|
1
|
Sindhoo A, Sipy S, Khan A, Selvaraj G, Alshammari A, Casida ME, Wei DQ. ESOMIR: a curated database of biomarker genes and miRNAs associated with esophageal cancer. Database (Oxford) 2023; 2023:baad063. [PMID: 37815872 PMCID: PMC10563827 DOI: 10.1093/database/baad063] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/10/2023] [Accepted: 09/16/2023] [Indexed: 10/12/2023]
Abstract
'Esophageal cancer' (EC) is a highly aggressive and deadly complex disease. It comprises two types, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), with Barrett's esophagus (BE) being the only known precursor. Recent research has revealed that microRNAs (miRNAs) play a crucial role in the development, prognosis and treatment of EC and are involved in various human diseases. Biological databases have become essential for cancer research as they provide information on genes, proteins, pathways and their interactions. These databases collect, store and manage large amounts of molecular data, which can be used to identify patterns, predict outcomes and generate hypotheses. However, no comprehensive database exists for EC and miRNA relationships. To address this gap, we developed a dynamic database named 'ESOMIR (miRNA in esophageal cancer) (https://esomir.dqweilab-sjtu.com)', which includes information about targeted genes and miRNAs associated with EC. The database uses analysis and prediction methods, including experimentally endorsed miRNA(s) information. ESOMIR is a user-friendly interface that allows easy access to EC-associated data by searching for miRNAs, target genes, sequences, chromosomal positions and associated signaling pathways. The search modules are designed to provide specific data access to users based on their requirements. Additionally, the database provides information about network interactions, signaling pathways and region information of chromosomes associated with the 3'untranslated region (3'UTR) or 5'UTR and exon sites. Users can also access energy levels of specific miRNAs with targeted genes. A fuzzy term search is included in each module to enhance the ease of use for researchers. ESOMIR can be a valuable tool for researchers and clinicians to gain insight into EC, including identifying biomarkers and treatments for this aggressive tumor. Database URL https://esomir.dqweilab-sjtu.com.
Collapse
Affiliation(s)
- Asma Sindhoo
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Dongchuan Road Minhang District, Shanghai 200240, PR China
| | - Saima Sipy
- Sindh Madressatul Islam University, Karachi, Sindh 74600, Pakistan
| | - Abbas Khan
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Dongchuan Road Minhang District, Shanghai 200240, PR China
- State Key Laboratory of Microbial Metabolism, Shanghai–Islamabad–Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai, Minhang 200030, PR China
| | - Gurudeeban Selvaraj
- Centre for Research in Molecular Modelling (CERMM), Department of Chemistry and Biochemistry, Concordia University, Montreal, Quebec H4B 1R6, Canada
| | - Abdulrahman Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mark Earl Casida
- Laboratoire de Spectrom´etrie, Interactions et Chimie th´eorique (SITh), D´epartement de Chimie Mol´eculaire (DCM, UMR CNRS/UGA 5250), Institut de Chimie Mol´eculaire de Grenoble (ICMG, FR2607), Universit´e Grenoble Alpes (UGA), 301 rue de la Chimie BP 53, Grenoble Cedex F-38041, France
| | - Dong-Qing Wei
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Dongchuan Road Minhang District, Shanghai 200240, PR China
- State Key Laboratory of Microbial Metabolism, Shanghai–Islamabad–Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai, Minhang 200030, PR China
- Peng Cheng Laboratory, Phase I Building 8, Xili Street, Montreal, Vanke Cloud City, Nashan District, Shenzhen, Guangdong 518055, PR China
| |
Collapse
|
|
2
|
Grosjean I, Roméo B, Domdom MA, Belaid A, D’Andréa G, Guillot N, Gherardi RK, Gal J, Milano G, Marquette CH, Hung RJ, Landi MT, Han Y, Brest P, Von Bergen M, Klionsky DJ, Amos CI, Hofman P, Mograbi B. Autophagopathies: from autophagy gene polymorphisms to precision medicine for human diseases. Autophagy 2022; 18:2519-2536. [PMID: 35383530 PMCID: PMC9629091 DOI: 10.1080/15548627.2022.2039994] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/20/2022] [Accepted: 02/06/2022] [Indexed: 12/15/2022] Open
Abstract
At a time when complex diseases affect globally 280 million people and claim 14 million lives every year, there is an urgent need to rapidly increase our knowledge into their underlying etiologies. Though critical in identifying the people at risk, the causal environmental factors (microbiome and/or pollutants) and the affected pathophysiological mechanisms are not well understood. Herein, we consider the variations of autophagy-related (ATG) genes at the heart of mechanisms of increased susceptibility to environmental stress. A comprehensive autophagy genomic resource is presented with 263 single nucleotide polymorphisms (SNPs) for 69 autophagy-related genes associated with 117 autoimmune, inflammatory, infectious, cardiovascular, neurological, respiratory, and endocrine diseases. We thus propose the term 'autophagopathies' to group together a class of complex human diseases the etiology of which lies in a genetic defect of the autophagy machinery, whether directly related or not to an abnormal flux in autophagy, LC3-associated phagocytosis, or any associated trafficking. The future of precision medicine for common diseases will lie in our ability to exploit these ATG SNP x environment relationships to develop new polygenetic risk scores, new management guidelines, and optimal therapies for afflicted patients.Abbreviations: ATG, autophagy-related; ALS-FTD, amyotrophic lateral sclerosis-frontotemporal dementia; ccRCC, clear cell renal cell carcinoma; CD, Crohn disease; COPD, chronic obstructive pulmonary disease; eQTL, expression quantitative trait loci; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; GTEx, genotype-tissue expression; GWAS, genome-wide association studies; LAP, LC3-associated phagocytosis; LC3-II, phosphatidylethanolamine conjugated form of LC3; LD, linkage disequilibrium; LUAD, lung adenocarcinoma; MAF, minor allele frequency; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NSCLC, non-small cell lung cancer; OS, overall survival; PtdIns3K CIII, class III phosphatidylinositol 3 kinase; PtdIns3P, phosphatidylinositol-3-phosphate; SLE, systemic lupus erythematosus; SNPs, single-nucleotide polymorphisms; mQTL, methylation quantitative trait loci; ULK, unc-51 like autophagy activating kinase; UTRs, untranslated regions; WHO, World Health Organization.
Collapse
Affiliation(s)
- Iris Grosjean
- University Côte d’Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, Centre Antoine Lacassagne, France
| | - Barnabé Roméo
- University Côte d’Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, Centre Antoine Lacassagne, France
| | - Marie-Angela Domdom
- University Côte d’Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, Centre Antoine Lacassagne, France
| | - Amine Belaid
- Université Côte d’Azur (UCA), INSERM U1065, C3M, Team 5, F-06204, France
| | - Grégoire D’Andréa
- University Côte d’Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, Centre Antoine Lacassagne, France
- ENT and Head and Neck surgery department, Institut Universitaire de la Face et du Cou, CHU de Nice, University Hospital, Côte d’Azur University, Nice, France
| | - Nicolas Guillot
- University Côte d’Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, Centre Antoine Lacassagne, France
| | - Romain K Gherardi
- INSERM U955 Team Relais, Faculty of Health, Paris Est University, France
| | - Jocelyn Gal
- University Côte d’Azur, Centre Antoine Lacassagne, Epidemiology and Biostatistics Department, Nice, France
| | - Gérard Milano
- Université Côte d’Azur, Centre Antoine Lacassagne, UPR7497, Nice, France
| | - Charles Hugo Marquette
- University Côte d’Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, Centre Antoine Lacassagne, France
- University Côte d’Azur, FHU-OncoAge, Department of Pulmonary Medicine and Oncology, CHU de Nice, Nice, France
| | - Rayjean J. Hung
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Maria Teresa Landi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Younghun Han
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Patrick Brest
- University Côte d’Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, Centre Antoine Lacassagne, France
| | - Martin Von Bergen
- Helmholtz Centre for Environmental Research GmbH - UFZ, Dep. of Molecular Systems Biology; University of Leipzig, Faculty of Life Sciences, Institute of Biochemistry, Leipzig, Germany
| | - Daniel J. Klionsky
- University of Michigan, Life Sciences Institute, Ann Arbor, MI, 48109, USA
| | - Christopher I. Amos
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Paul Hofman
- University Côte d’Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, Centre Antoine Lacassagne, France
- University Côte d’Azur, FHU-OncoAge, CHU de Nice, Laboratory of Clinical and Experimental Pathology (LPCE) Biobank(BB-0033-00025), Nice, France
| | - Baharia Mograbi
- University Côte d’Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, Centre Antoine Lacassagne, France
| |
Collapse
|
|
3
|
Macchia E, Torricelli F, Bollella P, Sarcina L, Tricase A, Di Franco C, Österbacka R, Kovács-Vajna ZM, Scamarcio G, Torsi L. Large-Area Interfaces for Single-Molecule Label-free Bioelectronic Detection. Chem Rev 2022; 122:4636-4699. [PMID: 35077645 DOI: 10.1021/acs.chemrev.1c00290] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Bioelectronic transducing surfaces that are nanometric in size have been the main route to detect single molecules. Though enabling the study of rarer events, such methodologies are not suited to assay at concentrations below the nanomolar level. Bioelectronic field-effect-transistors with a wide (μm2-mm2) transducing interface are also assumed to be not suited, because the molecule to be detected is orders of magnitude smaller than the transducing surface. Indeed, it is like seeing changes on the surface of a one-kilometer-wide pond when a droplet of water falls on it. However, it is a fact that a number of large-area transistors have been shown to detect at a limit of detection lower than femtomolar; they are also fast and hence innately suitable for point-of-care applications. This review critically discusses key elements, such as sensing materials, FET-structures, and target molecules that can be selectively assayed. The amplification effects enabling extremely sensitive large-area bioelectronic sensing are also addressed.
Collapse
Affiliation(s)
- Eleonora Macchia
- Faculty of Science and Engineering, Åbo Akademi University, 20500 Turku, Finland
| | - Fabrizio Torricelli
- Dipartimento Ingegneria dell'Informazione, Università degli Studi di Brescia, 25123 Brescia, Italy
| | - Paolo Bollella
- Dipartimento di Chimica, Università degli Studi di Bari "Aldo Moro", 70125 Bari, Italy.,Centre for Colloid and Surface Science - Università degli Studi di Bari "Aldo Moro", 70125 Bari, Italy
| | - Lucia Sarcina
- Dipartimento di Chimica, Università degli Studi di Bari "Aldo Moro", 70125 Bari, Italy
| | - Angelo Tricase
- Dipartimento di Chimica, Università degli Studi di Bari "Aldo Moro", 70125 Bari, Italy
| | - Cinzia Di Franco
- CNR, Istituto di Fotonica e Nanotecnologie, Sede di Bari, 70125 Bari, Italy
| | - Ronald Österbacka
- Faculty of Science and Engineering, Åbo Akademi University, 20500 Turku, Finland
| | - Zsolt M Kovács-Vajna
- Dipartimento Ingegneria dell'Informazione, Università degli Studi di Brescia, 25123 Brescia, Italy
| | - Gaetano Scamarcio
- CNR, Istituto di Fotonica e Nanotecnologie, Sede di Bari, 70125 Bari, Italy.,Dipartimento Interateneo di Fisica "M. Merlin", Università degli Studi di Bari "Aldo Moro", 70125 Bari, Italy
| | - Luisa Torsi
- Faculty of Science and Engineering, Åbo Akademi University, 20500 Turku, Finland.,Dipartimento di Chimica, Università degli Studi di Bari "Aldo Moro", 70125 Bari, Italy.,Centre for Colloid and Surface Science - Università degli Studi di Bari "Aldo Moro", 70125 Bari, Italy
| |
Collapse
|
|
4
|
Zhang A, Zhang R, Yang Z, Tian R. TNK2 promoted esophageal cancer progression via activating egfr-akt signaling. J Clin Lab Anal 2021; 35:e23700. [PMID: 33484472 PMCID: PMC7958005 DOI: 10.1002/jcla.23700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/15/2020] [Accepted: 12/30/2020] [Indexed: 11/16/2022] Open
Abstract
Background This study investigated the clinical implication of TNK2 expression in esophageal cancer patients’ cancer tissue samples. Methods The expression of TNK2 in esophageal cancer tissues and para‐carcinoma tissue was assessed with immunohistochemistry and Western blot analysis; besides, the proteins of CDC42, EGFR, and Akt were also analyzed. Then, Kaplan‐Meier survival curves of TNK2 protein expression level were assayed with 184 esophageal cancer patients from TCGA database. Moreover, with multiple linear regression analysis, we detected the correlations of TNK2 expression associated with tumor differentiation degree and metastasis status. Results It revealed that TNK2 was highly expressed in the cytoplasm of esophageal cancer tissues compared with para‐carcinoma tissue; besides, the proteins of CDC42, EGFR, and Akt were also up‐regulated in different levels of esophageal cancer tissues. However, there was no significant difference of the overall survival time of TNK2 protein expression in 184 esophageal cancer patients from TCGA database (p = 0.37). But, in the included study samples of our study, there was positive coefficience between TNK2 protein expression and differentiation degree in esophageal cancer with multiple linear regression analysis [R = 0.928, 95% confidence interval (0.085‐0.12)]. Conclusion Our results indicated that TNK2 was a potential diagnostic marker and promoted esophageal cancer progression through activating EGFR‐AKT signaling.
