021] [Accepted: 10/17/2021] [Indexed: 11/07/2022]
Abstract
PURPOSE The healthy human urine sediment proteome and metaproteome are investigated, to shed light on the variations of urine sediment proteins and metaproteins associated with sex and age. EXPERIMENTAL DESIGN Urine sediment samples are collected from 19 healthy subjects. Protein identification and quantification are performed by liquid chromatography coupled high-resolution mass spectrometry. RESULTS A total of 2736 human proteins were identified, which were primarily associated with inflammatory response and energy metabolism. For the metaproteome, 65 genera were identified that were primarily involved in translation and carbohydrate metabolic processes. The median biological coefficient variation of the proteome/metaproteome of human urine sediment was 0.5/0.72, similar to the proteome of human urine supernatant. In addition, sex and age were observed to affect the proteome and metaproteome of healthy human urine sediment. CONCLUSION AND CLINICAL RELEVANCE The healthy human urine sediment were characterized, indicating that urine sediment might represent an alternative resource for disease research in addition to urine supernatant, but the influence of sex and age must be considered in the study design process.
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Affiliation(s)
- XiaoLian Xiao
- Core Facility of Instrument, School of Basic Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Haidan Sun
- Core Facility of Instrument, School of Basic Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoyan Liu
- Core Facility of Instrument, School of Basic Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhengguang Guo
- Core Facility of Instrument, School of Basic Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Shuxin Zheng
- Core Facility of Instrument, School of Basic Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jiyu Xu
- Core Facility of Instrument, School of Basic Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jiameng Sun
- Core Facility of Instrument, School of Basic Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Ying Lan
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Chen Shao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Wei Sun
- Core Facility of Instrument, School of Basic Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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15
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Humayun-Zakaria N, Ward DG, Arnold R, Bryan RT. Trends in urine biomarker discovery for urothelial bladder cancer: DNA, RNA, or protein? Transl Androl Urol 2021; 10:2787-2808. [PMID: 34295762 PMCID: PMC8261432 DOI: 10.21037/tau-20-1327] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 04/23/2021] [Indexed: 02/01/2023] Open
Abstract
Urothelial bladder cancer is a complex disease displaying a landscape of heterogenous molecular subtypes, mutation profiles and clinical presentations. Diagnosis and surveillance rely on flexible cystoscopy which has high accuracy, albeit accompanied by a high-cost burden for healthcare providers and discomfort for patients. Advances in "omic" technologies and computational biology have provided insights into the molecular pathogenesis of bladder cancer and provided powerful tools to identify markers for disease detection, risk stratification, and predicting responses to therapy. To date, numerous attempts have been made to discover and validate diagnostic biomarkers that could be deployed as an adjunct to the cystoscopic diagnosis and long-term surveillance of bladder cancer. We report a comprehensive literature analysis using PubMed to assess the changing trends in investigating DNA, RNA, or proteins as diagnostic urinary biomarkers over a period of 5 decades: 1970-2020. A gradual shift has been observed in research away from protein biomarkers to nucleic acids including different classes of RNA, and DNA methylation and mutation markers. Until 2000, publications involving protein biomarker discovery constituted 87% of the total number of research articles with DNA comprising 6% and RNA 7%. Since 2000 the proportion of protein biomarker articles has fallen to 40%, and DNA and RNA studies increased to 32% and 28%, respectively. Clearly research focus, perhaps driven by technological innovation, has shifted from proteins to nucleic acids. We optimistically hypothesise that, following thorough validation, a clinically useful detection test for bladder cancer based on a panel of DNA or RNA markers could become reality within 5-10 years.
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Affiliation(s)
- Nada Humayun-Zakaria
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Douglas G Ward
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Roland Arnold
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Richard T Bryan
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
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16
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A bird eye view on cystic fibrosis: An underestimated multifaceted chronic disorder. Life Sci 2020; 268:118959. [PMID: 33383045 DOI: 10.1016/j.lfs.2020.118959] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/15/2020] [Accepted: 12/17/2020] [Indexed: 01/19/2023]
Abstract
Cystic fibrosis (CF) is an autosomal recessive disease which involves the mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF involves in the inflammatory processes and is considered as a multisystem disorder that is not confined to lungs, but it also affects other vital organs that leads to numerous co-morbidities. The respiratory disorder in the CF results in mortality and morbidity which is characterized by series of serious events involving mucus hypersecretion, microbial infections, airways obstruction, inflammation, destruction of epithelium, tissue remodeling and terminal lung diseases. Mucins are the high molecular weight glycoproteins important for the viscoelastic properties of the mucus, play a significant role in the disease mechanisms. Determining the functional association between the CFTR and mucins might help to identify the putative target for specific therapeutic approach. In fact, furin enzyme which helps in the entry of novel COVID-19 virus into the cell, is upregulated in CF and this can also serve as a potential target for CF treatment. Moreover, the use of nano-formulations for CF treatment is an area of research being widely studied as they have also demonstrated promising outcomes. The in-depth knowledge of non-coding RNAs like miRNAs and lncRNAs and their functional association with CFTR gene expression and mutation can provide a different range of opportunity to identify the promising therapeutic approaches for CF.
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17
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Verschuere S, Van Gils M, Nollet L, Vanakker OM. From membrane to mineralization: the curious case of the ABCC6 transporter. FEBS Lett 2020; 594:4109-4133. [PMID: 33131056 DOI: 10.1002/1873-3468.13981] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/12/2020] [Accepted: 10/16/2020] [Indexed: 12/13/2022]
Abstract
ATP-binding cassette subfamily C member 6 gene/protein (ABCC6) is an ATP-dependent transmembrane transporter predominantly expressed in the liver and the kidney. ABCC6 first came to attention in human medicine when it was discovered in 2000 that mutations in its encoding gene, ABCC6, caused the autosomal recessive multisystemic mineralization disease pseudoxanthoma elasticum (PXE). Since then, the physiological and pathological roles of ABCC6 have been the subject of intense research. In the last 20 years, significant findings have clarified ABCC6 structure as well as its physiological role in mineralization homeostasis in humans and animal models. Yet, several facets of ABCC6 biology remain currently incompletely understood, ranging from the precise nature of its substrate(s) to the increasingly complex molecular genetics. Nonetheless, advances in our understanding of pathophysiological mechanisms causing mineralization lead to several treatment options being suggested or already tested in pilot clinical trials for ABCC6 deficiency. This review highlights current knowledge of ABCC6 and the challenges ahead, particularly the attempts to translate basic science into clinical practice.
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Affiliation(s)
- Shana Verschuere
- Center for Medical Genetics, Ghent University Hospital, Belgium.,Department of Biomolecular Medicine, Ghent University, Belgium.,Ectopic Mineralization Research Group Ghent, Ghent, Belgium
| | - Matthias Van Gils
- Center for Medical Genetics, Ghent University Hospital, Belgium.,Department of Biomolecular Medicine, Ghent University, Belgium.,Ectopic Mineralization Research Group Ghent, Ghent, Belgium
| | - Lukas Nollet
- Center for Medical Genetics, Ghent University Hospital, Belgium.,Department of Biomolecular Medicine, Ghent University, Belgium.,Ectopic Mineralization Research Group Ghent, Ghent, Belgium
| | - Olivier M Vanakker
- Center for Medical Genetics, Ghent University Hospital, Belgium.,Department of Biomolecular Medicine, Ghent University, Belgium.,Ectopic Mineralization Research Group Ghent, Ghent, Belgium
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18
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Zappe K, Cichna-Markl M. Aberrant DNA Methylation of ABC Transporters in Cancer. Cells 2020; 9:cells9102281. [PMID: 33066132 PMCID: PMC7601986 DOI: 10.3390/cells9102281] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/18/2020] [Accepted: 09/21/2020] [Indexed: 12/21/2022] Open
Abstract
ATP-binding cassette (ABC) transporters play a crucial role in multidrug resistance (MDR) of cancers. They function as efflux pumps, resulting in limited effectiveness or even failure of therapy. Increasing evidence suggests that ABC transporters are also involved in tumor initiation, progression, and metastasis. Tumors frequently show multiple genetic and epigenetic abnormalities, including changes in histone modification and DNA methylation. Alterations in the DNA methylation status of ABC transporters have been reported for a variety of cancer types. In this review, we outline the current knowledge of DNA methylation of ABC transporters in cancer. We give a brief introduction to structure, function, and gene regulation of ABC transporters that have already been investigated for their DNA methylation status in cancer. After giving an overview of the applied methodologies and the CpGs analyzed, we summarize and discuss the findings on aberrant DNA methylation of ABC transporters by cancer types. We conclude our review with the discussion of the potential to target aberrant DNA methylation of ABC transporters for cancer therapy.
