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de Melo IG, Tavares V, Pereira D, Medeiros R. Contribution of Endothelial Dysfunction to Cancer Susceptibility and Progression: A Comprehensive Narrative Review on the Genetic Risk Component. Curr Issues Mol Biol 2024; 46:4845-4873. [PMID: 38785560 PMCID: PMC11120512 DOI: 10.3390/cimb46050292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 05/09/2024] [Accepted: 05/13/2024] [Indexed: 05/25/2024] Open
Abstract
Venous thromboembolism (VTE) is a challenging clinical obstacle in oncological settings, marked by elevated incidence rates and resulting morbidity and mortality. In the context of cancer-associated thrombosis (CAT), endothelial dysfunction (ED) plays a crucial role in promoting a pro-thrombotic environment as endothelial cells lose their ability to regulate blood flow and coagulation. Moreover, emerging research suggests that this disorder may not only contribute to CAT but also impact tumorigenesis itself. Indeed, a dysfunctional endothelium may promote resistance to therapy and favour tumour progression and dissemination. While extensive research has elucidated the multifaceted mechanisms of ED pathogenesis, the genetic component remains a focal point of investigation. This comprehensive narrative review thus delves into the genetic landscape of ED and its potential ramifications on cancer progression. A thorough examination of genetic variants, specifically polymorphisms, within key genes involved in ED pathogenesis, namely eNOS, EDN1, ACE, AGT, F2, SELP, SELE, VWF, ICAM1, and VCAM1, was conducted. Overall, these polymorphisms seem to play a context-dependent role, exerting both oncogenic and tumour suppressor effects depending on the tumour and other environmental factors. In-depth studies are needed to uncover the mechanisms connecting these DNA variations to the pathogenesis of malignant diseases.
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Affiliation(s)
- Inês Guerra de Melo
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/Pathology and Laboratory Medicine Dep., Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto. CCC), 4200-072 Porto, Portugal; (I.G.d.M.); (V.T.)
- Faculty of Medicine of University of Porto (FMUP), 4200-072 Porto, Portugal
| | - Valéria Tavares
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/Pathology and Laboratory Medicine Dep., Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto. CCC), 4200-072 Porto, Portugal; (I.G.d.M.); (V.T.)
- Faculty of Medicine of University of Porto (FMUP), 4200-072 Porto, Portugal
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
| | - Deolinda Pereira
- Oncology Department, Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal;
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/Pathology and Laboratory Medicine Dep., Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto. CCC), 4200-072 Porto, Portugal; (I.G.d.M.); (V.T.)
- Faculty of Medicine of University of Porto (FMUP), 4200-072 Porto, Portugal
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
- Faculty of Health Sciences, Fernando Pessoa University, 4200-150 Porto, Portugal
- Research Department, Portuguese League Against Cancer (NRNorte), 4200-172 Porto, Portugal
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Abdel Ghafar MT, Helmy AA. Genetic variants in the renin-angiotensin-aldosterone system: Impact on cancer risk, prognosis, and therapeutic directions. VITAMINS AND HORMONES 2024; 124:165-220. [PMID: 38408799 DOI: 10.1016/bs.vh.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
Although renin-angiotensin-aldosterone system (RAAS) is known to maintain blood pressure and electrolyte balance, it has recently been linked to a number of biological processes such as angiogenesis, tumorigenesis, metastasis, and cellular proliferation, increasing the risk of cancer development and progression. Multiple genetic variants have been found to affect the genes encoding RAAS components, altering gene transcription and protein expression. This review provides an up-to-date insight into the role of RAAS in carcinogenesis, as well as the impact of RAAS genetic variants on the risk of cancer development, progression, and patient survival and outcomes, as well as response to treatment. This paves the way for the application of precision medicine in cancer risk assessment and management by implementing preventative programs in individuals at risk and guiding the therapeutic direction in cancer patients.
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Affiliation(s)
| | - Aya A Helmy
- Clinical Pathology Departments, Faculty of Medicine, Tanta University, Egypt
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Schouten LJ, van de Pol J, Kviatkovsky MJ, van den Brandt PA. Reproductive and external hormonal factors and the risk of renal cell cancer in the Netherlands Cohort Study. Cancer Epidemiol 2022; 79:102171. [DOI: 10.1016/j.canep.2022.102171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/21/2022] [Accepted: 04/26/2022] [Indexed: 11/02/2022]
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Bergantin LB. The Interactions among Hypertension, Cancer, and COVID-19: Perspective with Regard to Ca 2+/cAMP Signalling. Curr Cancer Drug Targets 2022; 22:351-360. [PMID: 35168520 DOI: 10.2174/1568009622666220215143805] [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: 09/09/2021] [Revised: 12/02/2021] [Accepted: 12/16/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The hypothesis that hypertension is clinically associated with an enhanced risk of developing cancer has been highlighted. However, the working principles involved in this link are still under intensive discussion. A correlation among inflammation, hypertension, and cancer could accurately describe the clinical link between these diseases. In addition, dyshomeostasis of Ca2+ has been considered to be involved in both cancer and hypertension, and inflammation. There is a strong link between Ca2+ signalling, e.g. enhanced Ca2+ signals, and inflammatory outcomes. cAMP also modulates pro- and anti-inflammatory outcomes; pharmaceuticals, which increase intracellular cAMP levels, can decrease the production of proinflammatory mediators and enhance the production of antiinflammatory outcomes. OBJECTIVE This article highlights the participation of Ca2+/cAMP signalling in the clinical association among inflammation, hypertension, and an enhanced risk for the development of cancer. In addition, considering that research on coronavirus disease 2019 (COVID-19) is a rapidly evolving field, this article also reviews recent reports related to the role of Ca2+ channel blockers in restoring Ca2+ signalling disruption due to COVID-19, including the relationship among COVID-19, cancer, and hypertension. CONCLUSION An understanding of the association among these diseases could expand current pharmacotherapy, involving Ca2+ channel blockers and pharmaceuticals that facilitate a rise in cAMP levels.
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Affiliation(s)
- Leandro Bueno Bergantin
- Department of Pharmacology, Universidade Federal de São Paulo, Escola Paulista de Medicina, Laboratory of Autonomic and Cardiovascular Pharmacology, 55 11 5576-4973, Rua Pedro de Toledo, 669, Vila Clementino, São Paulo, SP, Brazil
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Bergantin LB. Diabetes and inflammatory diseases: An overview from the perspective of Ca 2+/3'-5'-cyclic adenosine monophosphate signaling. World J Diabetes 2021; 12:767-779. [PMID: 34168726 PMCID: PMC8192245 DOI: 10.4239/wjd.v12.i6.767] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 12/29/2020] [Accepted: 03/07/2021] [Indexed: 02/06/2023] Open
Abstract
A large amount of evidence has supported a clinical link between diabetes and inflammatory diseases, e.g., cancer, dementia, and hypertension. In addition, it is also suggested that dysregulations related to Ca2+ signaling could link these diseases, in addition to 3'-5'-cyclic adenosine monophosphate (cAMP) signaling pathways. Thus, revealing this interplay between diabetes and inflammatory diseases may provide novel insights into the pathogenesis of these diseases. Publications involving signaling pathways related to Ca2+ and cAMP, inflammation, diabetes, dementia, cancer, and hypertension (alone or combined) were collected by searching PubMed and EMBASE. Both signaling pathways, Ca2+ and cAMP signaling, control the release of neurotransmitters and hormones, in addition to neurodegeneration, and tumor growth. Furthermore, there is a clear relationship between Ca2+ signaling, e.g., increased Ca2+ signals, and inflammatory responses. cAMP also regulates pro- and anti-inflammatory responses. Due to the experience of our group in this field, this article discusses the role of Ca2+ and cAMP signaling in the correlation between diabetes and inflammatory diseases, including its pharmacological implications. As a novelty, this article also includes: (1) A timeline of the major events in Ca2+/cAMP signaling; and (2) As coronavirus disease 2019 (COVID-19) is an emerging and rapidly evolving situation, this article also discusses recent reports on the role of Ca2+ channel blockers for preventing Ca2+ signaling disruption due to COVID-19, including the correlation between COVID-19 and diabetes.