Collapse
Affiliation(s)
- Anqing Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of USTC, Division of life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P.R. China
| | - Rongxin Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of USTC, Division of life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P.R. China
| | - Zhiming Yang
- Department of Thoracic Surgery, The First Affiliated Hospital of USTC, Division of life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P.R. China
| | - Rui Tian
- Department of Thoracic Surgery, The First Affiliated Hospital of USTC, Division of life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P.R. China
| |
Collapse
|
|
5
|
Tamargo-Gómez I, Fernández ÁF, Mariño G. Pathogenic Single Nucleotide Polymorphisms on Autophagy-Related Genes. Int J Mol Sci 2020; 21:ijms21218196. [PMID: 33147747 PMCID: PMC7672651 DOI: 10.3390/ijms21218196] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/28/2020] [Accepted: 10/30/2020] [Indexed: 02/06/2023] Open
Abstract
In recent years, the study of single nucleotide polymorphisms (SNPs) has gained increasing importance in biomedical research, as they can either be at the molecular origin of a determined disorder or directly affect the efficiency of a given treatment. In this regard, sequence variations in genes involved in pro-survival cellular pathways are commonly associated with pathologies, as the alteration of these routes compromises cellular homeostasis. This is the case of autophagy, an evolutionarily conserved pathway that counteracts extracellular and intracellular stressors by mediating the turnover of cytosolic components through lysosomal degradation. Accordingly, autophagy dysregulation has been extensively described in a wide range of human pathologies, including cancer, neurodegeneration, or inflammatory alterations. Thus, it is not surprising that pathogenic gene variants in genes encoding crucial effectors of the autophagosome/lysosome axis are increasingly being identified. In this review, we present a comprehensive list of clinically relevant SNPs in autophagy-related genes, highlighting the scope and relevance of autophagy alterations in human disease.
Collapse
Affiliation(s)
- Isaac Tamargo-Gómez
- Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain;
- Departamento de Biología Funcional, Universidad de Oviedo, 33011 Oviedo, Spain
| | - Álvaro F. Fernández
- Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain;
- Departamento de Biología Funcional, Universidad de Oviedo, 33011 Oviedo, Spain
- Correspondence: (Á.F.F.); (G.M.); Tel.: +34-985652416 (G.M.)
| | - Guillermo Mariño
- Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain;
- Departamento de Biología Funcional, Universidad de Oviedo, 33011 Oviedo, Spain
- Correspondence: (Á.F.F.); (G.M.); Tel.: +34-985652416 (G.M.)
| |
Collapse
|
|
6
|
Macchia E, Manoli K, Di Franco C, Picca RA, Österbacka R, Palazzo G, Torricelli F, Scamarcio G, Torsi L. Organic Field-Effect Transistor Platform for Label-Free, Single-Molecule Detection of Genomic Biomarkers. ACS Sens 2020; 5:1822-1830. [PMID: 32495625 DOI: 10.1021/acssensors.0c00694] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The increasing interest in technologies capable of tracking a biomarker down to the physical limit points toward new opportunities in early diagnostics of progressive diseases. Indeed, single-molecule detection technologies are foreseen to enable clinicians to associate the tiniest increase in a biomarker with the progression of a disease, particularly at its early stage. Bioelectronic organic transistors represent an extremely powerful tool to achieve label-free and single-molecule detection of clinically relevant biomarkers. These electronic devices are millimetric in size and in the future could be mass-produced at low cost. The core of the single molecule with a large transistor (SiMoT) platform, based on an electrolyte-gated field-effect transistor, is a gold gate electrode biofunctionalized with a self-assembled monolayer, a densely packed layer of recognition elements. So far, only the SiMoT detection of proteins, using the corresponding antibodies as recognition elements, has been reported. In this study, the SiMoT sensing response toward genomic biomarkers is proposed. Herein, the gate is functionalized with a genomic biomarker for multiple sclerosis (miR-182). This is relevant, not only because a limit of detection of a single molecule is achieved but also because it proves that the SiMoT label-free, single-molecule detection principle is the only one of its kind that can detect, by means of the same platform, both protein and genomic markers.
Collapse
Affiliation(s)
- Eleonora Macchia
- The Faculty of Science and Engineering, Åbo Akademi University, 20500 Turku, Finland
| | - Kyriaki Manoli
- Dipartimento di Chimica, Università degli Studi di Bari “Aldo Moro”, 70125 Bari, Italy
| | - Cinzia Di Franco
- Dipartimento di Chimica, Università degli Studi di Bari “Aldo Moro”, 70125 Bari, Italy
- CNR, Istituto di Fotonica e Nanotecnologie, Sede di Bari, 70125 Bari, Italy
| | - Rosaria Anna Picca
- Dipartimento di Chimica, Università degli Studi di Bari “Aldo Moro”, 70125 Bari, Italy
| | - Ronald Österbacka
- The Faculty of Science and Engineering, Åbo Akademi University, 20500 Turku, Finland
| | - Gerardo Palazzo
- Dipartimento di Chimica, Università degli Studi di Bari “Aldo Moro”, 70125 Bari, Italy
- CSGI (Centre for Colloid and Surface Science), 70125 Bari, Italy
| | - Fabrizio Torricelli
- Dipartimento Ingegneria dell’Informazione, Università degli Studi di Brescia, 25121 Brescia, Italy
| | - Gaetano Scamarcio
- Dipartimento Interateneo di Fisica “M. Merlin”, Università degli Studi di Bari “Aldo Moro”, 70125 Bari, Italy
- CNR, Istituto di Fotonica e Nanotecnologie, Sede di Bari, 70125 Bari, Italy
| | - Luisa Torsi
- The Faculty of Science and Engineering, Åbo Akademi University, 20500 Turku, Finland
- Dipartimento di Chimica, Università degli Studi di Bari “Aldo Moro”, 70125 Bari, Italy
- CSGI (Centre for Colloid and Surface Science), 70125 Bari, Italy
| |
Collapse
|
|
7
|
Vsevolozhskaya OA, Shi M, Hu F, Zaykin DV. DOT: Gene-set analysis by combining decorrelated association statistics. PLoS Comput Biol 2020; 16:e1007819. [PMID: 32287273 PMCID: PMC7182280 DOI: 10.1371/journal.pcbi.1007819] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 04/24/2020] [Accepted: 03/23/2020] [Indexed: 12/12/2022] Open
Abstract
Historically, the majority of statistical association methods have been designed assuming availability of SNP-level information. However, modern genetic and sequencing data present new challenges to access and sharing of genotype-phenotype datasets, including cost of management, difficulties in consolidation of records across research groups, etc. These issues make methods based on SNP-level summary statistics particularly appealing. The most common form of combining statistics is a sum of SNP-level squared scores, possibly weighted, as in burden tests for rare variants. The overall significance of the resulting statistic is evaluated using its distribution under the null hypothesis. Here, we demonstrate that this basic approach can be substantially improved by decorrelating scores prior to their addition, resulting in remarkable power gains in situations that are most commonly encountered in practice; namely, under heterogeneity of effect sizes and diversity between pairwise LD. In these situations, the power of the traditional test, based on the added squared scores, quickly reaches a ceiling, as the number of variants increases. Thus, the traditional approach does not benefit from information potentially contained in any additional SNPs, while our decorrelation by orthogonal transformation (DOT) method yields steady gain in power. We present theoretical and computational analyses of both approaches, and reveal causes behind sometimes dramatic difference in their respective powers. We showcase DOT by analyzing breast cancer and cleft lip data, in which our method strengthened levels of previously reported associations and implied the possibility of multiple new alleles that jointly confer disease risk.
Collapse
Affiliation(s)
- Olga A. Vsevolozhskaya
- Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, Kentucky, United States of America
| | - Min Shi
- Biostatistics and Computational Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
| | - Fengjiao Hu
- Biostatistics and Computational Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
| | - Dmitri V. Zaykin
- Biostatistics and Computational Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
| |
Collapse
|
|
8
|
Lee DH, Kim GW, Jeon YH, Yoo J, Lee SW, Kwon SH. Advances in histone demethylase KDM4 as cancer therapeutic targets. FASEB J 2020; 34:3461-3484. [PMID: 31961018 DOI: 10.1096/fj.201902584r] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/20/2019] [Accepted: 01/08/2020] [Indexed: 12/26/2022]
Abstract
The KDM4 subfamily H3K9 histone demethylases are epigenetic regulators that control chromatin structure and gene expression by demethylating histone H3K9, H3K36, and H1.4K26. The KDM4 subfamily mainly consists of four proteins (KDM4A-D), all harboring the Jumonji C domain (JmjC) but with differential substrate specificities. KDM4A-C proteins also possess the double PHD and Tudor domains, whereas KDM4D lacks these domains. KDM4 proteins are overexpressed or deregulated in multiple cancers, cardiovascular diseases, and mental retardation and are thus potential therapeutic targets. Despite extensive efforts, however, there are very few KDM4-selective inhibitors. Defining the exact physiological and oncogenic functions of KDM4 demethylase will provide the foundation for the discovery of novel potent inhibitors. In this review, we focus on recent studies highlighting the oncogenic functions of KDM4s and the interplay between KDM4-mediated epigenetic and metabolic pathways in cancer. We also review currently available KDM4 inhibitors and discuss their potential as therapeutic agents for cancer treatment.
Collapse
Affiliation(s)
- Dong Hoon Lee
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
| | - Go Woon Kim
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
| | - Yu Hyun Jeon
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
| | - Jung Yoo
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
| | - Sang Wu Lee
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
| | - So Hee Kwon
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.,Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, Republic of Korea
| |
Collapse
|
|
9
|
Suo C, Qing T, Liu Z, Yang X, Yuan Z, Yang YJ, Fan M, Zhang T, Lu M, Jin L, Chen X, Ye W. Differential Cumulative Risk of Genetic Polymorphisms in Familial and Nonfamilial Esophageal Squamous Cell Carcinoma. Cancer Epidemiol Biomarkers Prev 2019; 28:2014-2021. [PMID: 31562207 DOI: 10.1158/1055-9965.epi-19-0484] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 07/31/2019] [Accepted: 09/23/2019] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND To explore the relationship between family history of esophageal cancer, SNPs, and the risk of esophageal squamous cell carcinoma (ESCC), we performed a population-based case-control study and developed a genetic family history-related risk (GFR) score and non-family history-related risk (GnFR) score to quantify the cumulative number of risk genotypes carried by each individual. METHODS We used data of 700 patients with nonfamilial ESCC, 341 patients with familial ESCC, 1,445 controls without a family history of esophageal cancer, and 319 controls with a family history. We genotyped 87 genetic variants associated with the risk for ESCC, and constructed GFR and GnFR scores for cases and controls. RESULTS Our results show that ESCC risk increased with higher GFR score (P trend = 0.0096). Among the familial subgroup, we observed a nearly 7-fold [95% confidence interval (CI), 1.92-24.77] higher risk of ESCC in the highest GFR score group. The corresponding estimate was only 2-fold (95% CI, 1.41-3.93) higher risk of ESCC, in the stratum without a reported family history of esophageal cancer. Certain cell signaling pathways and immune-related pathways were enriched, specifically in familial ESCC. Results from a reconstructed cohort analysis demonstrated that cumulative risk to get esophageal cancer by age 75 years was 13.3%, 10.2%, 8.2%, and 5.1%, respectively, in four subgroups as defined by first-degree relatives of cases or controls with high or low genetic risk score. In particular, the cohort of relatives of ESCC cases with low genetic risk score exhibit a higher cumulative risk than the cohort of relatives of controls with high genetic risk score. It demonstrates that environmental factors play a major role in esophageal cancer. CONCLUSIONS Further studies are warranted to dissect the mechanisms of shared environmental and genetic susceptibility affecting the risk of getting ESCC. IMPACT Our study highlights that the need of preventive strategies to screen certain genetic polymorphisms, especially in individuals whose relatives had ESCC.
Collapse
Affiliation(s)
- Chen Suo
- Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Tao Qing
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Zhenqiu Liu
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Xiaorong Yang
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China
| | - Ziyu Yuan
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Ya-Jun Yang
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Min Fan
- Taixing Disease Control and Prevention Center, Taizhou, China
| | - Tiejun Zhang
- Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China
| | - Ming Lu
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China. .,Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China
| | - Li Jin
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Fudan University Taizhou Institute of Health Sciences, Taizhou, China.,Human Phenome Institute, Fudan University, Shanghai, China
| | - Xingdong Chen
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China. .,Fudan University Taizhou Institute of Health Sciences, Taizhou, China.,Human Phenome Institute, Fudan University, Shanghai, China
| | - Weimin Ye
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China.,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
10
|
Wang KL, Chen XL, Lei L, Li P, Hong LL, Huang XC, Mao WM, Mukaisho K, Ling ZQ. Validation study of susceptibility loci for esophageal squamous cell carcinoma identified by GWAS in a Han Chinese subgroup from Eastern China. J Cancer 2019; 10:3624-3631. [PMID: 31333779 PMCID: PMC6636302 DOI: 10.7150/jca.32810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 05/04/2019] [Indexed: 11/05/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) occurs at a relatively high frequency in China and is one of the most prevalent cancers in the world. Genome-wide association studies (GWAS) have identified 24 single-nucleotide polymorphisms (SNPs) that could be associated with ESCC in Chinese patients. This retrospective study aimed to validate the association between these 24 SNPs and ESCC in a Han Chinese subgroup from East China. A total of 2280 and 1900 patients with ESCC (case group) and non-esophageal cancer (control group) were included from a single center. Genotyping of the 24 polymorphisms was performed using the Sequenom MassARRAY system. Unconditional logistic regression analyses were conducted for every polymorphism. It was found that rs12188136 (P=0.027, OR=1.158, 95% CI=1.016-1.319 for AG/AA) was associated with ESCC. Binary logistic regression analyses revealed a significant negative association of rs875339 in RORA (P=0.014, OR=0.762, 95% CI=0.613-0.947 for TT/CC). Under the dominant model, rs6854472 was slightly associated with ESCC risk (P=0.048, OR=1.192, 95% CI=1.002-1.418). Under the recessive model, a significant negative association was observed for rs875339 (P=0.010, OR=0.758, 95% CI=0.615-0.935). In a word, this large-scale replication study validated that rs12188136 and rs6854472 are associated with ESCC in a Han Chinese subgroup from Eastern China, and that rs875339 is negative associated with ESCC.