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19
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Liu Q, Lu F, Chen Z. Identification of MT1E as a novel tumor suppressor in hepatocellular carcinoma. Pathol Res Pract 2020; 216:153213. [PMID: 32956919 DOI: 10.1016/j.prp.2020.153213] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 09/06/2020] [Accepted: 09/08/2020] [Indexed: 11/26/2022]
Abstract
BACKGROUND Metallothioneins (MTs) involves in the tumorigenesis and prognosis of various cancers. The biological function and methylation status of MT1E in hepatocellular carcinoma (HCC) remain to be elucidated. METHODS We analyzed differentially expressed genes (DEGs) in tumor tissue samples and normal samples from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database, and identified the expression levels of MT1E in the HCC. Then, the expression levels and methylation status of MT1E in HCC tissues and cells were validated by qRT-PCR and methylation-specific PCR (MSP). Also, MTT, colony formation, transwell assays, and flow cytometry, as well as xenograft model, were used to assess the biological roles of MT1E in HCC. RESULTS Downregulated expression of MT1E was found in HCC tissues, and was notably correlated with an aberrant methylation level of the gene promoter. Moreover, our study verified that MT1E suppressed cell growth in vitro and vivo. Further study demonstrated that MT1E could induce apoptosis and suppress the metastasis of HCC cells. CONCLUSIONS Our results suggested that epigenetic silencing of MT1E due to promoter hypermethylation could play a vital role in HCC.
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Affiliation(s)
- Qichen Liu
- Departmentof General Surgery, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215000, China; Departmentof General Surgery, Binhai Country People's Hospital, Binhai, Jiangsu, 224500, China
| | - Feng Lu
- Departmentof General Surgery, Binhai Country People's Hospital, Binhai, Jiangsu, 224500, China
| | - Zhong Chen
- Departmentof General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226000, China.
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20
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Liu C, Song C, Li J, Sun Q. CFTR Functions as a Tumor Suppressor and Is Regulated by DNA Methylation in Colorectal Cancer. Cancer Manag Res 2020; 12:4261-4270. [PMID: 32606923 PMCID: PMC7292251 DOI: 10.2147/cmar.s248539] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 05/13/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose Cystic fibrosis transmembrane conductance regulator (CFTR) was shown to be downregulated or silenced in carcinomas and acts as a candidate tumor suppressor gene. However, the function of CFTR gene in colorectal cancer (CRC) is still unclear. This aim of this study was to investigate the CFTR promoter methylation status and its impact on the expression and functional role of CFTR in CRC development. Patients and Methods CFTR expression in CRC tissues and CRC cell lines was detected via quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The promoter methylation status of CFTR was measured using methylation-specific PCR (MSP). colony formation, transwell, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to evaluate the effect of CFTR overexpression in CRC cell lines. Results qRT-PCR and IHC results indicated that CFTR expression was downregulated in the CRC tissues compared to the adjacent normal tissues. The promoter methylation status of CFTR was further analyzed in 70 CRC specimens. MSP validation showed methylation of CFTR promoter in 62.2% (45/70) of CRC tissues. The methylation of CFTR promoter was significantly associated with age (P=0.013) and lymph node metastasis (P=0.026) in CRC tissues. Results of transwell, MTT, and colony formation assays showed that CFTR overexpression inhibited the migration, invasion, and proliferation of CRC cells. Conclusion CFTR expression was downregulated in CRC and promoter methylation may be responsible for this downregulation. Overexpression of CFTR may suppress CRC tumor growth by inhibiting the proliferation, migration, and invasion of CRC cells. CFTR promoter methylation was significantly correlated with lymph node metastasis; thus, CFTR may be a potential marker for lymph node metastasis of CRC.
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Affiliation(s)
- Can Liu
- Department of Pathology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, People's Republic of China
| | - Chao Song
- Department of Pathology, Zibo Central Hospital, Zibo, Shandong Province, People's Republic of China
| | - Jiaxi Li
- Department of Pathology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong Province, People's Republic of China
| | - Qing Sun
- Department of Pathology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, People's Republic of China.,Department of Pathology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong Province, People's Republic of China
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21
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Ostuni A, Carmosino M, Miglionico R, Abruzzese V, Martinelli F, Russo D, Laurenzana I, Petillo A, Bisaccia F. Inhibition of ABCC6 Transporter Modifies Cytoskeleton and Reduces Motility of HepG2 Cells via Purinergic Pathway. Cells 2020; 9:cells9061410. [PMID: 32517079 PMCID: PMC7349786 DOI: 10.3390/cells9061410] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/29/2020] [Accepted: 06/01/2020] [Indexed: 12/22/2022] Open
Abstract
ABCC6, belonging to sub-family C of ATP-binding cassette transporter, is an ATP-dependent transporter mainly present in the basolateral plasma membrane of hepatic and kidney cells. Although the substrates transported are still uncertain, ABCC6 has been shown to promote ATP release. The extracellular ATP and its derivatives di- and mono-nucleotides and adenosine by acting on specific receptors activate the so-called purinergic pathway, which in turn controls relevant cellular functions such as cell immunity, inflammation, and cancer. Here, we analyzed the effect of Abcc6 knockdown and probenecid-induced ABCC6 inhibition on cell cycle, cytoskeleton, and motility of HepG2 cells. Gene and protein expression were evaluated by quantitative Reverse Transcription PCR (RT-qPCR) and western blot, respectively. Cellular cycle analysis was evaluated by flow cytometry. Actin cytoskeleton dynamics was evaluated by laser confocal microscopy using fluorophore-conjugated phalloidin. Cell motility was analyzed by in vitro wound-healing migration assay. Cell migration is reduced both in Abcc6 knockdown HepG2 cells and in probenecid treated HepG2 cells by interfering with the extracellular reserve of ATP. Therefore, ABCC6 could contribute to cytoskeleton rearrangements and cell motility through purinergic signaling. Altogether, our findings shed light on a new role of the ABCC6 transporter in HepG2 cells and suggest that its inhibitor/s could be considered potential anti-metastatic drugs.
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Affiliation(s)
- Angela Ostuni
- Department of Sciences, University of Basilicata, viale Ateneo Lucano 10, 85100 Potenza, Italy; (M.C.); (R.M.); (V.A.); (F.M.); (D.R.); (A.P.)
- Correspondence: (A.O.); (F.B.); Tel.: +39-0971-205453 (A.O.); Tel.: +39-0971-205462 (F.B.)
| | - Monica Carmosino
- Department of Sciences, University of Basilicata, viale Ateneo Lucano 10, 85100 Potenza, Italy; (M.C.); (R.M.); (V.A.); (F.M.); (D.R.); (A.P.)
| | - Rocchina Miglionico
- Department of Sciences, University of Basilicata, viale Ateneo Lucano 10, 85100 Potenza, Italy; (M.C.); (R.M.); (V.A.); (F.M.); (D.R.); (A.P.)
| | - Vittorio Abruzzese
- Department of Sciences, University of Basilicata, viale Ateneo Lucano 10, 85100 Potenza, Italy; (M.C.); (R.M.); (V.A.); (F.M.); (D.R.); (A.P.)
| | - Fabio Martinelli
- Department of Sciences, University of Basilicata, viale Ateneo Lucano 10, 85100 Potenza, Italy; (M.C.); (R.M.); (V.A.); (F.M.); (D.R.); (A.P.)
| | - Daniela Russo
- Department of Sciences, University of Basilicata, viale Ateneo Lucano 10, 85100 Potenza, Italy; (M.C.); (R.M.); (V.A.); (F.M.); (D.R.); (A.P.)
| | - Ilaria Laurenzana
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture, Italy;
| | - Agata Petillo
- Department of Sciences, University of Basilicata, viale Ateneo Lucano 10, 85100 Potenza, Italy; (M.C.); (R.M.); (V.A.); (F.M.); (D.R.); (A.P.)
| | - Faustino Bisaccia
- Department of Sciences, University of Basilicata, viale Ateneo Lucano 10, 85100 Potenza, Italy; (M.C.); (R.M.); (V.A.); (F.M.); (D.R.); (A.P.)
- Correspondence: (A.O.); (F.B.); Tel.: +39-0971-205453 (A.O.); Tel.: +39-0971-205462 (F.B.)
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22
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Liu X, Wen J, Li C, Wang H, Wang J, Zou H. High-Yield Methylation Markers for Stool-Based Detection of Colorectal Cancer. Dig Dis Sci 2020; 65:1710-1719. [PMID: 31720923 DOI: 10.1007/s10620-019-05908-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 10/15/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Many methylation markers associated with colorectal cancer have been reported, but few of them are actually used in clinical practice. AIMS This study was designed to identify promising methylation markers for stool-based detection of colorectal cancer. METHODS We first tested 324 reported methylated genes in colorectal cancer cell lines. A total of 111 heavily methylated genes were selected for further evaluation with a pilot set of colorectal cancer and adjacent normal tissues. Ten high-yield methylated markers were further studied in 319 tissue samples. Eventually, the four best markers, namely methylated COL4A1, COL4A2, TLX2, and ITGA4, were validated in 240 stool samples. Methylation-specific PCR (MSP) and real-time MSP (qMSP) were employed for methylation detection. RESULTS After hierarchical selection, ten differentially methylated genes demonstrated high sensitivity and specificity for the detection of colorectal cancer in tissue. When validated in stool samples, the four with the best performance-COL4A1, COL4A2, TLX2, and ITGA4-were able to detect 82.5-92.5% of colorectal cancers and 41.6-58.4% of adenomas (≥ 1 cm) with specificity of 88.0-96.4%. The best combination, COL4A2 and TLX2, detected 91.3% of CRCs and 51.9% of advanced adenomas in stool with 97.6% specificity. CONCLUSIONS Methylated COL4A1, COL4A2, TLX2, and ITGA4 demonstrated high accuracy for the detection of colorectal neoplasms in stool. They are potentially valuable markers for the detection of colorectal cancer.