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Walsh N, Zhang H, Hyland PL, Yang Q, Mocci E, Zhang M, Childs EJ, Collins I, Wang Z, Arslan AA, Beane-Freeman L, Bracci PM, Brennan P, Canzian F, Duell EJ, Gallinger S, Giles GG, Goggins M, Goodman GE, Goodman PJ, Hung RJ, Kooperberg C, Kurtz RC, Malats N, LeMarchand L, Neale RE, Olson SH, Scelo G, Shu XO, Van Den Eeden SK, Visvanathan K, White E, Zheng W, Albanes D, Andreotti G, Babic A, Bamlet WR, Berndt SI, Borgida A, Boutron-Ruault MC, Brais L, Brennan P, Bueno-de-Mesquita B, Buring J, Chaffee KG, Chanock S, Cleary S, Cotterchio M, Foretova L, Fuchs C, M Gaziano JM, Giovannucci E, Goggins M, Hackert T, Haiman C, Hartge P, Hasan M, Helzlsouer KJ, Herman J, Holcatova I, Holly EA, Hoover R, Hung RJ, Janout V, Klein EA, Kurtz RC, Laheru D, Lee IM, Lu L, Malats N, Mannisto S, Milne RL, Oberg AL, Orlow I, Patel AV, Peters U, Porta M, Real FX, Rothman N, Sesso HD, Severi G, Silverman D, Strobel O, Sund M, Thornquist MD, Tobias GS, Wactawski-Wende J, Wareham N, Weiderpass E, Wentzensen N, Wheeler W, Yu H, Zeleniuch-Jacquotte A, Kraft P, Li D, Jacobs EJ, Petersen GM, Wolpin BM, Risch HA, Amundadottir LT, et alWalsh N, Zhang H, Hyland PL, Yang Q, Mocci E, Zhang M, Childs EJ, Collins I, Wang Z, Arslan AA, Beane-Freeman L, Bracci PM, Brennan P, Canzian F, Duell EJ, Gallinger S, Giles GG, Goggins M, Goodman GE, Goodman PJ, Hung RJ, Kooperberg C, Kurtz RC, Malats N, LeMarchand L, Neale RE, Olson SH, Scelo G, Shu XO, Van Den Eeden SK, Visvanathan K, White E, Zheng W, Albanes D, Andreotti G, Babic A, Bamlet WR, Berndt SI, Borgida A, Boutron-Ruault MC, Brais L, Brennan P, Bueno-de-Mesquita B, Buring J, Chaffee KG, Chanock S, Cleary S, Cotterchio M, Foretova L, Fuchs C, M Gaziano JM, Giovannucci E, Goggins M, Hackert T, Haiman C, Hartge P, Hasan M, Helzlsouer KJ, Herman J, Holcatova I, Holly EA, Hoover R, Hung RJ, Janout V, Klein EA, Kurtz RC, Laheru D, Lee IM, Lu L, Malats N, Mannisto S, Milne RL, Oberg AL, Orlow I, Patel AV, Peters U, Porta M, Real FX, Rothman N, Sesso HD, Severi G, Silverman D, Strobel O, Sund M, Thornquist MD, Tobias GS, Wactawski-Wende J, Wareham N, Weiderpass E, Wentzensen N, Wheeler W, Yu H, Zeleniuch-Jacquotte A, Kraft P, Li D, Jacobs EJ, Petersen GM, Wolpin BM, Risch HA, Amundadottir LT, Yu K, Klein AP, Stolzenberg-Solomon RZ. Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer. J Natl Cancer Inst 2019; 111:557-567. [PMID: 30541042 PMCID: PMC6579744 DOI: 10.1093/jnci/djy155] [Show More Authors] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 06/15/2018] [Accepted: 08/08/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. METHODS We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. RESULTS We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. CONCLUSION Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.
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Affiliation(s)
- Naomi Walsh
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland
| | - Han Zhang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Paula L Hyland
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
- Division of Applied Regulatory Science, Office of Translational Science, Center for Drug Evaluation & Research, U.S. Food and Drug Administration, Silver Spring, MD
| | - Qi Yang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Evelina Mocci
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
| | - Mingfeng Zhang
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
- Division of Epidemiology II, Office of Surveillance and Epidemiology, Center for Drug Evaluation & Research, U.S. Food and Drug Administration, Silver Spring, MD
| | - Erica J Childs
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
| | - Irene Collins
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Zhaoming Wang
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
- Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, Tennessee
| | - Alan A Arslan
- Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY
- Department of Environmental Medicine, New York University School of Medicine, New York, NY
- Department of Population Health, New York University School of Medicine, New York, NY
| | - Laura Beane-Freeman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Paige M Bracci
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA
| | - Paul Brennan
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Eric J Duell
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain
| | - Steven Gallinger
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Graham G Giles
- Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Michael Goggins
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD
| | - Gary E Goodman
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Phyllis J Goodman
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Rayjean J Hung
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Robert C Kurtz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Núria Malats
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain
- CIBERONC, Madrid, Spain
| | - Loic LeMarchand
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI
| | - Rachel E Neale
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Sara H Olson
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ghislaine Scelo
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Xiao O Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
| | | | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Emily White
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Epidemiology, University of Washington, Seattle, WA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
| | | | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Gabriella Andreotti
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Ana Babic
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - William R Bamlet
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Ayelet Borgida
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Marie-Christine Boutron-Ruault
- Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, Villejuif, France
| | - Lauren Brais
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Paul Brennan
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Bas Bueno-de-Mesquita
- Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Julie Buring
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Kari G Chaffee
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN
| | - Stephen Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Sean Cleary
- Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN
| | - Michelle Cotterchio
- Cancer Care Ontario, University of Toronto, Toronto, ON, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Lenka Foretova
- Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | | | - J Michael M Gaziano
- Division of Aging, Brigham and Women's Hospital, Boston, MA
- Boston VA Healthcare System, Boston, MA
| | - Edward Giovannucci
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Michael Goggins
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD
| | - Thilo Hackert
- Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Christopher Haiman
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Patricia Hartge
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Manal Hasan
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kathy J Helzlsouer
- Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Joseph Herman
- Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
| | - Ivana Holcatova
- Institute of Public Health and Preventive Medicine, Charles University, 2nd Faculty of Medicine, Prague, Czech Republic
| | - Elizabeth A Holly
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA
| | - Robert Hoover
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Rayjean J Hung
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Vladimir Janout
- Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, Czech Republic
- Faculty of Medicine, University of Olomouc, Olomouc, Czech Republic
| | - Eric A Klein
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH
| | - Robert C Kurtz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Daniel Laheru
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
| | - I-Min Lee
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Lingeng Lu
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT
| | - Núria Malats
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain
- CIBERONC, Madrid, Spain
| | - Satu Mannisto
- Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland
| | - Roger L Milne
- Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
| | - Ann L Oberg
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN
| | - Irene Orlow
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alpa V Patel
- Epidemiology Research Program, American Cancer Society, Atlanta, GA
| | - Ulrike Peters
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Miquel Porta
- CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
- Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Francisco X Real
- CIBERONC, Madrid, Spain
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
- Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
| | - Nathaniel Rothman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Howard D Sesso
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Gianluca Severi
- Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
- Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, Villejuif, France
| | - Debra Silverman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Oliver Strobel
- Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Malin Sund
- Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
| | - Mark D Thornquist
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Geoffrey S Tobias
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Jean Wactawski-Wende
- Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY
| | - Nick Wareham
- MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Elisabete Weiderpass
- Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Genetic Epidemiology Group, Folkhälsan Research Center and Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
| | - Nicolas Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | | | - Herbert Yu
- Perlmutter Cancer Center, New York University School of Medicine, New York, NY
| | - Anne Zeleniuch-Jacquotte
- Department of Population Health, New York University School of Medicine, New York, NY
- Department of Biostatistics, Harvard School of Public Health, Boston, MA
| | - Peter Kraft
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Eric J Jacobs
- Epidemiology Research Program, American Cancer Society, Atlanta, GA
| | - Gloria M Petersen
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN
| | - Brian M Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Harvey A Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT
| | - Laufey T Amundadottir
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Kai Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Alison P Klein
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD
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Perdomo-Pantoja A, Mejía-Pérez SI, Reynoso-Noverón N, Gómez-Flores-Ramos L, Soto-Reyes E, Sánchez-Correa TE, Guerra-Calderas L, Castro-Hernandez C, Vidal-Millán S, Sánchez-Corona J, Taja-Chayeb L, Gutiérrez O, Cacho-Diaz B, Alvarez-Gomez RM, Gómez-Amador JL, Ostrosky-Wegman P, Corona T, Herrera-Montalvo LA, Wegman-Ostrosky T. Angiotensinogen rs5050 germline genetic variant as potential biomarker of poor prognosis in astrocytoma. PLoS One 2018; 13:e0206590. [PMID: 30383794 PMCID: PMC6211735 DOI: 10.1371/journal.pone.0206590] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 10/16/2018] [Indexed: 01/11/2023] Open
Abstract
Introduction Renin-angiotensin system (RAS) in brain cancer represents a scarcely explored field in neuro-oncology. Recently, some pre- and clinical studies have reported that RAS components play a relevant role in the development and behavior of gliomas. The angiotensinogen (AGT) rs5050 genetic variant has been identified as a crucial regulator of the transcription of AGT mRNA, which makes it a logical and promising target of research. The aim of this study was to determine the relationship between the AGT rs5050 genetic variant in blood with prognosis in astrocytoma. Methods A prospective pilot study was performed on forty-eight astrocytoma patients, who received the standard-of-care treatment. Blood samples were taken prior to surgery and DNA was sequenced using Ion Torrent next-generation sequencing and analyzed by Ion Reporter software. Descriptive, bivariate, multivariate, and survival analyses were performed using SPSS v21, STATA 12 and GraphPad Prism 7. Results Median follow-up was 41 months (range 1–48). Survival analysis showed a significant difference between the rs5050 genotypes (p = .05). We found lower survival rates in individuals with the GG-genotype of rs5050 AGT compared to patients with the TT- and TG-genotype (2 months vs. 11.5 months, respectively [p = .01]). In bivariate and multivariate analyses, GG-genotype was negatively associated with survival. Conclusions In patients with astrocytoma, AGT rs5050 GG-genotype was associated with poor prognosis. We propose this germline genetic variant as a complementary biomarker, which can be detected practically and safely in blood samples or saliva.
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Affiliation(s)
- Alexander Perdomo-Pantoja
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, United States of America
- Departamento de Neurocirugía, Instituto Nacional de Neurología y Neurocirugía, "Manuel Velasco Suarez", Mexico City, Mexico
| | - Sonia Iliana Mejía-Pérez
- Departamento de Neurocirugía, Instituto Nacional de Neurología y Neurocirugía, "Manuel Velasco Suarez", Mexico City, Mexico
| | | | | | - Ernesto Soto-Reyes
- Dirección de Investigación, Instituto Nacional de Cancerología, Mexico City, Mexico
| | | | | | - Clementina Castro-Hernandez
- Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM-INCAN, Mexico City, Mexico
| | - Silvia Vidal-Millán
- Dirección de Investigación, Instituto Nacional de Cancerología, Mexico City, Mexico
| | | | - Lucia Taja-Chayeb
- Dirección de Investigación, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Olga Gutiérrez
- Dirección de Investigación, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Bernardo Cacho-Diaz
- Unidad de Neuro-oncologia, Instituto Nacional de Cancerologia, Mexico City, Mexico
| | | | - Juan Luis Gómez-Amador
- Departamento de Neurocirugía, Instituto Nacional de Neurología y Neurocirugía, "Manuel Velasco Suarez", Mexico City, Mexico
| | - Patricia Ostrosky-Wegman
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Teresa Corona
- Laboratorio Clínico de Enfermedades Neurodegenerativas, Instituto Nacional de Neurologia y Neurocirugia, "Manuel Velasco Suarez", Mexico City, Mexico
| | - Luis Alonso Herrera-Montalvo
- Dirección de Investigación, Instituto Nacional de Cancerología, Mexico City, Mexico
- Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM-INCAN, Mexico City, Mexico
| | - Talia Wegman-Ostrosky
- Dirección de Investigación, Instituto Nacional de Cancerología, Mexico City, Mexico
- * E-mail:
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Renin angiotensin system and its role in biomarkers and treatment in gliomas. J Neurooncol 2018; 138:1-15. [PMID: 29450812 DOI: 10.1007/s11060-018-2789-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 02/01/2018] [Indexed: 12/14/2022]
Abstract
Gliomas are the most common primary intrinsic tumor in the brain and are classified as low- or high-grade according to the World Health Organization (WHO). Patients with high-grade gliomas (HGG) who undergo surgical resection with adjuvant therapy have a mean overall survival of 15 months and 100% recurrence. The renin-angiotensin system (RAS), the primary regulator of cardiovascular circulation, exhibits local action and works as a paracrine system. In the context of this local regulation, the expression of RAS peptides and receptors has been detected in different kinds of tumors, including gliomas. The dysregulation of RAS components plays a significant role in the proliferation, angiogenesis, and invasion of these tumors, and therefore in their outcomes. The study and potential application of RAS peptides and receptors as biomarkers in gliomas could bring advantages against the limitations of current tumoral markers and should be considered in the future. The targeting of RAS components by RAS blockers has shown potential of being protective against cancer and improving immunotherapy. In gliomas, RAS blockers have shown a broad spectrum for beneficial effects and are being considered for use in treatment protocols. This review aims to summarize the background behind how RAS plays a role in gliomagenesis and explore the evidence that could lead to their use as biomarkers and treatment adjuvants.