Collapse
Affiliation(s)
- Kai-Lai Wang
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China
| | - Xiang-Liu Chen
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China
| | - Lan Lei
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China
| | - Pei Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Lian-Lian Hong
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China
| | - Xian-Chong Huang
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China
| | - Wei-Min Mao
- Department of Thoracic Tumor Surgery, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China.,Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (Lung and Esophagus), Hangzhou 310022, China
| | - Kenichi Mukaisho
- Department of Pathology, Division of Molecular Diagnostic Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Zhi-Qiang Ling
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China.,Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (Lung and Esophagus), Hangzhou 310022, China
| |
Collapse
|
|
11
|
Liu P, Zhao HR, Li F, Zhang L, Zhang H, Wang WR, Mao R, Su WP, Zhang Y, Bao YX. Correlations of ALDH2 rs671 and C12orf30 rs4767364 polymorphisms with increased risk and prognosis of esophageal squamous cell carcinoma in the Kazak and Han populations in Xinjiang province. J Clin Lab Anal 2017; 32. [PMID: 28464297 DOI: 10.1002/jcla.22248] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 04/02/2017] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Genetic polymorphisms in ALDH2 and C12orf30 genes have been reported to increase the risk of developing esophageal squamous cell carcinoma (ESCC). This study aims to investigate the relationship between ALDH2 rs671 and c12orf30 rs4767364 polymorphisms in the chromosome 12q24 gene, and risk and prognosis of individuals developing esophageal cancer (ESCC) in Xinjiang Kazak and Han populations. METHODS The case group consisted of 127 ESCC patients. The control group comprised of 125 healthy individuals. Subjects that were recruited all come from Xinjiang province. TaqMan and the Hardy-Weinberg equilibrium were the main methods employed to detect and examine the distribution of genotypes of rs671 and rs4767364. RESULTS The genotype frequencies of ALDH2 rs671 between the Kazak case and control groups were statistically significant, while no significant difference was observed between the Han case and control groups (P>.05). Moreover, ALDH2 rs671 (G>A) was associated with poor prognosis of ESCC in both Kazak and Han populations, and c12orf30 rs4767364 (A>G) was also connected with poor prognosis of ESCC in Kazak but not in Han population. CONCLUSION In the chromosome 12q24 locus, ALDH2 rs671 (G>A) is related to the susceptibility to ESCC in Kazak populations, and it is also associated with poor prognosis of EC in Kazak and Han populations. Furthermore, c12orf30 rs4767364 (A>G) may be correlated with poor ESCC prognosis in Kazak population.
Collapse
Affiliation(s)
- Pan Liu
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hua-Rong Zhao
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Fang Li
- Department of Ophthalmology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Lei Zhang
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hua Zhang
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Wen-Ran Wang
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Rui Mao
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Wei-Peng Su
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yang Zhang
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yong-Xing Bao
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| |
Collapse
|
|
12
|
Miao Y, Liu R, Pu Y, Yin L. Trends in esophageal and esophagogastric junction cancer research from 2007 to 2016: A bibliometric analysis. Medicine (Baltimore) 2017; 96:e6924. [PMID: 28514311 PMCID: PMC5440148 DOI: 10.1097/md.0000000000006924] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND This study aimed to analyze the scientific outputs of esophageal and esophagogastric junction (EGJ) cancer and construct a model to quantitatively and qualitatively evaluate pertinent publications from the past decade. METHODS Publications from 2007 to 2016 were retrieved from the Web of Science Core Collection database. Microsoft Excel 2016 (Redmond, WA) and the CiteSpace (Drexel University, Philadelphia, PA) software were used to analyze publication outcomes, journals, countries, institutions, authors, research areas, and research frontiers. RESULTS A total of 12,978 publications on esophageal and EGJ cancer were identified published until March 23, 2017. The Journal of Clinical Oncology had the largest number of publications, the USA was the leading country, and the University of Texas MD Anderson Cancer Center was the leading institution. Ajani JA published the most papers, and Jemal A had the highest co-citation counts. Esophageal squamous cell carcinoma ranked the first in research hotspots, and preoperative chemotherapy/chemoradiotherapy ranked the first in research frontiers. CONCLUSION The annual number of publications steadily increased in the past decade. A considerable number of papers were published in journals with high impact factor. Many Chinese institutions engaged in esophageal and EGJ cancer research but significant collaborations among them were not noted. Jemal A, Van Hagen P, Cunningham D, and Enzinger PC were identified as good candidates for research collaboration. Neoadjuvant therapy and genome-wide association study in esophageal and EGJ cancer research should be closely observed.
Collapse
Affiliation(s)
- Yan Miao
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu Province, China
| | | | | | | |
Collapse
|
|
13
|
Bhatia S, Baig NA, Timofeeva O, Pasquale EB, Hirsch K, MacDonald TJ, Dritschilo A, Lee YC, Henkemeyer M, Rood B, Jung M, Wang XJ, Kool M, Rodriguez O, Albanese C, Karam SD. Knockdown of EphB1 receptor decreases medulloblastoma cell growth and migration and increases cellular radiosensitization. Oncotarget 2016; 6:8929-46. [PMID: 25879388 PMCID: PMC4496193 DOI: 10.18632/oncotarget.3369] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 02/11/2015] [Indexed: 02/03/2023] Open
Abstract
The expression of members of the Eph family of receptor tyrosine kinases and their ephrin ligands is frequently dysregulated in medulloblastomas. We assessed the expression and functional role of EphB1 in medulloblastoma cell lines and engineered mouse models. mRNA and protein expression profiling showed expression of EphB1 receptor in the human medulloblastoma cell lines DAOY and UW228. EphB1 downregulation reduced cell growth and viability, decreased the expression of important cell cycle regulators, and increased the percentage of cells in G1 phase of the cell cycle. It also modulated the expression of proliferation, and cell survival markers. In addition, EphB1 knockdown in DAOY cells resulted in significant decrease in migration, which correlated with decreased β1-integrin expression and levels of phosphorylated Src. Furthermore, EphB1 knockdown enhanced cellular radiosensitization of medulloblastoma cells in culture and in a genetically engineered mouse medulloblastoma model. Using genetically engineered mouse models, we established that genetic loss of EphB1 resulted in a significant delay in tumor recurrence following irradiation compared to EphB1-expressing control tumors. Taken together, our findings establish that EphB1 plays a key role in medulloblastoma cell growth, viability, migration, and radiation sensitivity, making EphB1 a promising therapeutic target.
Collapse
Affiliation(s)
- Shilpa Bhatia
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Nimrah A Baig
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Olga Timofeeva
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | | | - Kellen Hirsch
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Tobey J MacDonald
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Anatoly Dritschilo
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.,Georgetown University Hospital, Washington, DC, USA
| | - Yi Chien Lee
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Mark Henkemeyer
- Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Brian Rood
- Children's National Medical Center, Washington DC, USA
| | - Mira Jung
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Xiao-Jing Wang
- Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Marcel Kool
- Division of Pediatric Neurooncology, German Cancer Research Center DKFZ, Heidelberg, Germany
| | - Olga Rodriguez
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Chris Albanese
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.,Department of Pathology, Georgetown University School of Medicine, Washington, DC, USA
| | - Sana D Karam
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.,Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| |
Collapse
|
|
14
|
Genomic-Wide Analysis with Microarrays in Human Oncology. MICROARRAYS 2015; 4:454-73. [PMID: 27600234 PMCID: PMC4996403 DOI: 10.3390/microarrays4040454] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 10/08/2015] [Accepted: 10/13/2015] [Indexed: 12/19/2022]
Abstract
DNA microarray technologies have advanced rapidly and had a profound impact on examining gene expression on a genomic scale in research. This review discusses the history and development of microarray and DNA chip devices, and specific microarrays are described along with their methods and applications. In particular, microarrays have detected many novel cancer-related genes by comparing cancer tissues and non-cancerous tissues in oncological research. Recently, new methods have been in development, such as the double-combination array and triple-combination array, which allow more effective analysis of gene expression and epigenetic changes. Analysis of gene expression alterations in precancerous regions compared with normal regions and array analysis in drug-resistance cancer tissues are also successfully performed. Compared with next-generation sequencing, a similar method of genome analysis, several important differences distinguish these techniques and their applications. Development of novel microarray technologies is expected to contribute to further cancer research.
Collapse
|
|
15
|
Geng TT, Xun XJ, Li S, Feng T, Wang LP, Jin TB, Hou P. Association of colorectal cancer susceptibility variants with esophageal cancer in a Chinese population. World J Gastroenterol 2015; 21:6898-6904. [PMID: 26078566 PMCID: PMC4462730 DOI: 10.3748/wjg.v21.i22.6898] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 02/14/2015] [Accepted: 03/12/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between colorectal cancer (CRC) genetic susceptibility variants and esophageal cancer in a Chinese Han population.
METHODS: A case-control study was conducted including 360 esophageal cancer patients and 310 healthy controls. Thirty-one single-nucleotide polymorphisms (SNPs) associated with CRC risk from previous genome-wide association studies were analyzed. SNPs were genotyped using Sequenom Mass-ARRAY technology, and genotypic frequencies in controls were tested for departure from Hardy-Weinberg equilibrium using a Fisher’s exact test. The allelic frequencies were compared between cases and controls using a χ2 test. Associations between the SNPs and the risk of esophageal cancer were tested using various genetic models (codominant, dominant, recessive, overdominant, and additive). ORs and 95%CIs were calculated by unconditional logistic regression with adjustments for age and sex.
RESULTS: The minor alleles of rs1321311 and rs4444235 were associated with a 1.53-fold (95%CI: 1.15-2.06; P = 0.004) and 1.28-fold (95%CI: 1.03-1.60; P = 0.028) increased risk of esophageal cancer in the allelic model analysis, respectively. In the genetic model analysis, the C/C genotype of rs3802842 was associated with a reduced risk of esophageal cancer in the codominant model (OR = 0.52, 95%CI: 0.31-0.88; P = 0.033) and recessive model (OR = 0.55, 95%CI: 0.34-0.87; P = 0.010). The rs4939827 C/T-T/T genotype was associated with a 0.67-fold (95%CI: 0.46-0.98; P = 0.038) decreased esophageal cancer risk under the dominant model. In addition, rs6687758, rs1321311, and rs4444235 were associated with an increased risk. In particular, the T/T genotype of rs1321311 was associated with an 8.06-fold (95%CI: 1.96-33.07; P = 0.004) increased risk in the codominant model.
CONCLUSION: These results provide evidence that known genetic variants associated with CRC risk confer risk for esophageal cancer, and may bring risk for other digestive system tumors.
Collapse
|
|
16
|
Sun LL, Wu JY, Wu ZY, Shen JH, Xu XE, Chen B, Wang SH, Li EM, Xu LY. A three-gene signature and clinical outcome in esophageal squamous cell carcinoma. Int J Cancer 2015; 136:E569-77. [PMID: 25220908 PMCID: PMC4477912 DOI: 10.1002/ijc.29211] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 09/04/2014] [Accepted: 09/09/2014] [Indexed: 02/05/2023]
Abstract
It is increasingly apparent that cancer development depends not only on genetic alterations, but also on epigenetic changes involving histone modifications. GASC1, member of the histone demethylases affecting heterochromatin formation and transcriptional repression, has been found to be dysregulation in many types of cancers including breast cancer, prostate cancer, metastatic lung sarcomatoid carcinoma, and leukemia. In this study, we examined the expression of GASC1 and certain GASC1-targeted genes (KLF4, MYC, SOX2, PPARG, MDM2, and NANOG) and identified a three-gene prognostic signature (PPARG, MDM2, and NANOG), using risk scores based on immunohistochemical analyses of 149 tumor specimens from patients with esophageal squamous cell carcinoma (ESCC). The presence of a high-risk three-gene signature in the ESCC tumors was significantly associated with decreased overall survival (OS) of the patients. We validated the predictive value of the three-gene signature in a second independent cohort of 101 patients with ESCC in order to determine whether it had predictive value. The results were similar to those in 149 patients. According to multivariate Cox proportional hazards analyses, the predictive model of a three-gene signature was an independent predictor for OS (p = 0.005 in cohort 1, p = 0.025 in cohort 2). In addition, ROC analysis indicated that the predictive ability of the three-gene model was more robust than that of a single biomarker. Therefore, our three-gene signature is closely associated with OS among patients with ESCC and may serve as a predictor for the poor prognosis of ESCC patients.