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Affiliation(s)
- Xianglin Liu
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
| | - Jialing Wen
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
| | - Chujun Li
- Digestive Endoscopy Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hui Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jianping Wang
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China.,Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hongzhi Zou
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China. .,Creative Biosciences (Guangzhou) CO., Ltd., Guangzhou, Guangdong, China.
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What Role Does CFTR Play in Development, Differentiation, Regeneration and Cancer? Int J Mol Sci 2020; 21:ijms21093133. [PMID: 32365523 PMCID: PMC7246864 DOI: 10.3390/ijms21093133] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/21/2020] [Accepted: 04/27/2020] [Indexed: 02/08/2023] Open
Abstract
One of the key features associated with the substantial increase in life expectancy for individuals with CF is an elevated predisposition to cancer, firmly established by recent studies involving large cohorts. With the recent advances in cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and the increased long-term survival rate of individuals with cystic fibrosis (CF), this is a novel challenge emerging at the forefront of this disease. However, the mechanisms linking dysfunctional CFTR to carcinogenesis have yet to be unravelled. Clues to this challenging open question emerge from key findings in an increasing number of studies showing that CFTR plays a role in fundamental cellular processes such as foetal development, epithelial differentiation/polarization, and regeneration, as well as in epithelial–mesenchymal transition (EMT). Here, we provide state-of-the-art descriptions on the moonlight roles of CFTR in these processes, highlighting how they can contribute to novel therapeutic strategies. However, such roles are still largely unknown, so we need rapid progress in the elucidation of the underlying mechanisms to find the answers and thus tailor the most appropriate therapeutic approaches.
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24
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Scott P, Anderson K, Singhania M, Cormier R. Cystic Fibrosis, CFTR, and Colorectal Cancer. Int J Mol Sci 2020; 21:E2891. [PMID: 32326161 PMCID: PMC7215855 DOI: 10.3390/ijms21082891] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/17/2020] [Accepted: 04/19/2020] [Indexed: 02/06/2023] Open
Abstract
Cystic fibrosis (CF), caused by biallelic inactivating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, has recently been categorized as a familial colorectal cancer (CRC) syndrome. CF patients are highly susceptible to early, aggressive colorectal tumor development. Endoscopic screening studies have revealed that by the age of forty 50% of CF patients will develop adenomas, with 25% developing aggressive advanced adenomas, some of which will have already advanced to adenocarcinomas. This enhanced risk has led to new CF colorectal cancer screening recommendations, lowering the initiation of endoscopic screening to age forty in CF patients, and to age thirty in organ transplant recipients. The enhanced risk for CRC also extends to the millions of people (more than 10 million in the US) who are heterozygous carriers of CFTR gene mutations. Further, lowered expression of CFTR is reported in sporadic CRC, where downregulation of CFTR is associated with poor survival. Mechanisms underlying the actions of CFTR as a tumor suppressor are not clearly understood. Dysregulation of Wnt/β-catenin signaling and disruption of intestinal stem cell homeostasis and intestinal barrier integrity, as well as intestinal dysbiosis, immune cell infiltration, stress responses, and intestinal inflammation have all been reported in human CF patients and in animal models. Notably, the development of new drug modalities to treat non-gastrointestinal pathologies in CF patients, especially pulmonary disease, offers hope that these drugs could be repurposed for gastrointestinal cancers.
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Affiliation(s)
| | | | | | - Robert Cormier
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA; (P.S.); (K.A.); (M.S.)
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25
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Ahmed AA, Adam Essa ME. Epigenetic alterations in female urogenital organs cancer: Premise, properties, and perspectives. SCIENTIFIC AFRICAN 2020. [DOI: 10.1016/j.sciaf.2020.e00318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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A Multiplex Test Assessing MiR663ame and VIMme in Urine Accurately Discriminates Bladder Cancer from Inflammatory Conditions. J Clin Med 2020; 9:jcm9020605. [PMID: 32102337 PMCID: PMC7073678 DOI: 10.3390/jcm9020605] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 02/14/2020] [Accepted: 02/18/2020] [Indexed: 01/03/2023] Open
Abstract
Bladder cancer (BlCa) is a common malignancy with significant morbidity and mortality. Current diagnostic methods are invasive and costly, showing the need for newer biomarkers. Although several epigenetic-based biomarkers have been proposed, their ability to discriminate BlCa from common benign conditions of the urinary tract, especially inflammatory diseases, has not been adequately explored. Herein, we sought to determine whether VIMme and miR663ame might accurately discriminate those two conditions, using a multiplex test. Performance of VIMme and miR663ame in tissue samples and urines in testing set confirmed previous results (96.3% sensitivity, 88.2% specificity, area under de curve (AUC) 0.98 and 92.6% sensitivity, 75% specificity, AUC 0.83, respectively). In the validation sets, VIMme-miR663ame multiplex test in urine discriminated BlCa patients from healthy donors or patients with inflammatory conditions, with 87% sensitivity, 86% specificity and 80% sensitivity, 75% specificity, respectively. Furthermore, positive likelihood ratio (LR) of 2.41 and negative LR of 0.21 were also disclosed. Compared to urinary cytology, VIMme-miR663ame multiplex panel correctly detected 87% of the analysed cases, whereas cytology only forecasted 41%. Furthermore, high miR663ame independently predicted worse clinical outcome, especially in patients with invasive BlCa. We concluded that the implementation of this panel might better stratify patients for confirmatory, invasive examinations, ultimately improving the cost-effectiveness of BlCa diagnosis and management. Moreover, miR663ame analysis might provide relevant information for patient monitoring, identifying patients at higher risk for cancer progression.
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27
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Klinakis A, Karagiannis D, Rampias T. Targeting DNA repair in cancer: current state and novel approaches. Cell Mol Life Sci 2020; 77:677-703. [PMID: 31612241 PMCID: PMC11105035 DOI: 10.1007/s00018-019-03299-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 08/06/2019] [Accepted: 09/09/2019] [Indexed: 12/12/2022]
Abstract
DNA damage response, DNA repair and genomic instability have been under study for their role in tumor initiation and progression for many years now. More recently, next-generation sequencing on cancer tissue from various patient cohorts have revealed mutations and epigenetic silencing of various genes encoding proteins with roles in these processes. These findings, together with the unequivocal role of DNA repair in therapeutic response, have fueled efforts toward the clinical exploitation of research findings. The successful example of PARP1/2 inhibitors has also supported these efforts and led to numerous preclinical and clinical trials with a large number of small molecules targeting various components involved in DNA repair singularly or in combination with other therapies. In this review, we focus on recent considerations related to DNA damage response and new DNA repair inhibition agents. We then discuss how immunotherapy can collaborate with these new drugs and how epigenetic drugs can rewire the activity of repair pathways and sensitize cancer cells to DNA repair inhibition therapies.
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Affiliation(s)
- Apostolos Klinakis
- Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece.
| | - Dimitris Karagiannis
- Department of Genetics and Development, Columbia University Medical Center, New York, NY, 10032, USA
| | - Theodoros Rampias
- Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece.
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Kim J, Kim WT, Kim WJ. Advances in urinary biomarker discovery in urological research. Investig Clin Urol 2020; 61:S8-S22. [PMID: 32055750 PMCID: PMC7004831 DOI: 10.4111/icu.2020.61.s1.s8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 10/22/2019] [Indexed: 12/27/2022] Open
Abstract
A disease-specific biomarker (or biomarkers) is a characteristic reflecting a pathological condition in human body, which can be used as a diagnostic or prognostic tool for the clinical management. A urine-based biomarker(s) may provide a clinical value as attractive tools for clinicians to utilize in the clinical setting in particular to bladder diseases including bladder cancer and other bladder benign dysfunctions. Urine can be easily obtained by patients with no preparation or painful procedures required from patients' side. Currently advanced omics technologies and computational power identified potential omics-based novel biomarkers. An unbiased profiling based on transcriptomics, proteomics, epigenetics, metabolomics approaches et al. found that expression at RNA, protein, and metabolite levels are linked with specific bladder diseases and outcomes. In this review, we will discuss about the urine-based biomarkers reported by many investigators including us and how these biomarkers can be applied as a diagnostic and prognostic tool in clinical trials and patient care to promote bladder health. Furthermore, we will discuss how these promising biomarkers can be developed into a smart medical device and what we should be cautious about toward being used in real clinical setting.