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9
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Sobczuk P, Szczylik C, Porta C, Czarnecka AM. Renin angiotensin system deregulation as renal cancer risk factor. Oncol Lett 2017; 14:5059-5068. [PMID: 29098020 PMCID: PMC5652144 DOI: 10.3892/ol.2017.6826] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 08/03/2017] [Indexed: 12/20/2022] Open
Abstract
For numerous years, the non-cardiovascular role of the renin-angiotensin system (RAS) was underestimated, but recent studies have advanced the understanding of its function in various processes, including carcinogenesis. Numerous evidence comes from preclinical and clinical studies on the use of antihypertensive agents targeting the RAS, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers. It has been demonstrated that the use of ACEIs can alter the incidence of renal cell carcinoma (RCC) and may have a positive effect by prolonging patient survival. It has an effect on the complex action of ACEI, resulting in decreased angiotensin II (Ang-II) production and altered levels of bradykinin or Ang 1-7. The present review discusses the existing knowledge on the effects of ACE and its inhibitors on RCC cell lines, xenograft models, and patient survival in clinical studies. A brief introduction to molecular pathways aids in understanding the non-cardiovascular effects of RAS inhibitors and enables the conduction of studies on combined cancer treatment with the application of ACEIs. Recent evidence regarding the treatment of hypertension associated with tyrosine kinase inhibitors, one of the most pronounced and common side effects in modern RCC treatment, are also outlined. Captopril, an ACEI, may be used to lower blood pressure in patients, particularly due to its additional renoprotective actions.
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Affiliation(s)
- Paweł Sobczuk
- Department of Oncology, Military Institute of Medicine, 04-141 Warsaw, Poland.,Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Cezary Szczylik
- Department of Oncology, Military Institute of Medicine, 04-141 Warsaw, Poland
| | - Camillo Porta
- Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation, I-27100 Pavia, Italy.,Italian Group of Onco-Nephrology/Gruppo Italiano di Onco-Nefrologia (G.I.O.N.), I-27100 Pavia, Italy
| | - Anna M Czarnecka
- Department of Oncology, Military Institute of Medicine, 04-141 Warsaw, Poland
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10
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Potential role of gene-environment interactions in ion transport mechanisms in the etiology of renal cell cancer. Sci Rep 2016; 6:34262. [PMID: 27686058 PMCID: PMC5043233 DOI: 10.1038/srep34262] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 09/07/2016] [Indexed: 01/20/2023] Open
Abstract
We investigated the ion transport mechanism (ITM) in renal cell cancer (RCC) etiology using gene-environment interactions between candidate single nucleotide polymorphisms (SNPs) and associated environmental factors, including dietary intakes of sodium, potassium and fluid, hypertension and diuretic medication. A literature-based selection of 13 SNPs in ten ITM genes were successfully genotyped in toenail DNA of 3,048 subcohort members and 419 RCC cases from the Netherlands Cohort Study. Diet and lifestyle were measured with baseline questionnaires. Cox regression analyses were conducted for main effects and gene-environment interactions. ADD1_rs4961 was significantly associated with RCC risk, showing a Hazard Ratio (HR) of 1.24 (95% confidence intervals (CI): 1.01–1.53) for the GT + TT (versus GG) genotype. Four of 65 tested gene-environment interactions were statistically significant. Three of these interactions clustered in SLC9A3_rs4957061, including the ones with fluid and potassium intake, and diuretic medication. For fluid intake, the RCC risk was significantly lower for high versus low intake in participants with the CC genotype (HR(95% CI): 0.47(0.26–0.86)), but not for the CT + TT genotype (P-interaction = 0.002). None of the main genetic effects and gene-environment interactions remained significant after adjustment for multiple testing. Data do not support the general hypothesis that the ITM is a disease mechanism in RCC etiology.
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11
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Wu Y, Zhang N, Li K, Chen H, Lin X, Yu Y, Gou Y, Hou J, Jiang D, Na R, Wang X, Ding Q, Xu J. Genetic scores based on risk-associated single nucleotide polymorphisms (SNPs) can reveal inherited risk of renal cell carcinoma. Oncotarget 2016; 7:18631-18637. [PMID: 27229762 PMCID: PMC4951315 DOI: 10.18632/oncotarget.7623] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 02/14/2016] [Indexed: 12/11/2022] Open
Abstract
The objective of this study was to evaluate whether renal cell carcinoma (RCC) risk-associated single nucleotide polymorphisms (SNPs) could reflect the individual inherited risks of RCC. A total of 346 RCC patients and 1,130 controls were recruited in this case-control study. Genetic scores were calculated for each individual based on the odds ratios and frequencies of risk-associated SNPs. Four SNPs were significantly associated with RCC in Chinese population. Two genetic score models were established, genetic score 1 (rs10054504, rs7023329 and rs718314) and genetic score 2 (rs10054504, rs7023329 and rs1049380). For genetic score 1, the individual likelihood of RCC with low (<0.8), medium (0.8-1.2) and high (≥1.2) genetic score 1 was 15.61%, 22.25% and 33.92% respectively (P-trend=6.88×10(-7)). For genetic score 2, individual with low (<0.8), medium (0.8-1.2) and high (≥1.2) genetic score 2 would have likelihood of RCC as 14.39%, 24.54% and 36.48%, respectively (P-trend=1.27×10(-10)). The area under the receiver operating curve (AUC) of genetic score 1 was 0.626, and AUC of genetic score 2 was 0.658. We concluded that genetic score can reveal personal risk and inherited risk of RCC, especially when family history is not available.
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Affiliation(s)
- Yishuo Wu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
| | - Ning Zhang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
| | - Kaiwen Li
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yet-sen University, Guangdong, PR China
| | - Haitao Chen
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, PR China
- Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, PR China
| | - Xiaolin Lin
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, PR China
- Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, PR China
| | - Yang Yu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
| | - Yuancheng Gou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
| | - Jiangang Hou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
| | - Deke Jiang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, PR China
| | - Rong Na
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
- Health Communication Institute, School of Public Health, Fudan University, Shanghai, PR China
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Chicago, IL, USA
| | - Xiang Wang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
| | - Qiang Ding
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
| | - Jianfeng Xu
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, PR China
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, PR China
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Chicago, IL, USA
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Lin J, Chen J, Liu C. AGT M235T variant is not associated with risk of cancer. J Renin Angiotensin Aldosterone Syst 2015; 16:448-452. [PMID: 23846033 DOI: 10.1177/1470320313496859] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE The angiotensinogen (AGT) gene has been considered to be implicated in the development of cancer. However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the association of AGT M235T variant with cancer risk. METHODS Published literature from PubMed and Embase were retrieved. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using a fixed- or random-effects model. RESULTS A total of seven articles including eight studies (3639 cancer cases and 6684 controls) for AGT M235T variant were included. The present meta-analysis showed that AGT M235T variant was marginally associated with cancer risk under dominant model (OR=1.12, 95% CI=1.02-1.24). However, the positive association was not stable after sensitivity analysis. Further subgroup analysis by cancer type did not suggest any association of AGT M235T variant with various cancers (all p>0.05). CONCLUSION The present meta-analysis demonstrated that AGT M235T variant was not associated with risk of all cancer or various cancers. Further well-designed studies with large sample size should be conducted to confirm or refute the non-significant association.