Collapse
Affiliation(s)
- Ling-Ling Sun
- Institute of Oncologic Pathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical CollegeShantou, Guangdong, China
- Department of Pathology, Shaoyang Central Hospital, Affiliated Shaoyang Hospital of University of South ChinaShaoyang, Hunan, China
| | - Jian-Yi Wu
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical CollegeShantou, Guangdong, China
| | - Zhi-Yong Wu
- Department of Oncology Surgery, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen UniversityShantou, Guangdong, China
| | - Jin-Hui Shen
- Department of Pathology, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen UniversityShantou, Guangdong, China
| | - Xiu-E Xu
- Institute of Oncologic Pathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical CollegeShantou, Guangdong, China
| | - Bo Chen
- Institute of Oncologic Pathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical CollegeShantou, Guangdong, China
| | - Shao-Hong Wang
- Department of Pathology, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen UniversityShantou, Guangdong, China
| | - En-Min Li
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical CollegeShantou, Guangdong, China
| | - Li-Yan Xu
- Institute of Oncologic Pathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical CollegeShantou, Guangdong, China
| |
Collapse
|
|
17
|
Xu W, Huang H, Yu L, Cao L. Meta-analysis of gene expression profiles indicates genes in spliceosome pathway are up-regulated in hepatocellular carcinoma (HCC). Med Oncol 2015; 32:96. [DOI: 10.1007/s12032-014-0425-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 11/29/2014] [Indexed: 11/25/2022]
|
|
18
|
LincRNA-uc002yug.2 involves in alternative splicing of RUNX1 and serves as a predictor for esophageal cancer and prognosis. Oncogene 2014; 34:4723-34. [PMID: 25486427 DOI: 10.1038/onc.2014.400] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 10/24/2014] [Accepted: 11/03/2014] [Indexed: 12/12/2022]
Abstract
Long intergenic noncoding RNAs (lincRNAs) have critical regulatory roles in cancer biology; however, the contributions of lincRNAs to esophageal squamous cell carcinoma (ESCC) have been infrequently explored. The aim of this study was to explore the contribution of lincRNAs, located at ESCC susceptibility loci identified by genome-wide association studies, to the risk and prognosis of ESCC. The associations between lincRNAs and the risk and prognosis of ESCC were analyzed in 358 diagnosed patients from eastern China, and the findings were validated in 326 additional patients from southern China. Functional relevance of lincRNAs was further examined by biochemical assays. We found that lincRNA-uc002yug.2 was commonly overexpressed in ESCC compared with paired peritumoral tissue in eastern and southern Chinese populations. The expression levels of lincRNA-uc002yug.2 in ESCC might be a prognostic factor for survival. Moreover, lincRNA-uc002yug.2 promoted a combination of RUNX1 and alternative splicing (AS) factors in the nucleus to produce more RUNX1a, the short isoform and inhibitor of RUNX1, and reduce CEBPα (CCAAT/enhancer-binding protein-α) gene expression, thereby promoting ESCC progression. These results indicated that lincRNA-uc002yug.2 might involve in AS of RUNX1/AML1 and serve as a predictor for esophageal cancer and prognosis.
Collapse
|
|
19
|
Kanamarlapudi V. Exchange factor EFA6R requires C-terminal targeting to the plasma membrane to promote cytoskeletal rearrangement through the activation of ADP-ribosylation factor 6 (ARF6). J Biol Chem 2014; 289:33378-90. [PMID: 25296758 PMCID: PMC4246094 DOI: 10.1074/jbc.m113.534156] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
ADP-ribosylation factor 6 (ARF6) small GTPase regulates membrane trafficking and cytoskeleton rearrangements at the plasma membrane (PM) by cycling between the GTP-bound active and GDP-bound inactive conformations. Guanine nucleotide exchange factors (GEFs) activate ARF6. The exchange factor for ARF6 (EFA6) R has been identified as a biomarker for ovarian cancer. EFA6R shares the catalytic Sec7, pleckstrin homology (PH), and coiled coil (CC) domains of the other EFA6 family GEFs. Here we report the functional characterization of EFA6R. Endogenous EFA6R was present in the plasma membrane fraction. The exogenously expressed FLAG- and GFP-tagged EFA6R were targeted to the PM. In vitro, GFP-EFA6R associated weakly but preferentially with phosphatidylinositol 4,5-bisphosphate (PIP2) through the PH domain. EFA6R required both its PH and CC domains localized at the C terminus to target the PM. Consistent with this, EFA6R lacking the CC domain (EFA6RΔCC) was released from the PM into the cytosol upon PIP2 depletion, whereas EFA6R release from the PM required both PIP2 depletion and actin destabilization. These results suggest that the dual targeting via the PH and CC domains is important for the PM localization of EFA6R. EFA6R specifically catalyzed the GTP loading of ARF6 in mammalian cells. Moreover, EFA6R regulated ARF6 localization and thereby actin stress fiber loss. The GEF activity of EFA6R was dependent on the presence of the Sec7 domain. The PH and CC domains were also required for the in vivo GEF activity of EFA6R but could be functionally replaced by the CAAX motif of K-Ras, suggesting a role for these domains in the membrane targeting of EFA6R.
Collapse
Affiliation(s)
- Venkateswarlu Kanamarlapudi
- From the Institute of Life Science 1, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, United Kingdom
| |
Collapse
|
|
20
|
Palma P, Cuadros M, Conde-Muíño R, Olmedo C, Cano C, Segura-Jiménez I, Blanco A, Bueno P, Ferrón JA, Medina P. Microarray profiling of mononuclear peripheral blood cells identifies novel candidate genes related to chemoradiation response in rectal cancer. PLoS One 2013; 8:e74034. [PMID: 24040155 PMCID: PMC3764031 DOI: 10.1371/journal.pone.0074034] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Accepted: 08/01/2013] [Indexed: 01/03/2023] Open
Abstract
Preoperative chemoradiation significantly improves oncological outcome in locally advanced rectal cancer. However there is no effective method of predicting tumor response to chemoradiation in these patients. Peripheral blood mononuclear cells have emerged recently as pathology markers of cancer and other diseases, making possible their use as therapy predictors. Furthermore, the importance of the immune response in radiosensivity of solid organs led us to hypothesized that microarray gene expression profiling of peripheral blood mononuclear cells could identify patients with response to chemoradiation in rectal cancer. Thirty five 35 patients with locally advanced rectal cancer were recruited initially to perform the study. Peripheral blood samples were obtained before neaodjuvant treatment. RNA was extracted and purified to obtain cDNA and cRNA for hybridization of microarrays included in Human WG CodeLink bioarrays. Quantitative real time PCR was used to validate microarray experiment data. Results were correlated with pathological response, according to Mandard´s criteria and final UICC Stage (patients with tumor regression grade 1-2 and downstaging being defined as responders and patients with grade 3-5 and no downstaging as non-responders). Twenty seven out of 35 patients were finally included in the study. We performed a multiple t-test using Significance Analysis of Microarrays, to find those genes differing significantly in expression, between responders (n = 11) and non-responders (n = 16) to CRT. The differently expressed genes were: BC 035656.1, CIR, PRDM2, CAPG, FALZ, HLA-DPB2, NUPL2, and ZFP36. The measurement of FALZ (p = 0.029) gene expression level determined by qRT-PCR, showed statistically significant differences between the two groups. Gene expression profiling reveals novel genes in peripheral blood samples of mononuclear cells that could predict responders and non-responders to chemoradiation in patients with locally advanced rectal cancer. Moreover, our investigation added further evidence to the importance of mononuclear cells' mediated response in the neoadjuvant treatment of rectal cancer.
Collapse
Affiliation(s)
- Pablo Palma
- Division of Colon and Rectal Surgery, HUVN, Granada, Spain
- * E-mail:
| | - Marta Cuadros
- Departments of Biochemistry, Molecular Biology and Immunology, University of Granada, Granada, Spain
| | | | - Carmen Olmedo
- Department of Surgical Research, HUVN, Granada, Spain
| | - Carlos Cano
- Department of Computer Science and Artificial Intelligence, University of Granada, Granada, Spain
| | | | - Armando Blanco
- Department of Computer Science and Artificial Intelligence, University of Granada, Granada, Spain
| | - Pablo Bueno
- Department of Surgical Research, HUVN, Granada, Spain
| | | | - Pedro Medina
- Departments of Biochemistry, Molecular Biology and Immunology, University of Granada, Granada, Spain
| |
Collapse
|
|
21
|
Wu H, Zheng J, Deng J, Hu M, You Y, Li N, Li W, Lu J, Zhou Y. A genetic polymorphism in lincRNA-uc003opf.1 is associated with susceptibility to esophageal squamous cell carcinoma in Chinese populations. Carcinogenesis 2013; 34:2908-17. [PMID: 23872665 DOI: 10.1093/carcin/bgt252] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The development of esophageal squamous cell carcinoma (ESCC) is a multifactorial process, and associations between genetic variants and ESCC have been identified in genome-wide association studies. The aim of this study was to evaluate the effects of single nucleotide polymorphisms (SNPs) of long intergenic non-coding RNAs (lincRNAs) on ESCC susceptibility in Chinese populations. We scoured exons of lincRNAs located in ESCC susceptibility loci for all probable functional SNPs. These 52 SNPs were opted for and genotyped in 1493 ESCC patients and 1553 cancer-free controls from eastern and southern Chinese populations, and their associations with the risk for ESCC were estimated using logistic regression. Functional relevance was further examined by biochemical assays. Significant differences were found between patients and controls in the genotype frequencies for the rs11752942A>G site in the lincRNA-uc003opf.1 exon. Compared with the rs11752942AA genotype, AG and GG genotypes had a significantly reduced risk of ESCC (adjusted odds ratio = 0.73; 95% confidence interval = 0.63-0.84). Biochemical analysis demonstrated that, when compared with the A allele, the rs11752942G allele could markedly attenuate the level of lincRNA-uc003opf.1 both in vivo and in vitro by binding micro-RNA-149*, thereby affecting cell proliferation and tumor growth. These findings indicated that functional polymorphism rs11752942A>G in lincRNA-uc003opf.1 exon might be a genetic modifier for the development of ESCC.
Collapse
Affiliation(s)
- Hongchun Wu
- Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou 215123, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Abnet CC, Wang Z, Song X, Hu N, Zhou FY, Freedman ND, Li XM, Yu K, Shu XO, Yuan JM, Zheng W, Dawsey SM, Liao LM, Lee MP, Ding T, Qiao YL, Gao YT, Koh WP, Xiang YB, Tang ZZ, Fan JH, Chung CC, Wang C, Wheeler W, Yeager M, Yuenger J, Hutchinson A, Jacobs KB, Giffen CA, Burdett L, Fraumeni JF, Tucker MA, Chow WH, Zhao XK, Li JM, Li AL, Sun LD, Wei W, Li JL, Zhang P, Li HL, Cui WY, Wang WP, Liu ZC, Yang X, Fu WJ, Cui JL, Lin HL, Zhu WL, Liu M, Chen X, Chen J, Guo L, Han JJ, Zhou SL, Huang J, Wu Y, Yuan C, Huang J, Ji AF, Kul JW, Fan ZM, Wang JP, Zhang DY, Zhang LQ, Zhang W, Chen YF, Ren JL, Li XM, Dong JC, Xing GL, Guo ZG, Yang JX, Mao YM, Yuan Y, Guo ET, Zhang W, Hou ZC, Liu J, Li Y, Tang S, Chang J, Peng XQ, Han M, Yin WL, Liu YL, Hu YL, Liu Y, Yang LQ, Zhu FG, Yang XF, Feng XS, Wang Z, Li Y, Gao SG, Liu HL, Yuan L, Jin Y, Zhang YR, Sheyhidin I, et alAbnet CC, Wang Z, Song X, Hu N, Zhou FY, Freedman ND, Li XM, Yu K, Shu XO, Yuan JM, Zheng W, Dawsey SM, Liao LM, Lee MP, Ding T, Qiao YL, Gao YT, Koh WP, Xiang YB, Tang ZZ, Fan JH, Chung CC, Wang C, Wheeler W, Yeager M, Yuenger J, Hutchinson A, Jacobs KB, Giffen CA, Burdett L, Fraumeni JF, Tucker MA, Chow WH, Zhao XK, Li JM, Li AL, Sun LD, Wei W, Li JL, Zhang P, Li HL, Cui WY, Wang WP, Liu ZC, Yang X, Fu WJ, Cui JL, Lin HL, Zhu WL, Liu M, Chen X, Chen J, Guo L, Han JJ, Zhou SL, Huang J, Wu Y, Yuan C, Huang J, Ji AF, Kul JW, Fan ZM, Wang JP, Zhang DY, Zhang LQ, Zhang W, Chen YF, Ren JL, Li XM, Dong JC, Xing GL, Guo ZG, Yang JX, Mao YM, Yuan Y, Guo ET, Zhang W, Hou ZC, Liu J, Li Y, Tang S, Chang J, Peng XQ, Han M, Yin WL, Liu YL, Hu YL, Liu Y, Yang LQ, Zhu FG, Yang XF, Feng XS, Wang Z, Li Y, Gao SG, Liu HL, Yuan L, Jin Y, Zhang YR, Sheyhidin I, Li F, Chen BP, Ren SW, Liu B, Li D, Zhang GF, Yue WB, Feng CW, Qige Q, Zhao JT, Yang WJ, Lei GY, Chen LQ, Li EM, Xu LY, Wu ZY, Bao ZQ, Chen JL, Li XC, Zhuang X, Zhou YF, Zuo XB, Dong ZM, Wang LW, Fan XP, Wang J, Zhou Q, Ma GS, Zhang QX, Liu H, Jian XY, Lian SY, Wang JS, Chang FB, Lu CD, Miao JJ, Chen ZG, Wang R, Guo M, Fan ZL, Tao P, Liu TJ, Wei JC, Kong QP, Fan L, Wang XZ, Gao FS, Wang TY, Xie D, Wang L, Chen SQ, Yang WC, Hong JY, Wang L, Qiu SL, Goldstein AM, Yuan ZQ, Chanock SJ, Zhang XJ, Taylor PR, Wang LD. Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies. Hum Mol Genet 2012; 21:2132-41. [PMID: 22323360 PMCID: PMC3315211 DOI: 10.1093/hmg/dds029] [Show More Authors] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 02/03/2012] [Indexed: 01/13/2023] Open
Abstract
Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.