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Affiliation(s)
- Jayoung Kim
- Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Medicine, University of California Los Angeles, CA, USA
| | - Won Tae Kim
- Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea
- Department of Urology, Chungbuk National University Hospital, Cheongju, Korea
| | - Wun-Jae Kim
- Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea
- Department of Urology, Chungbuk National University Hospital, Cheongju, Korea
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29
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Guo M, Peng Y, Gao A, Du C, Herman JG. Epigenetic heterogeneity in cancer. Biomark Res 2019; 7:23. [PMID: 31695915 PMCID: PMC6824025 DOI: 10.1186/s40364-019-0174-y] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 10/10/2019] [Indexed: 12/15/2022] Open
Abstract
Phenotypic and functional heterogeneity is one of the hallmarks of human cancers. Tumor genotype variations among tumors within different patients are known as interpatient heterogeneity, and variability among multiple tumors of the same type arising in the same patient is referred to as intra-patient heterogeneity. Subpopulations of cancer cells with distinct phenotypic and molecular features within a tumor are called intratumor heterogeneity (ITH). Since Nowell proposed the clonal evolution of tumor cell populations in 1976, tumor heterogeneity, especially ITH, was actively studied. Research has focused on the genetic basis of cancer, particularly mutational activation of oncogenes or inactivation of tumor-suppressor genes (TSGs). The phenomenon of ITH is commonly explained by Darwinian-like clonal evolution of a single tumor. Despite the monoclonal origin of most cancers, new clones arise during tumor progression due to the continuous acquisition of mutations. It is clear that disruption of the "epigenetic machinery" plays an important role in cancer development. Aberrant epigenetic changes occur more frequently than gene mutations in human cancers. The epigenome is at the intersection of the environment and genome. Epigenetic dysregulation occurs in the earliest stage of cancer. The current trend of epigenetic therapy is to use epigenetic drugs to reverse and/or delay future resistance to cancer therapies. A majority of cancer therapies fail to achieve durable responses, which is often attributed to ITH. Epigenetic therapy may reverse drug resistance in heterogeneous cancer. Complete understanding of genetic and epigenetic heterogeneity may assist in designing combinations of targeted therapies based on molecular information extracted from individual tumors.
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Affiliation(s)
- Mingzhou Guo
- 1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, 40 Daxue Road, Zhengzhou, Henan 450052 China
| | - Yaojun Peng
- 1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Aiai Gao
- 1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Chen Du
- 1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - James G Herman
- 3The Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Ave., Pittsburgh, PA 15213 USA
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High Detection Rate for Non-Muscle-Invasive Bladder Cancer Using an Approved DNA Methylation Signature Test. Clin Genitourin Cancer 2019; 18:210-221. [PMID: 32139301 DOI: 10.1016/j.clgc.2019.10.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/25/2019] [Accepted: 10/06/2019] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Cystoscopy and transurethral resection are the current reference standard tests to diagnose and histologically confirm non-muscle-invasive bladder cancer (NMIBC). In other tumor entities (ie, colon carcinoma, cervical cancer), DNA methylation markers have been approved as diagnostic tests with high diagnostic power. In our case-control study, we used an approved molecular cervical cancer diagnostics test that includes 6 DNA methylation markers (GynTect) for the detection of bladder cancer. PATIENTS AND METHODS We included samples from 40 patients with bladder cancer and 34 control subjects. In a pilot study, we analyzed DNA methylation in 38 tumor tissues and 4 healthy ureters using methylation-specific polymerase chain reaction. Subsequently, we determined the sensitivity and specificity of the GynTect for the detection of bladder cancer in urine sediments from 40 patients with bladder cancer and 30 control subjects with benign prostatic hyperplasia or urolithiasis. RESULTS The markers showed very different methylation rates in the NMIBC tissues, ranging from 2.6% to 78.9%. No methylation of any of the markers was detectable in the healthy ureters. Using the urine sediments from the patients with cancer and control subjects, we found surprisingly high sensitivity and specificity for the GynTect assay (60% and 96.7%, respectively). The application of different algorithms for evaluation of the markers included in GynTect resulted in a sensitivity of ≤ 90% and specificity of ≤ 100%. CONCLUSION The GynTect assay, originally designed for cervical cancer diagnostics, showed unexpectedly high diagnostic accuracy for bladder cancer detection. The inclusion of additional methylation markers might allow for the development of a suitable diagnostic marker set based on the GynTect test for NMIBC diagnostics.
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Anderson KJ, Cormier RT, Scott PM. Role of ion channels in gastrointestinal cancer. World J Gastroenterol 2019; 25:5732-5772. [PMID: 31636470 PMCID: PMC6801186 DOI: 10.3748/wjg.v25.i38.5732] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 07/26/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023] Open
Abstract
In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell. The functions of ion channels in the gastrointestinal (GI) tract influence a variety of cellular processes, many of which overlap with these hallmarks of cancer. In this review we focus on the roles of the calcium (Ca2+), sodium (Na+), potassium (K+), chloride (Cl-) and zinc (Zn2+) transporters in GI cancer, with a special emphasis on the roles of the KCNQ1 K+ channel and CFTR Cl- channel in colorectal cancer (CRC). Ca2+ is a ubiquitous second messenger, serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle, apoptosis, and migration. Various members of the TRP superfamily, including TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers, especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer. Voltage-gated sodium channels (VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells. The VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples. Studies have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer progression. Zn2+ transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers, in particular, ZIP4 up-regulation in pancreatic cancer (PC). More than 70 K+ channel genes, clustered in four families, are found expressed in the GI tract, where they regulate a range of cellular processes, including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract. Several distinct types of K+ channels are found dysregulated in the GI tract. Notable are hERG1 upregulation in PC, gastric cancer (GC) and CRC, leading to enhanced cancer angiogenesis and invasion, and KCNQ1 down-regulation in CRC, where KCNQ1 expression is associated with enhanced disease-free survival in stage II, III, and IV disease. Cl- channels are critical for a range of cellular and tissue processes in the GI tract, especially fluid balance in the colon. Most notable is CFTR, whose deficiency leads to mucus blockage, microbial dysbiosis and inflammation in the intestinal tract. CFTR is a tumor suppressor in several GI cancers. Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC. Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels (CLIC1, 3 & 4) and the chloride channel accessory proteins (CLCA1,2,4). CLIC1 & 4 are upregulated in PC, GC, gallbladder cancer, and CRC, while the CLCA proteins have been reported to be down-regulated in CRC. In summary, it is clear, from the diverse influences of ion channels, that their aberrant expression and/or activity can contribute to malignant transformation and tumor progression. Further, because ion channels are often localized to the plasma membrane and subject to multiple layers of regulation, they represent promising clinical targets for therapeutic intervention including the repurposing of current drugs.
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Affiliation(s)
- Kyle J Anderson
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
| | - Robert T Cormier
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
| | - Patricia M Scott
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
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Cao Z, Peng L, He K, Wang X, Lu Y, Zhang Y, Bi L. Value of quantitative and qualitative analyses of serum and urine cell-free DNA as diagnostic tools for bladder cancer: a meta-analysis. Expert Rev Anticancer Ther 2019; 19:645-653. [PMID: 31177855 DOI: 10.1080/14737140.2019.1626723] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Zhangjun Cao
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Longfei Peng
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Ke He
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xin Wang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Youlu Lu
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Ying Zhang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Liangkuan Bi
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Larsen LK, Lind GE, Guldberg P, Dahl C. DNA-Methylation-Based Detection of Urological Cancer in Urine: Overview of Biomarkers and Considerations on Biomarker Design, Source of DNA, and Detection Technologies. Int J Mol Sci 2019; 20:ijms20112657. [PMID: 31151158 PMCID: PMC6600406 DOI: 10.3390/ijms20112657] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 05/23/2019] [Accepted: 05/24/2019] [Indexed: 12/11/2022] Open
Abstract
Changes in DNA methylation have been causally linked with cancer and provide promising biomarkers for detection in biological fluids such as blood, urine, and saliva. The field has been fueled by genome-wide characterization of DNA methylation across cancer types as well as new technologies for sensitive detection of aberrantly methylated DNA molecules. For urological cancers, urine is in many situations the preferred "liquid biopsy" source because it contains exfoliated tumor cells and cell-free tumor DNA and can be obtained easily, noninvasively, and repeatedly. Here, we review recent advances made in the development of DNA-methylation-based biomarkers for detection of bladder, prostate, renal, and upper urinary tract cancers, with an emphasis on the performance characteristics of biomarkers in urine. For most biomarkers evaluated in independent studies, there was great variability in sensitivity and specificity. We discuss issues that impact the outcome of DNA-methylation-based detection of urological cancer and account for the great variability in performance, including genomic location of biomarkers, source of DNA, and technical issues related to the detection of rare aberrantly methylated DNA molecules. Finally, we discuss issues that remain to be addressed to fully exploit the potential of DNA-methylation-based biomarkers in the clinic, including the need for prospective trials and careful selection of control groups.