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Affiliation(s)
- Jianjun Lin
- The First People's Hospital of Xiangshan County, Ningbo, China
| | - Jiayu Chen
- Medical school, Taizhou University, Taizhou, China
| | - Chibo Liu
- Department of Clinical Laboratory, Taizhou Municipal Hospital, Taizhou, China
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Chu KF, Rotker K, Ellsworth P. The Impact of Obesity on Benign and Malignant Urologic Conditions. Postgrad Med 2015; 125:53-69. [DOI: 10.3810/pgm.2013.07.2679] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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14
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Brand S, Amann K, Mandel P, Zimnol A, Schupp N. Oxidative DNA damage in kidneys and heart of hypertensive mice is prevented by blocking angiotensin II and aldosterone receptors. PLoS One 2014; 9:e115715. [PMID: 25551569 PMCID: PMC4297153 DOI: 10.1371/journal.pone.0115715] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 11/28/2014] [Indexed: 12/24/2022] Open
Abstract
Introduction Recently, we could show that angiotensin II, the reactive peptide of the blood pressure-regulating renin-angiotensin-aldosterone-system, causes the formation of reactive oxygen species and DNA damage in kidneys and hearts of hypertensive mice. To further investigate on the one hand the mechanism of DNA damage caused by angiotensin II, and on the other hand possible intervention strategies against end-organ damage, the effects of substances interfering with the renin-angiotensin-aldosterone-system on angiotensin II-induced genomic damage were studied. Methods In C57BL/6-mice, hypertension was induced by infusion of 600 ng/kg • min angiotensin II. The animals were additionally treated with the angiotensin II type 1 receptor blocker candesartan, the mineralocorticoid receptor blocker eplerenone and the antioxidant tempol. DNA damage and the activation of transcription factors were studied by immunohistochemistry and protein expression analysis. Results Administration of angiotensin II led to a significant increase of blood pressure, decreased only by candesartan. In kidneys and hearts of angiotensin II-treated animals, significant oxidative stress could be detected (1.5-fold over control). The redox-sensitive transcription factors Nrf2 and NF-κB were activated in the kidney by angiotensin II-treatment (4- and 3-fold over control, respectively) and reduced by all interventions. In kidneys and hearts an increase of DNA damage (3- and 2-fold over control, respectively) and of DNA repair (3-fold over control) was found. These effects were ameliorated by all interventions in both organs. Consistently, candesartan and tempol were more effective than eplerenone. Conclusion Angiotensin II-induced DNA damage is caused by angiotensin II type 1 receptor-mediated formation of oxidative stress in vivo. The angiotensin II-mediated physiological increase of aldosterone adds to the DNA-damaging effects. Blocking angiotensin II and mineralocorticoid receptors therefore has beneficial effects on end-organ damage independent of blood pressure normalization.
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Affiliation(s)
- Susanne Brand
- Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany
| | - Kerstin Amann
- Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Philipp Mandel
- Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany
| | - Anna Zimnol
- Institute of Toxicology, University of Düsseldorf, Düsseldorf, Germany
| | - Nicole Schupp
- Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany
- Institute of Toxicology, University of Düsseldorf, Düsseldorf, Germany
- * E-mail:
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15
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Hu CS, Wu QH, Hu DY. Cardiovascular, diabetes, and cancer strips: evidences, mechanisms, and classifications. J Thorac Dis 2014; 6:1319-28. [PMID: 25276377 DOI: 10.3978/j.issn.2072-1439.2014.07.15] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 06/17/2014] [Indexed: 01/30/2023]
Abstract
OBJECTIVES To report and name firstly that there are cardiovascular disease (CVD), diabetes mellitus (DM) and cancers (CDC) strips; and disclose their mechanisms, classifications, and clinical significances. STUDY DESIGN Narrative and systematic review study and interpretive analysis. METHODS DATA SOURCES AND STUDY SELECTION to collect and present related evidences on CDC strips from evidence-based, open-access, both Chinese- and English-language literatures in recent 10 years on clinical trials from PubMed according to keywords "CVD, DM and cancers" as well as authors' extensive clinical experience with the treatment of more than fifty thousands of patients with CVD, diabetes and cancers over the past decades, and analyze their related mechanisms and categories which based on authors' previous works. DATA EXTRACTION data were mainly extracted from 48 articles which are listed in the reference section of this review. Qualitative, quantitative and mixed data were included, narratively and systematically reviewed. RESULTS With several conceptual and technical breakthrough, authors present related evidences on CDC strips, these are, CVD and DM, DM and cancers, cancers and CVD linked, respectively; And "Bad SEED" +/- "bad soil" theory or doctrine may explain this phenomenon due to "internal environmental injure, abnormal or unbalance" in human body resulting from the role of risk factors (RFs) related multi-pathways and multi-targets, which including organ & tissue (e.g., vascular-specific), cell and gene-based mechanisms. Their classifications include main strips/type B, and Branches/type A as showed by tables and figures in this article. CONCLUSIONS There are CDC strips and related mechanisms and classifications. CDC strips may help us to understand, prevent, and control related common non-communicable diseases (NCDs) as well as these high risk strips.
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Affiliation(s)
- Chun-Song Hu
- 1 Department of Cardiovascular Medicine, Nanchang University, Nanchang 330006, China ; 2 Cardiovascular Center, Peking University People's Hospital, Beijing 100044, China
| | - Qing-Hua Wu
- 1 Department of Cardiovascular Medicine, Nanchang University, Nanchang 330006, China ; 2 Cardiovascular Center, Peking University People's Hospital, Beijing 100044, China
| | - Da-Yi Hu
- 1 Department of Cardiovascular Medicine, Nanchang University, Nanchang 330006, China ; 2 Cardiovascular Center, Peking University People's Hospital, Beijing 100044, China
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16
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Deckers IA, van den Brandt PA, van Engeland M, van Schooten FJ, Godschalk RW, Keszei AP, Schouten LJ. Polymorphisms in genes of the renin-angiotensin-aldosterone system and renal cell cancer risk: interplay with hypertension and intakes of sodium, potassium and fluid. Int J Cancer 2014; 136:1104-16. [PMID: 24978482 DOI: 10.1002/ijc.29060] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 06/18/2014] [Indexed: 01/20/2023]
Abstract
Hypertension is an established risk factor for renal cell cancer (RCC). The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and is closely linked to hypertension. RAAS additionally influences homeostasis of electrolytes (e.g. sodium and potassium) and fluid. We investigated single nucleotide polymorphisms (SNPs) in RAAS and their interactions with hypertension and intakes of sodium, potassium and fluid regarding RCC risk in the Netherlands Cohort Study (NLCS), which was initiated in 1986 and included 120,852 participants aged 55 to 69 years. Diet and lifestyle were assessed by questionnaires and toenail clippings were collected. Genotyping of toenail DNA was performed using the SEQUENOM® MassARRAY® platform for a literature-based selection of 13 candidate SNPs in seven key RAAS genes. After 20.3 years of follow-up, Cox regression analyses were conducted using a case-cohort approach including 3,583 subcohort members and 503 RCC cases. Two SNPs in AGTR1 were associated with RCC risk. AGTR1_rs1492078 (AA vs. GG) decreased RCC risk [hazard ratio (HR) (95% confidence interval (CI)): 0.70(0.49-1.00)], whereas AGTR1_rs5186 (CC vs. AA) increased RCC risk [HR(95%CI): 1.49(1.08-2.05)]. Associations were stronger in participants with hypertension. The RCC risk for AGT_rs3889728 (AG + AA vs. GG) was modified by hypertension (p interaction = 0.039). SNP-diet interactions were not significant, although HRs suggested interaction between SNPs in ACE and sodium intake. SNPs in AGTR1 and AGT influenced RCC susceptibility, and their effects were modified by hypertension. Sodium intake was differentially associated with RCC risk across genotypes of several SNPs, yet some analyses had probably inadequate power to show significant interaction. Results suggest that RAAS may be a candidate pathway in RCC etiology.