Collapse
Affiliation(s)
| | - Zhaoming Wang
- Division of Cancer Epidemiology and Genetics and
- Core Genotyping Facility, NCI-Frederick, SAIC-Frederick, Frederick, MD, USA
| | - Xin Song
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Nan Hu
- Division of Cancer Epidemiology and Genetics and
| | - Fu-You Zhou
- Department of Thoracic Surgery and Tumor Prevention Treatment, Anyang Tumor Hospital, Anyang, Henan 455000, China
| | | | - Xue-Min Li
- Department of Pathology and Thoracic Surgery, Centre for Health Screening and Endoscopy, Cixian Hospital, Cixian, Hebei 056500, China
| | - Kai Yu
- Division of Cancer Epidemiology and Genetics and
| | - Xiao-Ou Shu
- Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA
| | - Jian-Min Yuan
- University of Pittsburgh Cancer Institute, Pittsburg, PA, USA
| | - Wei Zheng
- Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA
| | | | | | - Maxwell P. Lee
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ti Ding
- Shanxi Cancer Hospital, Taiyuan, Shanxi, China
| | - You-Lin Qiao
- Department of Epidemiology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Beijing, China
| | | | - Woon-Puay Koh
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
| | | | | | - Jin-Hu Fan
- Department of Epidemiology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Beijing, China
| | - Charles C. Chung
- Division of Cancer Epidemiology and Genetics and
- Core Genotyping Facility, NCI-Frederick, SAIC-Frederick, Frederick, MD, USA
| | - Chaoyu Wang
- Division of Cancer Epidemiology and Genetics and
| | - William Wheeler
- Information Management Services, Inc., Silver Spring, MD, USA
| | - Meredith Yeager
- Division of Cancer Epidemiology and Genetics and
- Core Genotyping Facility, NCI-Frederick, SAIC-Frederick, Frederick, MD, USA
| | - Jeff Yuenger
- Division of Cancer Epidemiology and Genetics and
- Core Genotyping Facility, NCI-Frederick, SAIC-Frederick, Frederick, MD, USA
| | - Amy Hutchinson
- Division of Cancer Epidemiology and Genetics and
- Core Genotyping Facility, NCI-Frederick, SAIC-Frederick, Frederick, MD, USA
| | - Kevin B. Jacobs
- Division of Cancer Epidemiology and Genetics and
- Core Genotyping Facility, NCI-Frederick, SAIC-Frederick, Frederick, MD, USA
| | - Carol A. Giffen
- Information Management Services, Inc., Silver Spring, MD, USA
| | - Laurie Burdett
- Division of Cancer Epidemiology and Genetics and
- Core Genotyping Facility, NCI-Frederick, SAIC-Frederick, Frederick, MD, USA
| | | | | | - Wong-Ho Chow
- Division of Cancer Epidemiology and Genetics and
| | - Xue-Ke Zhao
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Jiang-Man Li
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Ai-Li Li
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
- Department of Thoracic Surgery, Tumor Hospital of Linzhou, Linzhou, Henan 456550, China
| | - Liang-Dan Sun
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui 230032, China
| | - Wu Wei
- Institute of Hematologic Disease and Department of Pathology, Changzhi Medical University, Changzhi, Shanxi 046000, China
| | - Ji-Lin Li
- Department of Pathology and Thoracic Surgery, Linzhou Esophageal Cancer Hospital, Linzhou, Henan 456592, China
| | - Peng Zhang
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Hong-Lei Li
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Wen-Yan Cui
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Wei-Peng Wang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
- Department of Pathology and Thoracic Surgery, Centre for Health Screening and Endoscopy, Cixian Hospital, Cixian, Hebei 056500, China
| | - Zhi-Cai Liu
- Department of Thoracic Surgery, Tumor Hospital of Linzhou, Linzhou, Henan 456550, China
| | - Xia Yang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Wen-Jing Fu
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Ji-Li Cui
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Hong-Li Lin
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Wen-Liang Zhu
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Min Liu
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Xi Chen
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Jie Chen
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Li Guo
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Jing-Jing Han
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Sheng-Li Zhou
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Jia Huang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Yue Wu
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Chao Yuan
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Jing Huang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Ai-Fang Ji
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
- Institute of Hematologic Disease and Department of Pathology, Changzhi Medical University, Changzhi, Shanxi 046000, China
| | - Jian-Wei Kul
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
- Department of Oncology, The First Affiliated Hospital of Nanyang Medical College, Nanyang, Henan 473058, China
| | - Zhong-Min Fan
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Jian-Po Wang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
- Department of Thoracic Surgery and Tumor Prevention Treatment, Anyang Tumor Hospital, Anyang, Henan 455000, China
| | - Dong-Yun Zhang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Lian-Qun Zhang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
- Department of Thoracic Surgery and Tumor Prevention Treatment, Anyang Tumor Hospital, Anyang, Henan 455000, China
| | - Wei Zhang
- Department of Oncology, The First People's Hospital of Hebi, Hebi, Henan 458000, China
| | - Yuan-Fang Chen
- Department of Biostatistics, Hebi City Public Health Bureau, Hebi, Henan 458000, China
| | - Jing-Li Ren
- Department of Basic Oncology and Pathology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xiu-Min Li
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Jin-Cheng Dong
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
- Qixian Commerce Bureau, Hebi, Henan 456750, China
| | - Guo-Lan Xing
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Zhi-Gang Guo
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Jian-Xue Yang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
- Department of Oncology, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan 471003, China
| | - Yi-Ming Mao
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
- Department of Oncology, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan 471003, China
| | - Yuan Yuan
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Er-Tao Guo
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Wei Zhang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Zhi-Chao Hou
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Jing Liu
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Yan Li
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Sa Tang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Jia Chang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Xiu-Qin Peng
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
- Department of Oncology, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan 471003, China
| | - Min Han
- Department of Gastroenterology and Thoracic Surgery, The First People's Hospital of Shangqiu, Shangqiu, Henan 476100, China
| | - Wan-Li Yin
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Ya-Li Liu
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Yan-Long Hu
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Yu Liu
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Liu-Qin Yang
- Department of Radiotherapy, Xinxiang Central Hospital, Xinxiang, Henan 453000, China
| | - Fu-Guo Zhu
- Department of Gastroenterology and Thoracic Surgery, The First People's Hospital of Shangqiu, Shangqiu, Henan 476100, China
| | - Xiu-Feng Yang
- Department of Surgery, Hebi Dahejian Hospital, Hebi, Henan 458000, China
| | - Xiao-Shan Feng
- Department of Oncology, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan 471003, China
| | - Zhou Wang
- Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China
| | - Yin Li
- Department of Thoracic Surgery and Radiotherapy, Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450008, China
| | - She-Gan Gao
- Department of Oncology, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan 471003, China
| | - Hai-Lin Liu
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Ling Yuan
- Department of Thoracic Surgery and Radiotherapy, Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450008, China
| | - Yan Jin
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Yan-Rui Zhang
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Ilyar Sheyhidin
- Department of Thoracic Surgery and Medical Research Center, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830054, China
| | - Feng Li
- Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, China
| | - Bao-Ping Chen
- Department of Nephrology, Huaihe Hospital, Henan University, Kaifeng, Henan 475000, China
| | - Shu-Wei Ren
- Department of Oncology, Xinyang Central Hospital, Xinyang, Henan 464000, China
| | - Bin Liu
- Department of Gastroenterology, Beijing Tongren Hospital Affiliated to Capital Medical University, Beijing 100176, China
| | - Dan Li
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
- Department of Surgery, The Red Cross Hospital of Huojia, Xinxiang, Henan 453800, China
| | - Gao-Fu Zhang
- Department of Surgery, The Red Cross Hospital of Huojia, Xinxiang, Henan 453800, China
| | - Wen-Bin Yue
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
- Department of Oncology, Puyang City Oil Field Hospital, Puyang, Henan 457000, China
| | - Chang-Wei Feng
- Department of Basic Oncology and Pathology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Qirenwang Qige
- Department of Internal Mongolia Medicine, The Affiliated Hospital, Inner Mongolia Medical College, Huhhot, Inner Mongolia 010050, China
| | - Jian-Ting Zhao
- Department of Oncology, The First People's Hospital of Hebi, Hebi, Henan 458000, China
| | - Wen-Jun Yang
- Department of Biotechnology, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Guang-Yan Lei
- Department of Thoracic Surgery, Tumor Hospital of Shaanxi Province, Xi'an, Shaanxi 710061, China
| | - Long-Qi Chen
- Department of Thoracic and Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - En-Min Li
- Department of Oncologic Pathology and Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou, Guangdong 515041, China
| | - Li-Yan Xu
- Department of Oncologic Pathology and Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou, Guangdong 515041, China
| | - Zhi-Yong Wu
- Department of Oncologic Pathology and Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou, Guangdong 515041, China
| | - Zhi-Qin Bao
- Department of Pathology and Thoracic Surgery, Centre for Health Screening and Endoscopy, Cixian Hospital, Cixian, Hebei 056500, China
| | - Ji-Li Chen
- Department of Pathology and Thoracic Surgery, Centre for Health Screening and Endoscopy, Cixian Hospital, Cixian, Hebei 056500, China
| | - Xian-Chang Li
- Information Management Services, Inc., Silver Spring, MD, USA
| | - Xiang Zhuang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Ying-Fa Zhou
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Xian-Bo Zuo
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui 230032, China
| | - Zi-Ming Dong
- Department of Oncology and Pathology, Basic Medical College of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Lu-Wen Wang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Xue-Pin Fan
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Jin Wang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Qi Zhou
- Department of Oncology and Pathology, Basic Medical College of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Guo-Shun Ma
- Department of Biostatistics, Neihuang Public Health Bureau, Anyang, Henan 4563000, China
| | - Qin-Xian Zhang
- Department of Oncology and Pathology, Basic Medical College of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Hai Liu
- Department of Gastroenterology, The Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, China
| | - Xin-Ying Jian
- Department of Pathology and Thoracic Surgery, Linzhou Esophageal Cancer Hospital, Linzhou, Henan 456592, China
| | - Sin-Yong Lian
- Department of Thoracic Surgery, Tumor Hospital of Linzhou, Linzhou, Henan 456550, China
| | - Jin-Sheng Wang
- Institute of Hematologic Disease and Department of Pathology, Changzhi Medical University, Changzhi, Shanxi 046000, China
| | - Fu-Bao Chang
- Department of Thoracic Surgery, Chinese Medicine Hospital of Linzhou, Linzhou, Henan 456550, China
| | - Chang-Dong Lu
- Department of Thoracic Surgery and Tumor Prevention Treatment, Anyang Tumor Hospital, Anyang, Henan 455000, China
| | - Jian-Jun Miao
- Department of Pathology and Thoracic Surgery, Centre for Health Screening and Endoscopy, Cixian Hospital, Cixian, Hebei 056500, China
| | - Zhi-Guo Chen
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Ran Wang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Ming Guo
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Zeng-Lin Fan
- Department of Pathology and Thoracic Surgery, Centre for Health Screening and Endoscopy, Cixian Hospital, Cixian, Hebei 056500, China
| | - Ping Tao
- Department of Oncologic Pathology, Langzhongshi People's Hospital, Langzhong, Sichuan 637400, China
| | - Tai-Jing Liu
- Department of Surgery, The Red Cross Hospital of Huojia, Xinxiang, Henan 453800, China
| | - Jin-Chang Wei
- Department of Pathology and Thoracic Surgery, Linzhou Esophageal Cancer Hospital, Linzhou, Henan 456592, China
| | - Qing-Peng Kong
- State Key Laboratory of Genetic Resource and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Lei Fan
- Department of Pathology and Thoracic Surgery, Centre for Health Screening and Endoscopy, Cixian Hospital, Cixian, Hebei 056500, China
| | - Xian-Zeng Wang
- Department of Thoracic Surgery, Linzhou People's Hospital, Linzhou, Henan 456550, China
| | - Fu-Sheng Gao
- Department of Gastroenterology, Beijing Tongren Hospital Affiliated to Capital Medical University, Beijing 100176, China
| | - Tian-Yun Wang
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Dong Xie
- Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Li Wang
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | - Shu-Qing Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China and
| | - Wan-Cai Yang
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Jun-Yan Hong
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China and
| | - Liang Wang
- MCW Cancer Center, Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Song-Liang Qiu
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| | | | - Zhi-Qing Yuan
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | | | - Xue-Jun Zhang
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui 230032, China
| | | | - Li-Dong Wang
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China
- Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital and
| |
Collapse
|
|
23
|
Hu H, Yang J, Sun Y, Yang Y, Qian J, Jin L, Wang M, Bi R, Zhang R, Zhu M, Sun M, Ma H, Wei Q, Jiang G, Zhou X, Chen H. Putatively functional PLCE1 variants and susceptibility to esophageal squamous cell carcinoma (ESCC): a case-control study in eastern Chinese populations. Ann Surg Oncol 2011; 19:2403-10. [PMID: 22203178 DOI: 10.1245/s10434-011-2160-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2011] [Indexed: 12/19/2022]
Abstract
BACKGROUND A novel variant rs2274223 located in the phospholipase C epsilon 1 (PLCE1) gene was found to be associated with risk of esophageal squamous cell carcinoma (ESCC) by 2 large-scale genome-wide association studies (GWASs) in Chinese populations. In this study, we aimed to assess such an association in an eastern Chinese population and to address its possibly functional role in the etiology of ESCC. METHODS A total of 1061 ESCC cases and 1211 controls were recruited and successfully genotyped for 2 single nucleotide polymorphisms (SNPs) (rs2274223 and rs11187870) of the PLCE1 gene by the TaqMan assay. Real-time PCR and immunohistochemical (IHC) analysis were applied to assess mRNA and protein expression levels, respectively, in a subset of tumor samples. RESULTS SNP rs2274223 was independently associated with risk of ESCC (adjusted odds ratio [OR], 1.49; 95% confidence interval [95% CI], 1.03-2.17 for GG vs AA), and SNP rs11187870 was also found to be associated with risk of ESCC assuming a dominant model (adjusted OR, 1.20; 95% CI, 1.00-1.44 for CG/CC vs GG). The Grs2274223Crs11187870 haplotype increased the risk for ESCC by 1.22-fold (95% CI, 1.04-1.42). Further experiments showed that overall PLCE1 mRNA expression was lower in tumor than in paired normal tissues (0.067±0.016 vs 0.264±0.067, P<.05), and the IHC analysis showed the normal tissues of rs2274223 GG genotype had a lower PLCE1 staining score than that of the AG genotype (0.40±0.22 vs 1.33±0.32, P<.05). CONCLUSIONS PLCE1 SNP rs2274223 A>G change may reduce gene expression, and the variant G genotypes might contribute to risk of ESCC.