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Affiliation(s)
| | - Guro Elisabeth Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, the Norwegian Radium Hospital, NO-0424 Oslo, Norway.
| | - Per Guldberg
- Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
| | - Christina Dahl
- Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
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Aguilar-Medina M, Avendaño-Félix M, Lizárraga-Verdugo E, Bermúdez M, Romero-Quintana JG, Ramos-Payan R, Ruíz-García E, López-Camarillo C. SOX9 Stem-Cell Factor: Clinical and Functional Relevance in Cancer. JOURNAL OF ONCOLOGY 2019; 2019:6754040. [PMID: 31057614 PMCID: PMC6463569 DOI: 10.1155/2019/6754040] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 02/21/2019] [Indexed: 12/15/2022]
Abstract
Transcriptional and epigenetic embryonic programs can be reactivated in cancer cells. As result, a specific subset of undifferentiated cells with stem-cells properties emerges and drives tumorigenesis. Recent findings have shown that ectoderm- and endoderm-derived tissues continue expressing stem-cells related transcription factors of the SOX-family of proteins such as SOX2 and SOX9 which have been implicated in the presence of cancer stem-like cells (CSCs) in tumors. Currently, there is enough evidence suggesting an oncogenic role for SOX9 in different types of human cancers. This review provides a summary of the current knowledge about the involvement of SOX9 in development and progression of cancer. Understanding the functional roles of SOX9 and clinical relevance is crucial for developing novel treatments targeting CSCs in cancer.
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Affiliation(s)
- Maribel Aguilar-Medina
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Sinaloa, Mexico
| | - Mariana Avendaño-Félix
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Sinaloa, Mexico
| | - Erik Lizárraga-Verdugo
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Sinaloa, Mexico
| | - Mercedes Bermúdez
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Sinaloa, Mexico
| | | | - Rosalío Ramos-Payan
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Sinaloa, Mexico
| | - Erika Ruíz-García
- Laboratorio de Medicina Traslacional y Departamento de Tumores Gastro-Intestinales, Instituto Nacional de Cancerología. CDMX, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, CDMX, Mexico
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Misawa K, Kanazawa T, Mochizuki D, Imai A, Mima M, Yamada S, Morita K, Misawa Y, Shinmura K, Mineta H. Genes Located on 18q23 Are Epigenetic Markers and Have Prognostic Significance for Patients with Head and Neck Cancer. Cancers (Basel) 2019; 11:cancers11030401. [PMID: 30901947 PMCID: PMC6468360 DOI: 10.3390/cancers11030401] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 02/28/2019] [Accepted: 03/18/2019] [Indexed: 01/30/2023] Open
Abstract
Loss of heterozygosity (LOH) on chromosome 18q23 is associated with significantly decreased survival in head and neck cancer. In agreement with such tumor suppressive roles, the loss of function of genes located in this region can be achieved through LOH and promotor hypermethylation. In this study, the methylation status of promoters of 18q23 genes in 243 head and neck cancer patients was assessed by quantitative methylation-specific PCR. Promoter methylation was then compared to various clinical characteristics and patient survival. GALR1 and SALL3 promoter methylation correlated with reduced disease-free survival (log-rank test, p = 0.018 and p = 0.013, respectively). Furthermore, based on multivariate Cox proportional hazards analysis, these methylation events were associated with poor disease-free survival, with hazard ratios of 1.600 (95% confidence interval: CI, 1.027–2.493; p = 0.038) and 1.911 (95% CI, 1.155–3.162; p = 0.012), respectively. By comparison, GALR1 and SALL3 methylation were not prognostic for overall survival in The Cancer Genome Atlas (TCGA) cohort. Our findings suggest that the methylation status of 18q23 genes could serve as important biomarkers for the prediction of clinical outcomes in well-annotated head and neck squamous cell carcinoma cohorts. GALR1 and SALL3 methylation could thus help to facilitate risk stratification for individualized treatment.
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Affiliation(s)
- Kiyoshi Misawa
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
| | - Takeharu Kanazawa
- Department of Otolaryngology, Tokyo Voice Center, International University of Health and Welfare, Tokyo 107-0052, Japan.
| | - Daiki Mochizuki
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
| | - Atsushi Imai
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
| | - Masato Mima
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
| | - Satoshi Yamada
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
| | - Kotaro Morita
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
| | - Yuki Misawa
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
| | - Kazuya Shinmura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
| | - Hiroyuki Mineta
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
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Lam WKJ, Chan KCA, Lo YMD. Plasma Epstein-Barr virus DNA as an archetypal circulating tumour DNA marker. J Pathol 2019; 247:641-649. [PMID: 30714167 PMCID: PMC6594142 DOI: 10.1002/path.5249] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 01/09/2019] [Accepted: 01/11/2019] [Indexed: 12/12/2022]
Abstract
Analysis of circulating tumour DNA (ctDNA), as one type of ‘liquid biopsy’, has recently attracted great attention. Researchers are exploring many potential applications of liquid biopsy in many different types of cancer. In particular, it is of biological interest and clinical relevance to study the molecular characteristics of ctDNA. For such purposes, plasma Epstein–Barr virus (EBV) DNA from patients with nasopharyngeal carcinoma (NPC) would provide a good model to understand the biological properties and clinical applications of ctDNA in general. The strong association between EBV and NPC in endemic regions has made plasma EBV DNA a robust biomarker for this cancer. There are many clinical utilities of plasma EBV DNA analysis in NPC diagnostics. Its role in prognostication and surveillance of recurrence is well established. Plasma EBV DNA has also been validated for screening NPC in a recent large‐scale prospective study. Indeed, plasma EBV DNA could be regarded as an archetypal ctDNA marker. In this review, we discuss the biological properties of plasma EBV DNA from NPC samples and also the clinical applications of plasma EBV DNA analysis in the management of NPC. Of note, the recently reported size analysis of plasma EBV DNA in patients with NPC has highlighted size as an important analytical parameter of ctDNA and demonstrated clinical value in improving the diagnostic performance of an EBV DNA‐based NPC screening test. Such insights into ctDNA analysis (including size profiling) may help its full potential in cancer diagnostics for other types of cancer to be realised. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Wai Kei Jacky Lam
- Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR
| | - Kwan Chee Allen Chan
- Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR
| | - Yuk Ming Dennis Lo
- Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR
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Song T, Mao F, Shi L, Xu X, Wu Z, Zhou J, Xiao M. Urinary measurement of circulating tumor DNA for treatment monitoring and prognosis of metastatic colorectal cancer patients. ACTA ACUST UNITED AC 2018; 57:268-275. [PMID: 30016269 DOI: 10.1515/cclm-2017-0675] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 06/22/2018] [Indexed: 12/12/2022]
Abstract
Abstract
Background
Solid tumor tissue testing is the gold standard for molecular-based assays for metastatic colorectal cancer (mCRC). This poses challenges during treatment monitoring. Total DNA derived from urine specimens offers clear advantages to track the disease dynamics. Our study aims to evaluate the sensitivity for total DNA recovered from urine and its clinical relevance to mCRC.
Methods
KRAS mutations in urine specimens were examined in 150 mCRC patients. Baseline concordance was established to determined clinical relevance. The total DNA quantities were also prospectively examined in serial samplings during treatment.
Results
Analysis of the genetic mutations showed good agreement for baseline samples. Matched tumor and urine specimens’ molecular profiles were observed to have 90% concordance. Comparing with healthy volunteers, we established a cutoff of 8.15 ng that demonstrated elevated total DNA levels was associated with mCRC patients (sensitivity: 90.7%; specificity: 82.0%). For patients treated with chemotherapy or anti-epidermal growth factor receptor inhibitors, DNA quantity mirrored early treatment response. Survival analysis showed that patients with sustained elevated quantities of KRAS mutations had poorer outcome.
Conclusions
Total urine DNA offers a viable complement for mutation profiling in mCRC patients, given the good agreement with matched tumor samples. Our study also established that this is specific based on the results from healthy individuals. Serial monitoring of total DNA levels allowed early prediction to treatment response and was effective to identify high risk patients. This is potentially useful to complement current disease management.