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Affiliation(s)
- Ivette A Deckers
- Department of Epidemiology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, The Netherlands
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Eckel-Passow JE, Serie DJ, Bot BM, Joseph RW, Hart SN, Cheville JC, Parker AS. Somatic expression of ENRAGE is associated with obesity status among patients with clear cell renal cell carcinoma. Carcinogenesis 2013; 35:822-7. [PMID: 24374825 DOI: 10.1093/carcin/bgt485] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
An association between obesity and development of clear cell renal cell carcinoma (ccRCC) has been established in the literature; however, there are limited data regarding the molecular mechanisms that underlie this association. Therefore, we used a multistage design to identify and validate genes that are associated with obesity-related ccRCC. We conducted a microarray study and compared gene expression between obese and non-obese subjects in ccRCC tumors and patient-matched normal kidney tissues. Analyses were stratified by smoking status and subsequently performed on the combined cohort. The primary objective was to identify genes where the fold change of ccRCC tumor expression between obese and non-obese subjects was different than the fold change in the patient-matched normal kidney tissue. Thus, we utilized a mixed model and evaluated the tissue type-by-obesity status interaction term. Targeted validation was performed using reverse transcription-polymerase chain reaction (RT-PCR) on an independent cohort. ENRAGE was identified in the microarray study and subsequently validated using RT-PCR to have a statistically significant tissue type-by-obesity status interaction. Specifically, although ENRAGE is similarly expressed across obese and non-obese subjects in normal tissue, it is upregulated in the patient-matched ccRCC tumor tissue. Additionally, ENRAGE is upregulated in tumors that are wild-type for the von Hippel Lindau gene and in tumors for subjects with poorer overall survival. In summary, we provide evidence that overexpression of ENRAGE in ccRCC tumor tissue is an obesity-associated somatic alteration. Upregulation of ENRAGE could lead to local, autocrine stimulation of the RAGE receptor and thus support cancer progression.
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Audenet F, Cancel-Tassin G, Bigot P, Audouin M, Gaffory C, Ondet V, Thibault F, Auribault K, Gazut S, Benhabiles N, Azzouzi AR, Méjean A, Rouprêt M, Cussenot O. Germline genetic variations at 11q13 and 12p11 locus modulate age at onset for renal cell carcinoma. J Urol 2013; 191:487-92. [PMID: 23911636 DOI: 10.1016/j.juro.2013.07.064] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2013] [Indexed: 01/20/2023]
Abstract
PURPOSE Few risk factors have been identified for renal cell carcinoma. We performed a validation study in a population with a European background to identify the most significant variants previously identified in association with renal cell carcinoma risk. MATERIALS AND METHODS We performed a case-control validation study after recruiting 463 controls and 463 patients with a histologically confirmed diagnosis of clear cell renal cell carcinoma. For each patient and matched control we genotyped 8 single nucleotide polymorphisms selected from previous studies to evaluate the association between candidate single nucleotide polymorphisms and renal cell carcinoma susceptibility. RESULTS After adjusting for patient age, gender, smoking status and body mass index the AG + AA genotypes from rs7105934 (11q13) were associated with a decreased risk of renal cell carcinoma (OR 0.50, 95% CI 0.33-0.75, p = 0.001) and the AC + CC genotypes from rs1049380 (ITPR2) were associated with an increased risk (OR 1.66, 95% CI 1.28-2.16, p <0.001). Kidney cancer developed at an older age in patients carrying the dominant risk allele A for rs7105934 (mean age at diagnosis 73.1 vs 68.9 years, p = 0.002) and at a younger age in those carrying the dominant allele C for rs1049380 (mean 68.1 vs 70.8 years, p = 0.005). CONCLUSIONS In what is to our knowledge the first validation study of the main 8 single nucleotide polymorphism variants associated with renal cell carcinoma susceptibility we confirmed the association of 2 single nucleotide polymorphisms with the risk of renal cell carcinoma. Each variant influenced patient age at disease diagnosis.
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Affiliation(s)
- François Audenet
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France.
| | - Géraldine Cancel-Tassin
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
| | - Pierre Bigot
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
| | - Marie Audouin
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
| | - Cécile Gaffory
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
| | - Valérie Ondet
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
| | - Frédéric Thibault
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
| | - Karine Auribault
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
| | - Stéphane Gazut
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
| | - Nora Benhabiles
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
| | - Abdel-Rhamène Azzouzi
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
| | - Arnaud Méjean
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
| | - Morgan Rouprêt
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
| | - Olivier Cussenot
- Centre de Recherche pour les Pathologies Prostatiques (FA, GC-T, PB, MA, CG, VO, FT, ARA, MR, OC), Paris, France; Academic Department of Urology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (MR), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ONCOTYPE-Uro (FA, GC-T, MA, CG, VO, MR, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; ER 2 (FA, GC-T, MA, FT, KA, OC), Université Pierre et Marie Curie (Université Paris 06), Paris, France; Academic Department of Urology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes, University Paris V (FA, AM), Paris, France; Academic Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Groupement Hospitalier Universitaire Est (CG, VO, OC), Paris, France; Centre Hospitalier Universitaire d'Angers, Academic Department of Urology (PB, ARA), Angers, France; Sensors Signal and Information Processing Department, Information Models and Learning Laboratory, CEA LIST Institute, Saclay, France
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Su T, Han Y, Yu Y, Tan X, Li X, Hou J, DU Y, Shen J, Wang G, Ma L, Jiang S, Zhang H, Cao G. A GWAS-identified susceptibility locus on chromosome 11q13.3 and its putative molecular target for prediction of postoperative prognosis of human renal cell carcinoma. Oncol Lett 2013; 6:421-426. [PMID: 24137339 PMCID: PMC3789013 DOI: 10.3892/ol.2013.1422] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 06/19/2013] [Indexed: 12/27/2022] Open
Abstract
Genome-wide association studies have been used to identify single nucleotide polymorphisms (SNPs) associated with renal cell carcinoma (RCC) in European individuals. The current study aimed to evaluate the correlation between significant SNPs identified in European individuals and the occurrence and postoperative prognosis of RCC in Chinese individuals. A total of 400 cases and 806 controls were involved in the current study. rs4765623, rs7105934, rs7579899 and rs1867785 were genotyped using qPCR, and the expression of cyclin D1 in renal tissue and RCCs was determined via western blotting and immunohistochemistry. The correlation between the SNPs/cyclin D1 expression and overall survival was evaluated using multivariate Cox regression analyses. Of the four SNPs, only rs7105934 was found to significantly correlate with RCC risk in Chinese individuals. The rs7105934 GA + AA genotype was correlated with a reduced risk of RCC with an odds ratio of 0.64 (95% confidence interval [CI], 0.43–0.96), following adjustment for age. This genotype was found to independently predict an improved postoperative prognosis in the multivariate analysis, with a hazard ratio (HR) of 0.12 (95% CI, 0.02–0.93). Expression of cyclin D1, a putative regulated protein of rs7105934, did not vary in adjacent renal tissue and tumors when compared with that of various rs7105934 genotypes. However, cyclin D1 expression in RCCs inversely correlated with advanced tumor stage, and moderate to high expression of cyclin D1 in RCCs independently predicted improved postoperative prognosis, with an HR of 0.13 (95% CI, 0.02–0.96). Observations of the present study indicate that the rs7105934 A allele is associated with reduced risk and improved postoperative prognosis of RCC; however, this effect is unlikely to be caused by cyclin D1 expression.