Collapse
Affiliation(s)
- Haichuan Hu
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Wong G, Leckie C, Kowalczyk A. FSR: feature set reduction for scalable and accurate multi-class cancer subtype classification based on copy number. ACTA ACUST UNITED AC 2011; 28:151-9. [PMID: 22110244 DOI: 10.1093/bioinformatics/btr644] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
MOTIVATION Feature selection is a key concept in machine learning for microarray datasets, where features represented by probesets are typically several orders of magnitude larger than the available sample size. Computational tractability is a key challenge for feature selection algorithms in handling very high-dimensional datasets beyond a hundred thousand features, such as in datasets produced on single nucleotide polymorphism microarrays. In this article, we present a novel feature set reduction approach that enables scalable feature selection on datasets with hundreds of thousands of features and beyond. Our approach enables more efficient handling of higher resolution datasets to achieve better disease subtype classification of samples for potentially more accurate diagnosis and prognosis, which allows clinicians to make more informed decisions in regards to patient treatment options. RESULTS We applied our feature set reduction approach to several publicly available cancer single nucleotide polymorphism (SNP) array datasets and evaluated its performance in terms of its multiclass predictive classification accuracy over different cancer subtypes, its speedup in execution as well as its scalability with respect to sample size and array resolution. Feature Set Reduction (FSR) was able to reduce the dimensions of an SNP array dataset by more than two orders of magnitude while achieving at least equal, and in most cases superior predictive classification performance over that achieved on features selected by existing feature selection methods alone. An examination of the biological relevance of frequently selected features from FSR-reduced feature sets revealed strong enrichment in association with cancer. AVAILABILITY FSR was implemented in MATLAB R2010b and is available at http://ww2.cs.mu.oz.au/~gwong/FSR.
Collapse
Affiliation(s)
- Gerard Wong
- National ICT Australia, Victoria Research Laboratory, Parkville, Australia.
| | | | | |
Collapse
|
|
25
|
Mao X, Young BD, Lu YJ. The application of single nucleotide polymorphism microarrays in cancer research. Curr Genomics 2011; 8:219-28. [PMID: 18645599 DOI: 10.2174/138920207781386924] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2006] [Revised: 01/22/2007] [Accepted: 03/02/2007] [Indexed: 01/21/2023] Open
Abstract
The development of microarray technology has had a significant impact on the genetic analysis of human disease. The recently developed single nucleotide polymorphism (SNP) array can be used to measure both DNA polymorphism and dosage changes. Our laboratory has applied SNP microarray analysis to uncover frequent uniparental disomies and sub-microscopic genomic copy number gains and losses in different cancers. This review will focus on the wide range of applications of SNP microarray analysis to cancer research. SNP array genotyping can determine loss of heterozygosity, genomic copy number changes and DNA methylation alterations of cancer cells. The same technology can also be used to investigate allelic association in cancers. Therefore, it can be applied to the identification of cancer predisposition genes, oncogenes and tumor suppressor genes in specific types of tumors. As a consequence, they have potential in cancer risk assessment, diagnosis, prognosis and treatment selection.
Collapse
Affiliation(s)
- Xueying Mao
- Medical Oncology Centre, Cancer Institute, Barts and London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London, UK
| | | | | |
Collapse
|
|
26
|
Horne BD, Rasmusson KD, Alharethi R, Budge D, Brunisholz KD, Metz T, Carlquist JF, Connolly JJ, Porter TF, Lappé DL, Muhlestein JB, Silver R, Stehlik J, Park JJ, May HT, Bair TL, Anderson JL, Renlund DG, Kfoury AG. Genome-wide significance and replication of the chromosome 12p11.22 locus near the PTHLH gene for peripartum cardiomyopathy. ACTA ACUST UNITED AC 2011; 4:359-66. [PMID: 21665988 DOI: 10.1161/circgenetics.110.959205] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Peripartum (PP) cardiomyopathy (CM) is a rare condition of unknown etiology that occurs in late pregnancy or early postpartum. Initial evidence suggests that genetic factors may influence PPCM. This study evaluated and replicated genome-wide association of single nucleotide polymorphisms with PPCM. METHODS AND RESULTS Genome-wide single nucleotide polymorphisms in women with verified PPCM diagnosis (n=41) were compared separately with local control subjects (n=49 postmenopausal age-discordant women with parity ≥1 and no heart failure) and iControls (n=654 women ages 30 to 84 years with unknown phenotypes). A replication study of independent population samples used new cases (PPCM2, n=30) compared with new age-discordant control subjects (local2, n=124) and with younger control subjects (n=89) and obstetric control subjects (n=90). A third case set of pregnancy-associated CM cases not meeting strict PPCM definitions (n=29) was also studied. In the genome-wide association study, 1 single nucleotide polymorphism (rs258415) met genome-wide significance for PPCM versus local control subjects (P=2.06×10(-8); odds ratio [OR], 5.96). This was verified versus iControls (P=7.92×10(-19); OR, 8.52). In the replication study for PPCM2 cases, rs258415 (ORs are per C allele) replicated at P=0.009 versus local2 control subjects (OR, 2.26). This replication was verified for PPCM2 versus younger control subjects (P=0.029; OR, 2.15) and versus obstetric control subjects (P=0.013; OR, 2.44). In pregnancy-associated cardiomyopathy cases, rs258415 had a similar effect versus local2 control subjects (P=0.06; OR, 1.79), younger control subjects (P=0.14; OR, 1.65), and obstetric control subjects (P=0.038; OR, 1.99). CONCLUSIONS Genome-wide association with PPCM was discovered and replicated for rs258415 at chromosome 12p11.22 near PTHLH. This study indicates a role of genetic factors in PPCM and provides a new locus for further pathophysiological and clinical investigation.
Collapse
Affiliation(s)
- Benjamin D Horne
- Cardiovascular Department, Intermountain Medical Center, Genetic Epidemiology Division, University of Utah, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Baine MJ, Chakraborty S, Smith LM, Mallya K, Sasson AR, Brand RE, Batra SK. Transcriptional profiling of peripheral blood mononuclear cells in pancreatic cancer patients identifies novel genes with potential diagnostic utility. PLoS One 2011; 6:e17014. [PMID: 21347333 PMCID: PMC3037404 DOI: 10.1371/journal.pone.0017014] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Accepted: 01/19/2011] [Indexed: 12/27/2022] Open
Abstract
Background It is well known that many malignancies, including pancreatic cancer (PC), possess the ability to evade the immune system by indirectly downregulating the mononuclear cell machinery necessary to launch an effective immune response. This knowledge, in conjunction with the fact that the trancriptome of peripheral blood mononuclear cells has been shown to be altered in the context of many diseases, including renal cell carcinoma, lead us to study if any such alteration in gene expression exists in PC as it may have diagnostic utility. Methods and Findings PBMC samples from 26 PC patients and 33 matched healthy controls were analyzed by whole genome cDNA microarray. Three hundred eighty-three genes were found to be significantly different between PC and healthy controls, with 65 having at least a 1.5 fold change in expression. Pathway analysis revealed that many of these genes fell into pathways responsible for hematopoietic differentiation, cytokine signaling, and natural killer (NK) cell and CD8+ T-cell cytotoxic response. Unsupervised hierarchical clustering analysis identified an eight-gene predictor set, consisting of SSBP2, Ube2b-rs1, CA5B, F5, TBC1D8, ANXA3, ARG1, and ADAMTS20, that could distinguish PC patients from healthy controls with an accuracy of 79% in a blinded subset of samples from treatment naïve patients, giving a sensitivity of 83% and a specificity of 75%. Conclusions In summary, we report the first in-depth comparison of global gene expression profiles of PBMCs between PC patients and healthy controls. We have also identified a gene predictor set that can potentially be developed further for use in diagnostic algorithms in PC. Future directions of this research should include analysis of PBMC expression profiles in patients with chronic pancreatitis as well as increasing the number of early-stage patients to assess the utility of PBMCs in the early diagnosis of PC.
Collapse
Affiliation(s)
- Michael J. Baine
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center Omaha, Omaha, Nebraska, United States of America
| | - Subhankar Chakraborty
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Lynette M. Smith
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Kavita Mallya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Aaron R. Sasson
- Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Randall E. Brand
- Division of Gastroenterology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Surinder K. Batra
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center Omaha, Omaha, Nebraska, United States of America
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- * E-mail:
| |
Collapse
|
|
28
|
Duncan EM, Allis CD. Errors in erasure: links between histone lysine methylation removal and disease. PROGRESS IN DRUG RESEARCH. FORTSCHRITTE DER ARZNEIMITTELFORSCHUNG. PROGRES DES RECHERCHES PHARMACEUTIQUES 2011; 67:69-90. [PMID: 21141725 DOI: 10.1007/978-3-7643-8989-5_4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Many studies have demonstrated that covalent histone modifications are dynamically regulated to cause both chemical and physical changes to the chromatin template. Such changes in the chromatin template lead to biologically significant consequences, including differential gene expression. Histone lysine methylation, in particular, has been shown to correlate with gene expression both positively and negatively, depending on the specific site and degree (i.e., mono-, di-, or tri-) of methylation within the histone sequence. Although genetic alterations in the proteins that establish, or "write," methyl modifications and their effect in various human pathologies have been documented, connections between the misregulation of proteins that remove, or "erase," histone methylation and disease have emerged more recently. Here we discuss three mechanisms through which histone methylation can be removed from the chromatin template. We describe how these "erasure" mechanisms are linked to pathways that are known to be misregulated in diseases, such as cancer. We further describe how errors in the removal of histone methylation can and do lead to human pathologies, both directly and indirectly.
Collapse
Affiliation(s)
- Elizabeth M Duncan
- Department of Neurobiology and Anatomy, University of Utah, 20 North 1900 East, Salt Lake City, UT 84132, USA
| | | |
Collapse
|
|
29
|
Li XY, Guo YB, Su M, Cheng L, Lu ZH, Tian DP. Association of mitochondrial haplogroup D and risk of esophageal cancer in Taihang Mountain and Chaoshan areas in China. Mitochondrion 2011; 11:27-32. [PMID: 20601191 DOI: 10.1016/j.mito.2010.06.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2010] [Revised: 06/23/2010] [Accepted: 06/23/2010] [Indexed: 02/05/2023]
Abstract
Both the Taihang Mountain area in north-central China and Chaoshan area in the southeastern littoral of China are areas with high risk of esophageal cancer (EC). Our previous study confirmed that populations from the two areas might share similar matrilineal backgrounds and found that mitochondrial DNA (mtDNA) haplogroup D, especially subhaplogroups D4a and D5a, might be genetic background markers of EC in Chaoshan area. Here, to further determine whether D4a, D5a, and D might be susceptibility markers for EC in the two high-risk areas, we performed a case-control study with larger samples and analyzed the distributions of these three haplogroups in subjects (controls [n = 898] and patients [n = 768]) from the two areas. D4a haplogroup was significantly associated with increased risk of EC in Taihang Mountain subjects, especially women. D5 haplogroup was associated with EC at the general population level in the Taihang Mountain area and in subjects ≤ 60 years, especially women ≤ 60 years, in the Chaoshan area. D haplogroup was associated with EC only in subjects ≤ 60 years, especially men ≤ 60 years, in the Chaoshan area. D4a and D5 showing positive association with EC in the Taihang Mountain area became the predominant subhaplogroups of D in Chaoshan controls. In conclusion, D, D4a, and D5 haplogroups might be susceptibility markers for EC in the two high-risk areas in China, particularly D4a and D5 for the Taihang Mountain area and D and D5 for the Chaoshan area.