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Affiliation(s)
- Tao Song
- Department of Clinical Laboratory, Xiangyang No. 1 People’s Hospital , Hubei University of Medicine , Xiangyang , P.R. China
| | - Fei Mao
- Department of Urology, Xiangyang No. 1 People’s Hospital , Hubei University of Medicine , Xiangyang , P.R. China
| | - Li Shi
- Department of Clinical Laboratory, Xiangyang No. 1 People’s Hospital , Hubei University of Medicine , Xiangyang , P.R. China
| | - Xuemei Xu
- Department of Clinical Laboratory, Xiangyang No. 1 People’s Hospital , Hubei University of Medicine , Xiangyang , P.R. China
| | - Zirong Wu
- Department of Clinical Laboratory, Xiangyang No. 1 People’s Hospital , Hubei University of Medicine , Xiangyang , P.R. China
| | - Juan Zhou
- Department of Clinical Laboratory, Xiangyang No. 1 People’s Hospital , Hubei University of Medicine , Xiangyang , P.R. China
| | - Meifang Xiao
- Center for Laboratory Medicine, Maternal and Child Health Hospital of Hainan Province , Longkun Road 75 , 570206 Haikou , P.R. China
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Xu XH, Bao Y, Wang X, Yan F, Guo S, Ma Y, Xu D, Jin L, Xu J, Wang J. Hypoxic-stabilized EPAS1 proteins transactivate DNMT1 and cause promoter hypermethylation and transcription inhibition of EPAS1 in non-small cell lung cancer. FASEB J 2018; 32:fj201700715. [PMID: 29920222 DOI: 10.1096/fj.201700715] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality globally. Although cigarette smoking is by far the most important risk factor for lung cancer, the aberrant expression of oncogenes and tumor suppressor genes contributes a great deal to tumorigenesis. Here, we reveal that aberrant expression of endothelial PAS domain-containing protein 1 ( EPAS1) gene, which encodes hypoxia inducible factor 2α, has a critical role in NSCLC. Our results showed EPAS1 mRNA was down-regulated in 82.5% of NSCLC tissues, and a new region of EPAS1 promoter was found to be highly methylated in lung cancer cell lines and NSCLC tissues. Moreover, the methylation rates were negatively correlated to EPAS1 mRNA expression in lung tissues. Further, demethylation analysis demonstrated EPAS1 was regulated by DNA methyltransferases (DNMTs) in NSCLC. In contrast, DNMT1 was verified as an EPAS1 target gene by chromatin immunoprecipitation assay and could be transactivated by stabilized EPAS1 proteins in hypoxic lung cells, thereby decreasing EPAS1 mRNA expression by methylation regulation. Collectively, our study suggests there might be a mechanism of negative-feedback regulation for EPAS1 in NSCLC. That is, hypoxic-stabilized EPAS1 proteins transactivated DNMT1, which further promoted the hypermethylation of EPAS1 promoter and decreased EPAS1 mRNA expression levels in NSCLC.-Xu, X.-H., Bao, Y., Wang, X., Yan, F., Guo, S., Ma, Y., Xu, D., Jin, L., Xu, J., Wang, J. Hypoxic-stabilized EPAS1 proteins transactivate DNMT1 and cause promoter hypermethylation and transcription inhibition of EPAS1 in non-small cell lung cancer.
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Affiliation(s)
- Xiang-Hong Xu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yang Bao
- Department of Cardiothoracic Surgery, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Xiaotian Wang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Fengyang Yan
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Shicheng Guo
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Yanyun Ma
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Dong Xu
- Department of Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China; and
| | - Li Jin
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Human Phenome Institute, Fudan University, Shanghai, China
| | - Jibin Xu
- Department of Cardiothoracic Surgery, Changzheng Hospital Affiliated to the Second Military Medical University, Shanghai, China
| | - Jiucun Wang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Human Phenome Institute, Fudan University, Shanghai, China
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van der Heijden AG, Mengual L, Ingelmo-Torres M, Lozano JJ, van Rijt-van de Westerlo CCM, Baixauli M, Geavlete B, Moldoveanud C, Ene C, Dinney CP, Czerniak B, Schalken JA, Kiemeney LALM, Ribal MJ, Witjes JA, Alcaraz A. Urine cell-based DNA methylation classifier for monitoring bladder cancer. Clin Epigenetics 2018; 10:71. [PMID: 29854012 PMCID: PMC5975622 DOI: 10.1186/s13148-018-0496-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 05/03/2018] [Indexed: 01/12/2023] Open
Abstract
Background Current standard methods used to detect and monitor bladder cancer (BC) are invasive or have low sensitivity. This study aimed to develop a urine methylation biomarker classifier for BC monitoring and validate this classifier in patients in follow-up for bladder cancer (PFBC). Methods Voided urine samples (N = 725) from BC patients, controls, and PFBC were prospectively collected in four centers. Finally, 626 urine samples were available for analysis. DNA was extracted from the urinary cells and bisulfite modificated, and methylation status was analyzed using pyrosequencing. Cytology was available from a subset of patients (N = 399). In the discovery phase, seven selected genes from the literature (CDH13, CFTR, NID2, SALL3, TMEFF2, TWIST1, and VIM2) were studied in 111 BC and 57 control samples. This training set was used to develop a gene classifier by logistic regression and was validated in 458 PFBC samples (173 with recurrence). Results A three-gene methylation classifier containing CFTR, SALL3, and TWIST1 was developed in the training set (AUC 0.874). The classifier achieved an AUC of 0.741 in the validation series. Cytology results were available for 308 samples from the validation set. Cytology achieved AUC 0.696 whereas the classifier in this subset of patients reached an AUC 0.768. Combining the methylation classifier with cytology results achieved an AUC 0.86 in the validation set, with a sensitivity of 96%, a specificity of 40%, and a positive and negative predictive value of 56 and 92%, respectively. Conclusions The combination of the three-gene methylation classifier and cytology results has high sensitivity and high negative predictive value in a real clinical scenario (PFBC). The proposed classifier is a useful test for predicting BC recurrence and decrease the number of cystoscopies in the follow-up of BC patients. If only patients with a positive combined classifier result would be cystoscopied, 36% of all cystoscopies can be prevented. Electronic supplementary material The online version of this article (10.1186/s13148-018-0496-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | - Lourdes Mengual
- 2Laboratory and Department of Urology, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain.,Hospital Clínic de Barcelona, Centre de Recerca Biomèdica CELLEX, office B22, C/Casanova, 143, 08036 Barcelona, Spain
| | - Mercedes Ingelmo-Torres
- 2Laboratory and Department of Urology, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Juan J Lozano
- 3CIBERehd, Plataforma de Bioinformática, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | | | - Montserrat Baixauli
- 2Laboratory and Department of Urology, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | | | | | - Cosmin Ene
- 4Saint John Emergency Clinical Hospital, Bucharest, Romania
| | | | | | - Jack A Schalken
- 1Department of Urology Radboud University Medical Center, Nijmegen, The Netherlands
| | | | - Maria J Ribal
- 2Laboratory and Department of Urology, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - J Alfred Witjes
- 1Department of Urology Radboud University Medical Center, Nijmegen, The Netherlands
| | - Antonio Alcaraz
- 2Laboratory and Department of Urology, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
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40
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Bosschieter J, Lutz C, Segerink LI, Vis AN, Zwarthoff EC, A van Moorselaar RJ, van Rhijn BWG, Heymans MW, Jansma EP, Steenbergen RDM, Nieuwenhuijzen JA. The diagnostic accuracy of methylation markers in urine for the detection of bladder cancer: a systematic review. Epigenomics 2018; 10:673-687. [DOI: 10.2217/epi-2017-0156] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Aim: Several urinary hypermethylation-markers (hmDNA) have been described for bladder cancer (BC) detection, but none have been able to replace cystoscopy yet. We systematically reviewed and evaluated current literature on urinary hmDNA markers for BC diagnostics. Patients & methods: A systematic search of PubMed, EMBASE.com and The Cochrane Library up to February 2017 using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, was conducted. Results: A total of 30/42 studies included compared gene panels, with varying sensitivities (52–100%) and specificities (0–100%). Considerable heterogeneity across studies was observed and most was case–control studies. Conclusion: Reported diagnostic accuracy of urinary hmDNA for BC detection is highly variable and there is a lack of validation studies. Recent studies indicate that complementary markers are needed to allow for clinical implementation.
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Affiliation(s)
- Judith Bosschieter
- Department of Urology, VU University Medical Center, Amsterdam, The Netherlands
| | - Catrin Lutz
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
| | - Loes I Segerink
- BIOS Lab on a Chip group, MESA+ & MIRA institutes, University of Twente, Enschede, The Netherlands
| | - André N Vis
- Department of Urology, VU University Medical Center, Amsterdam, The Netherlands
| | - Ellen C Zwarthoff
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Bas WG van Rhijn
- Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Martijn W Heymans
- Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands
| | - Elizabeth P Jansma
- Medical Library, VU University Medical Center, Amsterdam, The Netherlands
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41
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Zhang J, Wang Y, Jiang X, Chan HC. Cystic fibrosis transmembrane conductance regulator-emerging regulator of cancer. Cell Mol Life Sci 2018; 75:1737-1756. [PMID: 29411041 PMCID: PMC11105598 DOI: 10.1007/s00018-018-2755-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 12/27/2017] [Accepted: 01/17/2018] [Indexed: 12/11/2022]
Abstract
Mutations of cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis, the most common life-limiting recessive genetic disease among Caucasians. CFTR mutations have also been linked to increased risk of various cancers but remained controversial for a long time. Recent studies have begun to reveal that CFTR is not merely an ion channel but also an important regulator of cancer development and progression with multiple signaling pathways identified. In this review, we will first present clinical findings showing the correlation of genetic mutations or aberrant expression of CFTR with cancer incidence in multiple cancers. We will then focus on the roles of CFTR in fundamental cellular processes including transformation, survival, proliferation, migration, invasion and epithelial-mesenchymal transition in cancer cells, highlighting the signaling pathways involved. Finally, the association of CFTR expression levels with patient prognosis, and the potential of CFTR as a cancer prognosis indicator in human malignancies will be discussed.
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Affiliation(s)
- Jieting Zhang
- Faculty of Medicine, Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China
- School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China
| | - Yan Wang
- Faculty of Medicine, Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China
- School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China
| | - Xiaohua Jiang
- Faculty of Medicine, Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China.