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Affiliation(s)
- Tong Su
- Department of Epidemiology, Second Military Medical University
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Schutz FAB, Pomerantz MM, Gray KP, Atkins MB, Rosenberg JE, Hirsch MS, McDermott DF, Lampron ME, Lee GSM, Signoretti S, Kantoff PW, Freedman ML, Choueiri TK. Single nucleotide polymorphisms and risk of recurrence of renal-cell carcinoma: a cohort study. Lancet Oncol 2012; 14:81-7. [PMID: 23219378 DOI: 10.1016/s1470-2045(12)70517-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Germline genetic polymorphisms might affect the risk of recurrence in patients with localised renal-cell carcinoma. We investigated the association between genetic polymorphisms and recurrence of renal-cell carcinoma. METHODS We analysed germline DNA samples extracted from patients with localised renal-cell carcinoma treated at the Dana-Farber/Harvard Cancer Center (Boston, MA, USA). We selected a discovery cohort from a prospective database at the Dana-Farber/Harvard Cancer Center and selected a validation cohort from department records at the Brigham and Women's Hospital (Boston, MA, USA). We validated the findings from the discovery cohort in the validation cohort. We genotyped 70 genes involved in the pathogenesis of renal-cell carcinoma (including the VHL/HIF/VEGF and PI3K/AKT/mTOR pathways, and genes involved in immune regulation and metabolism) for single nucleotide polymorphisms. We assessed the association between genotype and recurrence-free survival, adjusted for baseline characteristics, with the Cox proportional hazards model, the Kaplan-Meier method, and the log-rank test. We used a false discovery rate q value to adjust for multiple comparisons. FINDINGS We included 554 patients (403 in the discovery cohort and 151 in the validation cohort). We successfully genotyped 290 single nucleotide polymorphisms in the discovery cohort, but excluded five because they did not have a variant group for comparison. The polymorphism rs11762213, which causes a synonymous aminoacid change in MET (144G→A, located in exon 2), was associated with recurrence-free survival. Patients with one or two copies of the minor (risk) allele had an increased risk of recurrence or death (hazard ratio [HR] 1·86, 95% CI 1·17-2·95; p=0·0084) in multivariate analysis. Median recurrence-free survival for carriers of the risk allele was 19 months (95% CI 9-not reached) versus 50 months (95% CI 37-75) for patients without the risk allele. In the validation cohort the HR was 2·45 (95% CI 1·01-5·95; p=0·048). INTERPRETATION Patients with localised renal-cell carcinoma and the MET polymorphism rs11762213 might have an increased risk of recurrence after nephrectomy. If these results are further validated in a similar population, they could be incorporated into future prognostic instruments, potentially aiding the design of adjuvant clinical trials of MET inhibitors and management of renal-cell carcinoma. FUNDING Conquer Cancer Foundation and American Society of Clinical Oncology (Career Development Award); The Trust Family Research Fund for Kidney Cancer; US National Institutes of Health, National Cancer Institute Kidney Cancer Specialized Program of Research Excellence.
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Stocks T, Van Hemelrijck M, Manjer J, Bjørge T, Ulmer H, Hallmans G, Lindkvist B, Selmer R, Nagel G, Tretli S, Concin H, Engeland A, Jonsson H, Stattin P. Blood pressure and risk of cancer incidence and mortality in the Metabolic Syndrome and Cancer Project. Hypertension 2012; 59:802-10. [PMID: 22353615 DOI: 10.1161/hypertensionaha.111.189258] [Citation(s) in RCA: 187] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Observational studies have shown inconsistent results for the association between blood pressure and cancer risk. We investigated the association in 7 cohorts from Norway, Austria, and Sweden. In total, 577799 adults with a mean age of 44 years were followed for, on average, 12 years. Incident cancers were 22184 in men and 14744 in women, and cancer deaths were 8724 and 4525, respectively. Cox regression was used to calculate hazard ratios of cancer per 10-mmHg increments of midblood pressure, which corresponded with 0.7 SDs and, for example, an increment of systolic/diastolic blood pressure of 130/80 to 142/88 mmHg. All of the models used age as the time scale and were adjusted for possible confounders, including body mass index and smoking status. In men, midblood pressure was positively related to total incident cancer (hazard ratio per 10 mmHg increment: 1.07 [95% CI: 1.04-1.09]) and to cancer of the oropharynx, colon, rectum, lung, bladder, kidney, malignant melanoma, and nonmelanoma skin cancer. In women, midblood pressure was not related to total incident cancer but was positively related to cancer of the liver, pancreas, cervix, uterine corpus, and malignant melanoma. A positive association was also found for cancer mortality, with HRs per 10-mmHg increment of 1.12 (95% CI: 1.08-1.15) for men and 1.06 (95% CI: 1.02-1.11) for women. These results suggest a small increased cancer risk overall in men with elevated blood pressure level and a higher risk for cancer death in men and women.
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Affiliation(s)
- Tanja Stocks
- Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.
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Abstract
PURPOSE OF REVIEW Incidence of obesity and renal cell carcinoma (RCC) are increasing, and RCC remains a lethal disease if not identified at an early stage. There is an increasing body of evidence linking obesity to the risk of developing RCC. RECENT FINDINGS There is a wealth of epidemiological evidence supporting a higher risk of developing RCC in obese individuals, and in a dose-response manner. This is particularly pertinent in the development of the clear cell subtype (ccRCC), in which there appears to be a special interplay between ccRCC, obesity and von Hippel-Lindau (VHL) gene defects, driving the proangiogenic/proliferative pathway as a result of metabolites produced by adipose tissue, the epigenetic silencing of a tumour suppressor in close proximity to the VHL gene, hypoxia, obesity-related hypertension, lipid peroxidation and increased insulin-like growth factor-1. SUMMARY Obesity-related diseases, including cancers, are increasing. There are many complex biomolecular pathways interacting in obesity, especially in ccRCC in which there appears to be a specific interplay in VHL mutations.