Collapse
Affiliation(s)
- Xiao-Yun Li
- Department of Pathology, The Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, Shantou, Guangdong Province 515031, China
| | | | | | | | | | | |
Collapse
|
|
30
|
Wang LD, Zhou FY, Li XM, Sun LD, Song X, Jin Y, Li JM, Kong GQ, Qi H, Cui J, Zhang LQ, Yang JZ, Li JL, Li XC, Ren JL, Liu ZC, Gao WJ, Yuan L, Wei W, Zhang YR, Wang WP, Sheyhidin I, Li F, Chen BP, Ren SW, Liu B, Li D, Ku JW, Fan ZM, Zhou SL, Guo ZG, Zhao XK, Liu N, Ai YH, Shen FF, Cui WY, Song S, Guo T, Huang J, Yuan C, Huang J, Wu Y, Yue WB, Feng CW, Li HL, Wang Y, Tian JY, Lu Y, Yuan Y, Zhu WL, Liu M, Fu WJ, Yang X, Wang HJ, Han SL, Chen J, Han M, Wang HY, Zhang P, Li XM, Dong JC, Xing GL, Wang R, Guo M, Chang ZW, Liu HL, Guo L, Yuan ZQ, Liu H, Lu Q, Yang LQ, Zhu FG, Yang XF, Feng XS, Wang Z, Li Y, Gao SG, Qige Q, Bai LT, Yang WJ, Lei GY, Shen ZY, Chen LQ, Li EM, Xu LY, Wu ZY, Cao WK, Wang JP, Bao ZQ, Chen JL, Ding GC, Zhuang X, Zhou YF, Zheng HF, Zhang Z, Zuo XB, Dong ZM, Fan DM, He X, Wang J, et alWang LD, Zhou FY, Li XM, Sun LD, Song X, Jin Y, Li JM, Kong GQ, Qi H, Cui J, Zhang LQ, Yang JZ, Li JL, Li XC, Ren JL, Liu ZC, Gao WJ, Yuan L, Wei W, Zhang YR, Wang WP, Sheyhidin I, Li F, Chen BP, Ren SW, Liu B, Li D, Ku JW, Fan ZM, Zhou SL, Guo ZG, Zhao XK, Liu N, Ai YH, Shen FF, Cui WY, Song S, Guo T, Huang J, Yuan C, Huang J, Wu Y, Yue WB, Feng CW, Li HL, Wang Y, Tian JY, Lu Y, Yuan Y, Zhu WL, Liu M, Fu WJ, Yang X, Wang HJ, Han SL, Chen J, Han M, Wang HY, Zhang P, Li XM, Dong JC, Xing GL, Wang R, Guo M, Chang ZW, Liu HL, Guo L, Yuan ZQ, Liu H, Lu Q, Yang LQ, Zhu FG, Yang XF, Feng XS, Wang Z, Li Y, Gao SG, Qige Q, Bai LT, Yang WJ, Lei GY, Shen ZY, Chen LQ, Li EM, Xu LY, Wu ZY, Cao WK, Wang JP, Bao ZQ, Chen JL, Ding GC, Zhuang X, Zhou YF, Zheng HF, Zhang Z, Zuo XB, Dong ZM, Fan DM, He X, Wang J, Zhou Q, Zhang QX, Jiao XY, Lian SY, Ji AF, Lu XM, Wang JS, Chang FB, Lu CD, Chen ZG, Miao JJ, Fan ZL, Lin RB, Liu TJ, Wei JC, Kong QP, Lan Y, Fan YJ, Gao FS, Wang TY, Xie D, Chen SQ, Yang WC, Hong JY, Wang L, Qiu SL, Cai ZM, Zhang XJ. Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54. Nat Genet 2010; 42:759-63. [PMID: 20729853 DOI: 10.1038/ng.648] [Show More Authors] [Citation(s) in RCA: 338] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2010] [Accepted: 06/29/2010] [Indexed: 12/13/2022]
Abstract
We performed a genome-wide association study of esophageal squamous cell carcinoma (ESCC) by genotyping 1,077 individuals with ESCC and 1,733 control subjects of Chinese Han descent. We selected 18 promising SNPs for replication in an additional 7,673 cases of ESCC and 11,013 control subjects of Chinese Han descent and 303 cases of ESCC and 537 control subjects of Chinese Uygur-Kazakh descent. We identified two previously unknown susceptibility loci for ESCC: PLCE1 at 10q23 (P(Han combined for ESCC) = 7.46 x 10(-56), odds ratio (OR) = 1.43; P(Uygur-Kazakh for ESCC) = 5.70 x 10(-4), OR = 1.53) and C20orf54 at 20p13 (P(Han combined for ESCC) = 1.21 x 10(-11), OR = 0.86; P(Uygur-Kazakh for ESCC) = 7.88 x 10(-3), OR = 0.66). We also confirmed association in 2,766 cases of gastric cardia adenocarcinoma cases and the same 11,013 control subjects (PLCE1, P(Han for GCA) = 1.74 x 10(-39), OR = 1.55 and C20orf54, P(Han for GCA) = 3.02 x 10(-3), OR = 0.91). PLCE1 and C20orf54 have important biological implications for both ESCC and GCA. PLCE1 might regulate cell growth, differentiation, apoptosis and angiogenesis. C20orf54 is responsible for transporting riboflavin, and deficiency of riboflavin has been documented as a risk factor for ESCC and GCA.
Collapse
Affiliation(s)
- Li-Dong Wang
- Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan, China.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Onvani S, Etame AB, Smith CA, Rutka JT. Genetics of medulloblastoma: clues for novel therapies. Expert Rev Neurother 2010; 10:811-23. [PMID: 20420498 DOI: 10.1586/ern.10.31] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Medulloblastoma is the most common malignant brain tumor in children. Current medulloblastoma therapy entails surgery, radiation and chemotherapy. The 5-year survival rate for patients ranges from 40 to 70%, with most survivors suffering from serious long-term treatment-related sequelae. Additional research on the molecular biology and genetics of medulloblastoma is needed to identify robust prognostic markers for disease-risk stratification, to improve current treatment regimes and to discover novel and more effective molecular-targeted therapies. Recent advances in molecular biology have led to the development of powerful tools for the study of medulloblastoma tumorigenesis, which have revealed new insights into the molecular underpinnings of this disease. Here we discuss the signaling pathway alterations implicated in medulloblastoma pathogenesis, the techniques used in molecular profiling of these tumors and recent molecular subclassification schemes. Particular emphasis is given to the identification of novel molecular targets for less toxic, patient-tailored therapeutic approaches.
Collapse
Affiliation(s)
- Sara Onvani
- The Hospital for Sick Children, Ontario, Canada
| | | | | | | |
Collapse
|
|
32
|
The progress on genetic analysis of nasopharyngeal carcinoma. Comp Funct Genomics 2010:57513. [PMID: 18288251 PMCID: PMC2233780 DOI: 10.1155/2007/57513] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2007] [Accepted: 12/09/2007] [Indexed: 12/14/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world, but is one of the most common cancers in Southeast Asia. Both genetic and environmental factors contribute to the tumorigenesis of NPC, most notably the consumption of certain salted food items and Epstein-Barr virus infection. This review will focus on the current progress of the genetic analysis of NPC (genetic susceptibilities and somatic alterations). We will review the current advances in genomic technologies and their shaping of the future direction of NPC research.
Collapse
|
|
33
|
van der Loos MJHM, Koellinger PD, Groenen PJF, Thurik AR. Genome-wide association studies and the genetics of entrepreneurship. Eur J Epidemiol 2010; 25:1-3. [PMID: 20054611 PMCID: PMC2807937 DOI: 10.1007/s10654-009-9418-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2009] [Accepted: 12/15/2009] [Indexed: 11/30/2022]
Affiliation(s)
- Matthijs J H M van der Loos
- Department of Applied Economics, Erasmus School of Economics, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
| | | | | | | |
Collapse
|
|
34
|
Zeng J, Ge Z, Wang L, Li Q, Wang N, Björkholm M, Jia J, Xu D. The histone demethylase RBP2 Is overexpressed in gastric cancer and its inhibition triggers senescence of cancer cells. Gastroenterology 2010; 138:981-92. [PMID: 19850045 DOI: 10.1053/j.gastro.2009.10.004] [Citation(s) in RCA: 126] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2009] [Revised: 08/24/2009] [Accepted: 10/08/2009] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS The aberrant expression of histone-modifying enzymes such as histone deacetylases contributes to oncogenesis. It is unclear whether RBP2, a newly identified histone demethylase, is involved in cancer development/progression. We determined RBP2 expression in gastric cancer and its biologic function in cancer cells. METHODS Cancerous and matched normal gastric specimens from 42 patients with gastric cancer were analyzed for RBP2 expression using quantitative real-time polymerase chain reaction and immunohistochemistry. Gene expression was assessed using quantitative real-time polymerase chain reaction and immunoblotting and depleted with small interference RNA. Clonogenesis and cellular senescence were examined by foci formation and beta-Galactosidase staining. Promoter activity was determined by luciferase reporter assay. Chromatin immunoprecipitation was used to detect RBP2 and methylated histone H3-K4 on promoters. RESULTS RBP2 messenger RNA and protein expression were increased in 71.5% (30/42) and 100% (20/20) of gastric cancer specimens, respectively. Significantly diminished foci numbers coupled with massive senescence/growth arrest and elevated expression of cyclin-dependent kinase inhibitors (CDKIs) p21(CIP1), p27(kip1), and/or p16(ink4a) occurred in RBP2-depleted gastric and cervical cancer cells. RBP2 depletion-mediated senescence and clonogenic defect were attenuated by inhibiting p21(CIP1) or p27(kip1) expression. The promoter activity of all 3 CDKIs genes was enhanced by RBP2 inhibition. RBP2 occupied these promoters in control cells, and the loss of RBP2 occupancy was accompanied by enhanced H3-K4 trimethylation following RBP2 depletion. CONCLUSIONS RBP2 is overexpressed in gastric cancer, and its inhibition triggers senescence of malignant cells at least partially by derepressing its target genes CDKIs. Histone demethylase inhibition by targeting RBP2 may be an anticancer strategy.
Collapse
Affiliation(s)
- Jiping Zeng
- Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Abstract
Poor femoral neck bone geometry at the femur is an important risk factor for hip fracture. We conducted a genome-wide association study (GWAS) of femoral neck bone geometry, examining approximately 379,000 eligible single-nucleotide polymorphisms (SNPs) in 1000 Caucasians. A common genetic variant, rs7430431 in the receptor transporting protein 3 (RTP3) gene, was identified in strong association with the buckling ratio (BR, P = 1.6 x 10(-7)), an index of bone structural instability, and with femoral cortical thickness (CT, P = 1.9 x 10(-6)). The RTP3 gene is located in 3p21.31, a region that we found to be linked with CT (LOD = 2.19, P = 6.0 x 10(-4)) in 3998 individuals from 434 pedigrees. The replication analyses in 1488 independent Caucasians and 2118 Chinese confirmed the association of rs7430431 to BR and CT (combined P = 7.0 x 10(-3) for BR and P = 1.4 x 10(-2) for CT). In addition, 350 hip fracture patients and 350 healthy control individuals were genotyped to assess the association of the RTP3 gene with the risk of hip fracture. Significant association between a nearby common SNP, rs10514713 of the RTP3 gene, and hip fracture (P = 1.0 x 10(-3)) was found. Our observations suggest that RTP3 may be a novel candidate gene for femoral neck bone geometry.
Collapse
|
|
36
|
Abstract
Identification of hereditary factors that predispose to cancer allows targeted cancer screening and better quantification of environmental risk factors. The ability to identify which single nucleotide polymorphisms (SNPs) are associated with cancer or segregate with disease in families allows high-risk loci to be identified. In this chapter, two platforms for analysing SNPs are discussed, the Affymetrix and Illumina systems. Application of both platforms requires the same principles of good laboratory practice but there are important differences in materials and methods, which will be discussed.
Collapse
Affiliation(s)
- Julie Earl
- Division of Surgery and Oncology, University of Liverpool, Liverpool, UK
| | | |
Collapse
|
|
37
|
Genetic scoring analysis: a way forward in genome wide association studies? Eur J Epidemiol 2009; 24:585-7. [PMID: 19728114 PMCID: PMC2762531 DOI: 10.1007/s10654-009-9387-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2009] [Accepted: 08/20/2009] [Indexed: 01/29/2023]
|
|
38
|
Cui R, Kamatani Y, Takahashi A, Usami M, Hosono N, Kawaguchi T, Tsunoda T, Kamatani N, Kubo M, Nakamura Y, Matsuda K. Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk. Gastroenterology 2009; 137:1768-75. [PMID: 19698717 DOI: 10.1053/j.gastro.2009.07.070] [Citation(s) in RCA: 262] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2009] [Revised: 07/20/2009] [Accepted: 07/31/2009] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Esophageal squamous cell carcinoma (ESCC) is prevalent among Asian populations, with marked regional variations in incidence and mortality. Patients with ESCC have a very poor prognosis, but detection of ESCC at earlier stages could improve clinical outcome. Therefore, identification of epidemiologic factors that influence the development of ESCC would facilitate prevention and/or early detection of the disease. METHODS We performed a 2-step genome-wide association study with subsequent replication analysis using a total of 1070 Japanese ESCC cases and 2836 controls. We also used logistic regression analysis to estimate the effect of gene-gene and gene-environmental interactions. RESULTS We identified the significant associations of ESCC with 4q21-23 and 12q24 regions, which include nonsynonymous single nucleotide polymorphisms (SNP) in ADH1B (rs1229984, P = 6.76 x 10(-35)) and ALDH2 (rs671, P = 3.68 x 10(-68)) that were previously shown to be associated with ESCC susceptibility. Multiple logistic regression analysis revealed SNP rs671, rs1229984, alcohol drinking, and smoking as the independent risk factors for ESCC (odds ratios of 1.66, 1.85, 1.92, and 1.79, respectively). Moreover, individuals who had both genetic and lifestyle-related risk factors had a nearly 190 times higher risk of ESCC than those who had neither of these. CONCLUSIONS We found 2 known functional variants involved in the metabolism of alcohol and tobacco by-products as the most significant risk factors for the development of ESCC in a Japanese population. The individuals carrying both risk genotypes have a higher baseline risk of ESCC that is substantially increased by 2 lifestyle risk factors.