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China.
- School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China.
| | - Hsiao Chang Chan
- Faculty of Medicine, Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China.
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China.
- School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China.
- Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Chengdu, People's Republic of China.
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Guo RQ, Xiong GY, Yang KW, Zhang L, He SM, Gong YQ, He Q, Li XY, Wang ZC, Bao ZQ, Li XS, Zhang K, Zhou LQ. Detection of urothelial carcinoma, upper tract urothelial carcinoma, bladder carcinoma, and urothelial carcinoma with gross hematuria using selected urine-DNA methylation biomarkers: A prospective, single-center study. Urol Oncol 2018; 36:342.e15-342.e23. [PMID: 29706459 DOI: 10.1016/j.urolonc.2018.04.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 03/20/2018] [Accepted: 04/03/2018] [Indexed: 10/17/2022]
Abstract
INTRODUCTION Hematuria is the most common symptom of urothelial carcinomas (UC) but is often idiopathic. Cystoscopy is expensive which involves considerable patient discomfort, and conventional urine cytology for noninvasive UC detection and disease monitoring suffers from poor sensitivity. We aim to evaluate the performance of genes selected from a previous study in detecting UC, especially among patients with gross hematuria, as well as upper tract urothelial carcinoma (UTUC) and bladder carcinoma separately, in voided urine samples. METHODS Using methylation-specific polymerase chain reaction, we examined the promoter methylation status of 10 genes in voided urine samples among 473 patients at our institution, including 217 UC patients and 256 control subjects. RESULTS The final combination of VIM, CDH1, SALL3, TMEFF2, RASSF1A, BRCA1, GDF15, and ABCC6 identified UC with a sensitivity of 0.83 and a specificity of 0.60. Additionally, a panel of selected genes (CDH1, HSPA2, RASSF1A, TMEFF2, VIM, and GDF15) identified UTUC with a sensitivity of 0.82 and a specificity of 0.68, while a panel of selected genes (VIM, RASSF1A, GDF15, and TMEFF2) identified bladder carcinoma with a sensitivity of 0.82 and a specificity of 0.53. Remarkably, a different panel (CDH1, SALL3, THBS1, TMEFF2, VIM, and GDF15) identified UC in patients with gross hematuria with 0.89 sensitivity and 0.74 specificity, and sensitivity (0.91) and specificity (0.92) could be achieved when cytology was included. CONCLUSIONS The selected urine-DNA methylation biomarkers are reliable, noninvasive, and cost-effective diagnostic tools for bladder carcinoma and UTUC, especially among patients with gross hematuria.
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Affiliation(s)
- Run-Qi Guo
- Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Research Center for Genitourinary Oncology, Beijing, China
| | - Geng-Yan Xiong
- Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Research Center for Genitourinary Oncology, Beijing, China
| | - Kai-Wei Yang
- Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Research Center for Genitourinary Oncology, Beijing, China
| | - Lei Zhang
- Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Research Center for Genitourinary Oncology, Beijing, China
| | - Shi-Ming He
- Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Research Center for Genitourinary Oncology, Beijing, China
| | - Yan-Qing Gong
- Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Research Center for Genitourinary Oncology, Beijing, China
| | - Qun He
- Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Research Center for Genitourinary Oncology, Beijing, China
| | - Xue-Ying Li
- Department of Medical Statistics, Peking University First Hospital, Beijing, China
| | - Zi-Cheng Wang
- Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Research Center for Genitourinary Oncology, Beijing, China
| | - Zhen-Qing Bao
- Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Research Center for Genitourinary Oncology, Beijing, China
| | - Xue-Song Li
- Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Research Center for Genitourinary Oncology, Beijing, China.
| | - Kai Zhang
- Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Research Center for Genitourinary Oncology, Beijing, China.
| | - Li-Qun Zhou
- Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Research Center for Genitourinary Oncology, Beijing, China.
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Guan B, Xing Y, Xiong G, Cao Z, Fang D, Li Y, Zhan Y, Peng D, Liu L, Li X, Zhou L. Predictive value of gene methylation for second recurrence following surgical treatment of first bladder recurrence of a primary upper-tract urothelial carcinoma. Oncol Lett 2018; 15:9397-9405. [PMID: 29805663 DOI: 10.3892/ol.2018.8498] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 09/12/2017] [Indexed: 12/18/2022] Open
Abstract
The clinical relevance of aberrant DNA promoter methylation is being increasingly recognized in urothelial carcinoma. The present study was conducted to explore the methylation status of patients with upper-tract urothelial carcinoma (UTUC) who experienced bladder recurrence, and to evaluate the predictive value of gene methylation for second bladder recurrence and tumor progression. A total of 85 patients with primary UTUC, who experienced bladder recurrence after radical nephroureterectomy, were enrolled between January 2001 and December 2013. Using methylation-sensitive polymerase chain reaction, the promoter methylation statuses of 10 genes were analyzed in the bladder tumor specimens. Among the patient group, 32 patients experienced second bladder recurrence, and bladder progression was detected in 16. With the exception of BRCA1, the methylation rate of the majority of genes tended to gradually increase to varying extents with the number of recurrences; a smaller proportion of primary tumors exhibited gene methylation when compared with the first recurrent tumors and second recurrent tumors. Univariate and multivariate Cox regression analyses revealed that unmethylated GDF15 [hazard ratio (HR)=0.36; 95% confidence interval (CI), 0.14-0.92] and methylated VIM (HR=2.91; 95% CI, 1.11-7.61) in the first recurrent bladder tumor, as well as male gender (HR=2.28; 95% CI, 1.06-4.87), first recurrence interval <8 months (HR=2.34; 95% CI, 1.15-4.78) and primary UTUC tumor size ≥5 cm (HR=3.48; 95% CI, 1.43-8.45) were independent risk factors for a second bladder recurrence after surgery for the first bladder recurrence; the Harrell's concordance index (c-index) for the related nomogram was 0.71 (95% CI: 0.61-0.81). Furthermore, methylated CDH1 (HR=2.91; 95% CI, 1.08-7.77) and VIM (HR=4.91; 95% CI, 1.11-21.7) in the first recurrent bladder tumor, male gender (HR=3.6; 95% CI, 1.1-11.73), and primary tumor stage T2-T4 (HR=4.57; 95% CI, 1.22-17.13), multifocality (HR=3.64; 95% CI, 1.19-11.16) and size ≥5 cm (HR=3.1; 95% CI, 1.91-10.54) for the primary UTUC were considered to be predictors of tumor progression; the c-index for the nomogram was 0.88 (95% CI, 0.69-0.92). The present findings demonstrated that promoter methylation of cancer-related genes was frequently observed in patients with urothelial carcinoma, and that the gene methylation rate of certain genes tended to gradually increase with the number of bladder recurrences. This may be used as a predictive factor for a second bladder recurrence and tumor progression after the surgical treatment of the first bladder recurrence.
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Affiliation(s)
- Bao Guan
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Yunchao Xing
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Gengyan Xiong
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Zhenpeng Cao
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Dong Fang
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Yifan Li
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Yonghao Zhan
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Ding Peng
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Libo Liu
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Xuesong Li
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Liqun Zhou
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
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Fang D, He S, Xiong G, Singla N, Cao Z, Zhang L, Li X, Zhou L. Comparison of clinicopathologic characteristics, epigenetic biomarkers and prognosis between renal pelvic and ureteral tumors in upper tract urothelial carcinoma. BMC Urol 2018; 18:22. [PMID: 29587736 PMCID: PMC5870733 DOI: 10.1186/s12894-018-0334-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 03/12/2018] [Indexed: 12/14/2022] Open
Abstract
Background There's no consensus about the difference between renal pelvic and ureteral tumors in terms of clinical features, pathological outcomes, epigenetic biomarkers and prognosis. Methods The data of 341 patients with renal pelvic tumors and 271 patients with ureteral tumors who underwent radical nephroureterectomy between 1999 and 2011 were retrospectively reviewed. The clinicopathologic features, gene promoters methylation status and oncologic outcomes were compared. Regression analysis was performed to identify oncologic prognosticators. Results Patients with ureteral tumors were relatively older (p = 0.002), and had higher likelihood of pre-operative renal insufficiency (p < 0.001), hypertension (p = 0.038) and hydronephrosis (P < 0.001), while in patients with renal pelvic tumors gross hematuria was more prevalent (p < 0.001). Renal pelvic tumors tended to exhibit non-organ-confined disease (p = 0.004) and larger tumor diameter (p = 0.001), while ureteral tumors had a higher likelihood of exhibiting high grade (p < 0.001) and sessile architecture (p = 0.023). Hypermethylated gene promoters were significantly more prevalent in renal pelvic tumors (p < 0.001), specifically for TMEFF2, GDF15, RASSF1A, SALL3 and ABCC6 (all p < 0.05). Tumor location failed to independently predict cancer-specific survival, overall survival, intravesical or contralateral recurrence (all p > 0.05), while gene methylation status was demonstrated to be an independent prognostic factor. Conclusion Renal pelvic tumors and ureteral tumors exhibited significant differences in clinicopathologic characteristics and epigenetic biomarkers. Gene promoter methylation might be an important mechanism in explaining distinct tumor patterns and behaviors in UTUC.