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Audenet F, Yates DR, Cancel-Tassin G, Cussenot O, Rouprêt M. Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine. BJU Int 2011; 109:1864-70. [PMID: 22035299 DOI: 10.1111/j.1464-410x.2011.10661.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
What's known on the subject? and What does the study add? Sporadic clear cell Renal Cell Carcinoma (ccRCC) is dominated by nutations of the VHL gene located on chromosome 3p in up to 90% of cases. This gene plays a critical role in hypoxia response, including stimulation of neoangiogenesis. Since 2006, anti-angiogenci therapies targeting this pathway are used in metastatic patients with objective response rate as high as 45%. However, these treatments don't target directly the tumour cell, allowing the potential for disease progession despite treatment. Large scale analysis recently showed that substantial genetic heterogeneity exists in ccRCC. Associated alterations include genes implicated in methylation regulation in 15% of cases, underlying the importance of epigenetic modifications, and truncating mutations in chromatin remodelling complex PRMB1 in 41% of cases. Systematic screening of these tumours is a way to fully determine the somatic genetic architecture of RCC in order to improve tumour classification, to develop prognostic and predictive markers and to target new molecular pathways involved in carcinogenesis. • A critical review is provided of the recent progress in oncogenetics applied to renal cell carcinoma (RCC) by highlighting our current understanding of the genetic pathways involved in carcinogenesis and its current and future clinical application. • RCC comprises a model of translational research because an improved understanding of molecular pathways has led to several targeted therapy options for patients with metastatic RCC. • Alteration of the product of the Von Hippel-Lindau gene/hypoxia inductible factor/vascular endothelial growth factor pathway is well characterized in carcinogenesis and is the target of the current therapies for metastatic RCC. • However, substantial genetic heterogeneity exists in this cancer and current treatments do not target directly the tumour cell. • Improving overall survival still remains a challenging objective but, currently, there is a lack of prognostic and predictive biomarkers for response to treatment. • Further information is awaited from the genomic approach to tumour classification, prognostic markers and predictive indicators of response to the treatment, as well as the personal susceptibility of developing RCC when exposed to risk factors. • Recent technological developments, such as large-scale analysis and high-speed sequencing, will allow the systematic screening of tumours to fully determine the somatic genetic architecture of RCC.
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Affiliation(s)
- François Audenet
- The Academic Department of Urology of La Pitié-Salpétrière and of Tenon, Groupe Hospitalo-Universitaire Est, Assistance-Publique Hôpitaux de Paris Faculté , Paris, France
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de Martino M, Klatte T, Schatzl G, Waldert M, Remzi M, Haitel A, Kramer G, Marberger M. Insertion/deletion polymorphism of angiotensin I-converting enzyme gene is linked with chromophobe renal cell carcinoma. Urology 2011; 77:1005.e9-1005.e13. [PMID: 21477733 DOI: 10.1016/j.urology.2010.11.033] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2010] [Revised: 11/25/2010] [Accepted: 11/25/2010] [Indexed: 11/16/2022]
Abstract
OBJECTIVES To study the putative significance of angiotensin I-converting enzyme (ACE) in renal cell carcinoma (RCC). Recent evidence has suggested that a 287-base pair insertion (I)/deletion (D) polymorphism (rs4646994) of the angiotensin I-converting enzyme (ACE) might be associated with cancer risk and progression. METHODS The present case-control study accrued 383 subjects, including 210 with RCC and 173 age- and sex-matched healthy individuals without evidence or a history of cancer. Genomic DNA was extracted from the peripheral blood leukocytes. The ACE fragment containing the polymorphism was amplified using conventional polymerase chain reaction using specific primer pairs and subsequently genotyped using agarose gel electrophoresis. RESULTS Overall, a DD genotype and D allele were more frequently noted in the patients with RCC than in the controls (P = .042 and P = .045, respectively), and resulted from a greater frequency of DD and D in chromophobe RCC (P = .023 and P = .020, respectively). In contrast, the genotype and allele distribution of the controls and patients with papillary or clear cell RCC was similar. The II genotype was not observed in any patient with chromophobe RCC. On multivariate logistic regression analysis, the ACE genotype was an independent risk factor for chromophobe RCC (P = .012). Neither the ACE genotypes or alleles were associated with the tumor stage or grade. CONCLUSIONS The results of the present study have shown for the first time that the ACE insertion/deletion gene polymorphism rs4646994 might be linked with the development of chromophobe RCC. Neither the ACE genotypes nor the alleles were associated with RCC progression.
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Common cardiovascular medications in cancer therapeutics. Pharmacol Ther 2011; 130:177-90. [DOI: 10.1016/j.pharmthera.2011.01.009] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2011] [Accepted: 01/13/2011] [Indexed: 12/16/2022]
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Abstract
After more than two decades of rising rates, in recent years the total kidney cancer incidence worldwide has shown signs of stabilizing, or even decreasing. In adults, kidney cancer consists of renal cell carcinoma (RCC), the predominant form, and renal transitional cell carcinoma (RTCC); these types primarily arise in the renal parenchyma and renal pelvis, respectively. Although temporal trends by kidney cancer type are not well established worldwide, incidence of RCC in the US has continued to rise, mainly for early-stage tumors, while that of RTCC has declined, and total kidney cancer mortality rates have leveled. Stabilization of kidney cancer mortality rates has also been reported in Europe. These trends are consistent with reports of increasing incidental diagnoses and a downward shift in tumor stage and size in clinical series. The changing prevalence of known risk factors for RCC, including cigarette smoking, obesity, and hypertension, is also likely to affect incidence trends, although their relative impact may differ between populations. Accumulating evidence suggests an etiologic role in RCC for physical activity, alcohol consumption, occupational exposure to trichloroethylene, and high parity among women, but further research is needed into the potential causal effects of these factors. Genetic factors and their interaction with environmental exposures are believed to influence risk of developing RCC, but a limited number of studies using candidate-gene approaches have not produced conclusive results. Large consortium efforts employing genome-wide scanning technology are underway, which hold promise for novel discoveries in renal carcinogenesis.
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Sinha R, Sinha I, Facompre N, Russell S, Somiari RI, Richie JP, El-Bayoumy K. Selenium-responsive proteins in the sera of selenium-enriched yeast-supplemented healthy African American and Caucasian men. Cancer Epidemiol Biomarkers Prev 2010; 19:2332-40. [PMID: 20643827 DOI: 10.1158/1055-9965.epi-10-0253] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Studies have shown that supplementation of adult men with selenium-enriched yeast (SY) was protective against prostate cancer (PCa) and also reduced oxidative stress and levels of prostate-specific antigen. Here, we determined the effect of SY supplementation on global serum protein expression in healthy men to provide new insights into the mechanism of selenium chemoprevention; such proteins may also serve as biomarkers of disease progression. METHODS Serum samples from 36 adult men were obtained from our previous SY clinical trial, 9 months after supplementation with either SY (247 microg/d; n = 17) or placebo (nonenriched yeast; n = 19). RESULTS Proteomic profiling using two-dimensional difference in gel electrophoresis followed by liquid chromatography-tandem mass spectrometry revealed a total of 1,496 candidate proteins, of which, 11 were differentially expressed in the SY group as compared with placebo. Eight proteins were upregulated [clusterin isoform 1 (CLU), transthyretin, alpha-1B-glycoprotein, transferrin, complement component 4B proprotein, isocitrate dehydrogenase, haptoglobin, and keratin 1] and three proteins were downregulated [alpha-1 antitrypsin (AAT), angiotensin precursor, and albumin precursor] by SY. All of the identified proteins were redox-sensitive or involved in the regulation of redox status. Because both AAT and CLU have been previously linked to PCa development, their identities were confirmed by two-dimensional Western blot analysis. CONCLUSIONS We identified AAT and CLU as potential candidate proteins involved in the mechanism of PCa prevention by SY. Collectively, proteins identified in this study might serve as potential new biomarkers for monitoring and comparing responses to selenium-based chemopreventive agents. IMPACT Proteomic analysis of serum might be useful for the early detection and monitoring efficacy of chemopreventive agents.
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Affiliation(s)
- Raghu Sinha
- Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, Pennsylvania, USA.
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