Collapse
Affiliation(s)
- Ri Cui
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
van der Zwaluw CS, Franke B, Engels RCME. Research Highlights. Pharmacogenomics 2009. [DOI: 10.2217/pgs.09.107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Carmen S van der Zwaluw
- Behavioural Science Institute, Radboud University Nijmegen, PO Box 9104, 6500 HE Nijmegen, The Netherlands
| | - Barbara Franke
- Behavioural Science Institute, Radboud University Nijmegen, PO Box 9104, 6500 HE Nijmegen, The Netherlands
| | - Rutger CME Engels
- Behavioural Science Institute, Radboud University Nijmegen, PO Box 9104, 6500 HE Nijmegen, The Netherlands
| |
Collapse
|
|
40
|
Shimada Y, Sato F, Shimizu K, Tsujimoto G, Tsukada K. cDNA microarray analysis of esophageal cancer: discoveries and prospects. Gen Thorac Cardiovasc Surg 2009; 57:347-56. [DOI: 10.1007/s11748-008-0406-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2008] [Indexed: 12/23/2022]
|
|
41
|
Canova C, Hashibe M, Simonato L, Nelis M, Metspalu A, Lagiou P, Trichopoulos D, Ahrens W, Pigeot I, Merletti F, Richiardi L, Talamini R, Barzan L, Macfarlane GJ, Macfarlane TV, Holcátová I, Bencko V, Benhamou S, Bouchardy C, Kjaerheim K, Lowry R, Agudo A, Castellsagué X, Conway DI, McKinney PA, Znaor A, McCartan BE, Healy CM, Marron M, Brennan P. Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 European countries: the ARCAGE project. Cancer Res 2009; 69:2956-65. [PMID: 19339270 DOI: 10.1158/0008-5472.can-08-2604] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cancers of the upper aerodigestive tract (UADT) include malignant tumors of the oral cavity, pharynx, larynx, and esophagus and account for 6.4% of all new cancers in Europe. In the context of a multicenter case-control study conducted in 14 centers within 10 European countries and comprising 1,511 cases and 1,457 controls (ARCAGE study), 115 single nucleotide polymorphisms (SNP) from 62 a priori-selected genes were studied in relation to UADT cancer. We found 11 SNPs that were statistically associated with UADT cancers overall (5.75 expected). Considering the possibility of false-positive results, we focused on SNPs in CYP2A6, MDM2, tumor necrosis factor (TNF), and gene amplified in squamous cell carcinoma 1 (GASC1), for which low P values for trend (P trend<0.01) were observed in the main effects analyses of UADT cancer overall or by subsite. The rare variant of CYP2A6 -47A>C (rs28399433), a phase I metabolism gene, was associated with reduced UADT cancer risk (P trend=0.01). Three SNPs in the MDM2 gene, involved in cell cycle control, were associated with UADT cancer. MDM2 IVS5+1285A>G (rs3730536) showed a strong codominant effect (P trend=0.007). The rare variants of two SNPs in the TNF gene were associated with a decreased risk; for TNF IVS1+123G>A (rs1800610), the P trend was 0.007. Variants in two SNPs of GASC1 were found to be strongly associated with increased UADT cancer risk (for both, P trend=0.008). This study is the largest genetic epidemiologic study on UADT cancers in Europe. Our analysis points to potentially relevant genes in various pathways.
Collapse
Affiliation(s)
- Cristina Canova
- Department of Environmental Medicine and Public Health, University of Padova, Padova, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Knight JA, Skol AD, Shinde A, Hastings D, Walgren RA, Shao J, Tennant TR, Banerjee M, Allan JM, Le Beau MM, Larson RA, Graubert TA, Cox NJ, Onel K. Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility. Blood 2009; 113:5575-82. [PMID: 19299336 PMCID: PMC2689055 DOI: 10.1182/blood-2008-10-183244] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2008] [Accepted: 03/09/2009] [Indexed: 12/25/2022] Open
Abstract
Therapy-related acute myeloid leukemia (t-AML) is a rare but fatal complication of cytotoxic therapy. Whereas sporadic cancer results from interactions between complex exposures and low-penetrance alleles, t-AML results from an acute exposure to a limited number of potent genotoxins. Consequently, we hypothesized that the effect sizes of variants associated with t-AML would be greater than in sporadic cancer, and, therefore, that these variants could be detected even in a modest-sized cohort. To test this, we undertook an association study in 80 cases and 150 controls using Affymetrix Mapping 10K arrays. Even at nominal significance thresholds, we found a significant excess of associations over chance; for example, although 6 associations were expected at P less than .001, we found 15 (P(enrich) = .002). To replicate our findings, we genotyped the 10 most significantly associated single nucleotide polymorphisms (SNPs) in an independent t-AML cohort (n = 70) and obtained evidence of association with t-AML for 3 SNPs in the subset of patients with loss of chromosomes 5 or 7 or both, acquired abnormalities associated with prior exposure to alkylator chemotherapy. Thus, we conclude that the effect of genetic factors contributing to cancer risk is potentiated and more readily discernable in t-AML compared with sporadic cancer.
Collapse
Affiliation(s)
- Jeffrey A Knight
- Committee on Cancer Biology, University of Chicago, IL 60637, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Sakaeda T, Yamamori M, Kuwahara A, Nishiguchi K. Pharmacokinetics and pharmacogenomics in esophageal cancer chemoradiotherapy. Adv Drug Deliv Rev 2009; 61:388-401. [PMID: 19135108 DOI: 10.1016/j.addr.2008.10.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2008] [Accepted: 10/30/2008] [Indexed: 12/15/2022]
Abstract
Esophageal cancer is one of the most lethal malignancies. Surgical resection of the tumor from the primary site has been the standard treatment, especially for localized squamous cell carcinoma, but considerable clinical efforts during the last decade have resulted in novel courses of treatment. These options include chemoradiotherapy, consisting of a continuous infusion of 5-fluorouracil (5-FU), cisplatin (CDDP), and concurrent radiation. Given the substantial inter- and/or intra-individual variation in clinical outcome, future improvements will likely require the incorporation of a novel anticancer drug, pharmacokinetically guided administration of CDDP or 5-FU, and identification of potential responders by patient genetic profiling prior to treatment. In this review, the latest information on incidence, risk factors, biomarkers, therapeutic strategies, and the pharmacokinetically guided or genotype-guided administration of CDDP and 5-FU is summarized for future individualization of esophageal cancer treatment.
Collapse
Affiliation(s)
- Toshiyuki Sakaeda
- Center for Integrative Education of Pharmacy Frontier, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
| | | | | | | |
Collapse
|
|
44
|
Abstract
Investigations into inherited genetic variations in the DNA code (known as polymorphisms) in the field of oncology have provided preliminary support for an association with cancer risks and outcomes. Early studies have highlighted several genes with this potential predictive and prognostic power. However, these studies have had methodological limitations and have produced inconsistent results, making impractical as yet the routine evaluation of such genetic polymorphisms in general clinical practice. Continued research in this area is essential if we are to be able to soon use genetic polymorphisms to better select patients for targeted anticancer interventions. This review discusses the role of genetic polymorphisms and their association with esophageal cancer risk and prognosis. The article also highlights future directions in this new, emerging field of molecular epidemiology.
Collapse
|
|
45
|
Kim KY, Lee SK, Kim MH, Cheong JY, Cho SW, Yang KS, Kwack KB. Erythropoietin-producing Human Hepatocellular Carcinoma Receptor B1 Polymorphisms are Associated with HBV-infected Chronic Liver Disease and Hepatocellular Carcinoma in a Korean Population. Genomics Inform 2008. [DOI: 10.5808/gi.2008.6.4.192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
|
|
46
|
Vineis P, Manuguerra M, Kavvoura FK, Guarrera S, Allione A, Rosa F, Di Gregorio A, Polidoro S, Saletta F, Ioannidis JPA, Matullo G. A field synopsis on low-penetrance variants in DNA repair genes and cancer susceptibility. J Natl Cancer Inst 2008; 101:24-36. [PMID: 19116388 DOI: 10.1093/jnci/djn437] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Several genes encoding for DNA repair molecules implicated in maintaining genomic integrity have been proposed as cancer-susceptibility genes. Although efforts have been made to create synopses for specific fields that summarize the data from genetic association studies, such an overview is not available for genes involved in DNA repair. METHODS We have created a regularly updated database of studies addressing associations between DNA repair gene variants (excluding highly penetrant mutations) and different types of cancer. Using 1087 datasets and publicly available data from genome-wide association platforms, meta-analyses using dominant and recessive models were performed on 241 associations between individual variants and specific cancer types that had been tested in two or more independent studies. The epidemiological strength of each association was graded with Venice criteria that assess amount of evidence, replication, and protection from bias. All statistical tests were two-sided. RESULTS Thirty-one nominally statistically significant (ie, P < .05 without adjustment for multiple comparisons) associations were recorded for 16 genes in dominant and/or recessive model analyses (BRCA2, CCND1, ERCC1, ERCC2, ERCC4, ERCC5, MGMT, NBN, PARP1, POLI, TP53, XPA, XRCC1, XRCC2, XRCC3, and XRCC4). XRCC1, XRCC2, TP53, and ERCC2 variants were each nominally associated with several types of cancer. Three associations were graded as having "strong" credibility, another four had modest credibility, and 24 had weak credibility based on Venice criteria. Requiring more stringent P values to account for multiplicity of comparisons, only the associations of ERCC2 codon 751 (recessive model) and of XRCC1 -77 T>C (dominant model) with lung cancer had P <or= .0001 and retained P <or= .001 even when the first published studies on the respective associations were excluded. CONCLUSIONS We have conducted meta-analyses of 241 associations between variants in DNA repair genes and cancer and have found sparse association signals with strong epidemiological credibility. This synopsis offers a model to survey the current status and gaps in evidence in the field of DNA repair genes and cancer susceptibility, may indicate potential pleiotropic activity of genes and gene pathways, and may offer mechanistic insights in carcinogenesis.
Collapse
Affiliation(s)
- Paolo Vineis
- Department of Epidemiology and Public Health, Imperial College, London, UK
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Huang YT, Chao KM. A new framework for the selection of tag SNPs by multimarker haplotypes. J Biomed Inform 2008; 41:953-61. [DOI: 10.1016/j.jbi.2008.04.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2007] [Revised: 03/31/2008] [Accepted: 04/04/2008] [Indexed: 10/22/2022]
|
|
48
|
A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups. Blood 2008; 113:100-7. [PMID: 18838613 DOI: 10.1182/blood-2008-07-166801] [Citation(s) in RCA: 151] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Inactivation of the tumor suppressor gene, CDKN2A, can occur by deletion, methylation, or mutation. We assessed the principal mode of inactivation in childhood acute lymphoblastic leukemia (ALL) and frequency in biologically relevant subgroups. Mutation or methylation was rare, whereas genomic deletion occurred in 21% of B-cell precursor ALL and 50% of T-ALL patients. Single nucleotide polymorphism arrays revealed copy number neutral (CNN) loss of heterozygosity (LOH) in 8% of patients. Array-based comparative genomic hybridization demonstrated that the mean size of deletions was 14.8 Mb and biallelic deletions composed a large and small deletion (mean sizes, 23.3 Mb and 1.4 Mb). Among 86 patients, only 2 small deletions were below the resolution of detection by fluorescence in situ hybridization. Patients with high hyperdiploidy, ETV6-RUNX1, or 11q23/MLL rearrangements had low rates of deletion (11%, 15%, 13%), whereas patients with t(9;22), t(1;19), TLX3, or TLX1 rearrangements had higher frequencies (61%, 42%, 78%, and 89%). In conclusion, CDKN2A deletion is a significant secondary abnormality in childhood ALL strongly correlated with phenotype and genotype. The variation in the incidence of CDKN2A deletions by cytogenetic subgroup may explain its inconsistent association with outcome. CNN LOH without apparent CDKN2A inactivation suggests the presence of other relevant genes in this region.
Collapse
|
|
49
|
Ng D, Hu N, Hu Y, Wang C, Giffen C, Tang ZZ, Han XY, Yang HH, Lee MP, Goldstein AM, Taylor PR. Replication of a genome-wide case-control study of esophageal squamous cell carcinoma. Int J Cancer 2008; 123:1610-5. [PMID: 18649358 PMCID: PMC2552411 DOI: 10.1002/ijc.23682] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
In a previous pilot case-control study of individuals diagnosed with esophageal squamous cell carcinoma (ESCC) and matched controls from a high-risk area in China, we identified 38 single nucleotide polymorphisms (SNPs) associated with ESCC located in or near one of 33 genes. In our study, we attempted to replicate the results of these 38 gene-related SNPs in a new sample of 300 ESCC cases and 300 matched controls from the same study conducted in Shanxi Province, China. Among 36 evaluable SNPs, 4 were significant in one or more analyses, including SNPs located in EPHB1, PGLYRP2, PIK3C3 and SLC9A9, although the odds ratios (ORs) for these genotypes were modest. Associations were found with EPHB1/rs1515366 (OR 0.92, 95% CI 0.86-0.99; p = 0.019), PIK3C3/rs52911 (OR 0.93, 95% CI 0.88-0.99; p = 0.02) and PGLYRP2/rs959117 (OR 0.93, 95% CI, 0.86-1.01; p = 0.061) in general linear models (additive mode); and the genotype distribution differed between cases and controls for SLC9A9/rs956062 (p = 0.024). To examine these 4 genes in more detail, 40 HapMap-based tag SNPs from these 4 genes were evaluated in the same subjects and 7 additional SNPs associated with ESCC were identified. Further confirmation of these findings in other populations and other studies are needed to determine if the signals from these SNPs are indirectly associated due to linkage disequilibrium, or are directly related to biologic function and the development of ESCC.
Collapse
Affiliation(s)
- David Ng
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Rm 7112, Bethesda, MD 20892-7236, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Matthews AG, Haynes C, Liu C, Ott J. Collapsing SNP genotypes in case-control genome-wide association studies increases the type I error rate and power. Stat Appl Genet Mol Biol 2008; 7:Article23. [PMID: 18673292 PMCID: PMC2789285 DOI: 10.2202/1544-6115.1325] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Genome-wide association studies are now widely used tools to identify genes and/or regions which may contribute to the development of various diseases. With case-control data a 2x3 contingency table can be constructed for each SNP to perform genotype-based tests of association. An increasingly common technique to increase the power to detect an association is to collapse each 2x3 table into a table assuming either a dominant or recessive mode of inheritance (2x2 table). We consider three different methods of determining which genetic model to choose and show that each of these methods of collapsing genotypes increases the type I error rate (i.e., the rate of false positives). However, one of these methods does lead to an increase in power compared with the usual genotype- and allele-based tests for most genetic models.
Collapse
|