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Affiliation(s)
- Dong Fang
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Centre, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China
| | - Shiming He
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Centre, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China
| | - Gengyan Xiong
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Centre, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China
| | - Nirmish Singla
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Zhenpeng Cao
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Centre, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China
| | - Lei Zhang
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Centre, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China
| | - Xuesong Li
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Centre, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China.
| | - Liqun Zhou
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Centre, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China.
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Mostafavi-Pour Z, Ashrafi MR, Talaei-Khozani T. Down regulation of ITGA4 and ITGA5 genes after formation of 3D spherules by human Wharton's jelly stem cells (hWJSCs). Mol Biol Rep 2018; 45:245-252. [PMID: 29411210 DOI: 10.1007/s11033-018-4157-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 01/30/2018] [Indexed: 12/27/2022]
Abstract
Human Wharton's jelly mesenchymal stem cells (hWJSCs) are multipotent stem cells that could be aggregated into 3D spherules. ITGA4 and ITGA5 genes encode α4 and α5 subunits of integrins, respectively. In this study, we analyzed expression levels of ITGA4 and ITGA5 gene mRNAs in undifferentiated and 3D spherules forming hWJSCs in order to determine their expression pattern for possible future treatment of cancer cells in a co-culture fashion. For the purpose of obtaining hWJSCs, umbilical cords were collected from patients with caesarian section at full term delivery. The cells were then characterized according to cell surface markers using flow cytometry. Furthermore pluripotency of the obtained cells was verified. Subsequently the cells were aggregated in 3D spherules using hanging drop cultures. Expression levels of ITGA4 and ITGA5 gene mRNAs were determined by RT-PCR and Real time PCR, both in the initial undifferentiated cells and those aggregated in the spherules. The obtained hWJSCs demonstrated pluripotency, differentiating to adipogenic and osteogenic cells. They also expressed mesenchymal stem cell surface markers. Following the aggregation of these cells and formation of 3D spherules, mRNA expression levels of both genes were significantly reduced (P < 0.05) compared with the initial undifferentiated state. The results of this study demonstrated that aggregation of hWJSCs into spherules alters their expression of ITGA4 and ITGA5. The implications of such an alteration would require further research.
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Affiliation(s)
- Zohreh Mostafavi-Pour
- Recombinant Protein Laboratory, School of Advance Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran. .,Biochemistry Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mohammad Reza Ashrafi
- Biochemistry Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Biochemistry, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Tahereh Talaei-Khozani
- Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Tissue Engineering Lab, Anatomy Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Abstract
Precision medicine is designed to tailor treatments for individual patients by factoring in each person's specific biology and mechanism of disease. This paradigm shifted from a "one size fits all" approach to "personalized and precision care" requires multiple layers of molecular profiling of biomarkers for accurate diagnosis and prediction of treatment responses. Intensive studies are also being performed to understand the complex and dynamic molecular profiles of bladder cancer. These efforts involve looking bladder cancer mechanism at the multiple levels of the genome, epigenome, transcriptome, proteome, lipidome, metabolome etc. The aim of this short review is to outline the current technologies being used to investigate molecular profiles and discuss biomarker candidates that have been investigated as possible diagnostic and prognostic indicators of bladder cancer.
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Affiliation(s)
- Xuan-Mei Piao
- Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Young Joon Byun
- Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Wun-Jae Kim
- Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Jayoung Kim
- Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,Department of Medicine, University of California, Los Angeles, CA, USA
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Gao D, Herman JG, Guo M. The clinical value of aberrant epigenetic changes of DNA damage repair genes in human cancer. Oncotarget 2018; 7:37331-37346. [PMID: 26967246 PMCID: PMC5095080 DOI: 10.18632/oncotarget.7949] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Accepted: 02/20/2016] [Indexed: 12/22/2022] Open
Abstract
The stability and integrity of the human genome are maintained by the DNA damage repair (DDR) system. Unrepaired DNA damage is a major source of potentially mutagenic lesions that drive carcinogenesis. In addition to gene mutation, DNA methylation occurs more frequently in DDR genes in human cancer. Thus, DNA methylation may play more important roles in DNA damage repair genes to drive carcinogenesis. Aberrant methylation patterns in DNA damage repair genes may serve as predictive, diagnostic, prognostic and chemosensitive markers of human cancer. MGMT methylation is a marker for poor prognosis in human glioma, while, MGMT methylation is a sensitive marker of glioma cells to alkylating agents. Aberrant epigenetic changes in DNA damage repair genes may serve as therapeutic targets. Treatment of MLH1-methylated colon cancer cell lines with the demethylating agent 5′-aza-2′-deoxycytidine induces the expression of MLH1 and sensitizes cancer cells to 5-fluorouracil. Synthetic lethality is a more exciting approach in patients with DDR defects. PARP inhibitors are the most effective anticancer reagents in BRCA-deficient cancer cells.
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Affiliation(s)
- Dan Gao
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China.,Medical College of NanKai University, Tianjin, China
| | - James G Herman
- The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Mingzhou Guo
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
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49
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Shindo T, Shimizu T, Nojima M, Niinuma T, Maruyama R, Kitajima H, Kai M, Itoh N, Suzuki H, Masumori N. Evaluation of Urinary DNA Methylation as a Marker for Recurrent Bladder Cancer: A 2-Center Prospective Study. Urology 2017; 113:71-78. [PMID: 29196070 DOI: 10.1016/j.urology.2017.11.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Revised: 11/08/2017] [Accepted: 11/14/2017] [Indexed: 10/18/2022]
Abstract
OBJECTIVE To clarify the clinical utility of urinary DNA methylation for detection of intravesical recurrence of non-muscle invasive BCa (NMIBC), we performed a 2-center prospective study. PATIENTS AND METHODS A series of 207 self-voided urine samples were prospectively collected from 132 patients with NMIBC who had undergone transurethral resection of BCa. Methylation of miRNA genes (miR-9-3, miR-124-2, miR-124-3, and miR-137) was analyzed using bisulfite pyrosequencing. The primary end point was detection of intravesical recurrence; the secondary end point was prediction of late recurrence. The number of methylated genes (M-score) or quantitative level of methylation were compared with outcomes. RESULTS Twenty-six urine specimens were collected on the same day intravesical recurrence was detected, and 14 were collected from patients whose recurrences were found during the subsequent follow-up period (0-632 days, mean, 342.2 days). For detection of current recurrence, M-scores achieved 61.5% sensitivity and 74.0% specificity, and the area under the ROC curve was 0.71. Regarding prediction of late recurrence, patients with a high M-score (≥3) showed worse recurrence-free survival (P <.01). Multivariate analysis revealed that high M-scores were independently associated with current (P = .028) and late recurrence (P = .026). Elevated levels of urinary DNA methylation were also strongly associated with recurrence and radical cystectomy. CONCLUSION Our data suggest that urinary methylation of miRNA genes may be a useful marker for detecting and predicting BCa recurrence.
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Affiliation(s)
- Tetsuya Shindo
- Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takashi Shimizu
- Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masanori Nojima
- Center for Translational Research, The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, Japan
| | - Takeshi Niinuma
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Reo Maruyama
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Kitajima
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masahiro Kai
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Naoki Itoh
- Department of Urology, NTT East Corporation Sapporo Hospital, Sapporo, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
| | - Naoya Masumori
- Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Angulo JC, López JI, Ropero S. DNA Methylation and Urological Cancer, a Step Towards Personalized Medicine: Current and Future Prospects. Mol Diagn Ther 2017; 20:531-549. [PMID: 27501813 DOI: 10.1007/s40291-016-0231-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Urologic malignancies are some of the commonest tumors often curable when diagnosed at early stage. However, accurate diagnostic markers and faithful predictors of prognosis are needed to avoid over-diagnosis leading to overtreatment. Many promising exploratory studies have identified epigenetic markers in urinary malignancies based on DNA methylation, histone modification and non-coding ribonucleic acid (ncRNA) expression that epigenetically regulate gene expression. We review and discuss the current state of development and the future potential of epigenetic biomarkers for more accurate and less invasive detection of urological cancer, tumor recurrence and progression of disease serving to establish diagnosis and monitor treatment efficacies. The specific clinical implications of such methylation tests on therapeutic decisions and patient outcome and current limitations are also discussed.
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Affiliation(s)
- Javier C Angulo
- Servicio de Urología, Hospital Universitario de Getafe, Departamento Clínico, Facultad de Ciencias Biomédicas, Universidad Europea de Madrid, Laureate Universities, Hospital Universitario de Getafe, Carretera de Toledo Km 12.5, Getafe, 28905, Madrid, Spain.
| | - Jose I López
- Servicio de Anatomía Patológica, Hospital Universitario de Cruces, Instituto BioCruces,Universidad del País Vasco (UPV-EHU), Bilbao, Spain
| | - Santiago Ropero
- Departamento de Biología de Sistemas, Unidad Docente de Bioquímica y Biología Molecular, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
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