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Rahmatallah Y, Glazko G. Improving data interpretability with new differential sample variance gene set tests. BMC Bioinformatics 2025; 26:103. [PMID: 40229677 PMCID: PMC11998189 DOI: 10.1186/s12859-025-06117-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 03/20/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Gene set analysis methods have played a major role in generating biological interpretations of omics data such as gene expression datasets. However, most methods focus on detecting homogenous pattern changes in mean expression while methods detecting pattern changes in variance remain poorly explored. While a few studies attempted to use gene-level variance analysis, such approach remains under-utilized. When comparing two phenotypes, gene sets with distinct changes in subgroups under one phenotype are overlooked by available methods although they reflect meaningful biological differences between two phenotypes. Multivariate sample-level variance analysis methods are needed to detect such pattern changes. RESULTS We used ranking schemes based on minimum spanning tree to generalize the Cramer-Von Mises and Anderson-Darling univariate statistics into multivariate gene set analysis methods to detect differential sample variance or mean. We characterized the detection power and Type I error rate of these methods in addition to two methods developed earlier using simulation results with different parameters. We applied the developed methods to microarray gene expression dataset of prednisolone-resistant and prednisolone-sensitive children diagnosed with B-lineage acute lymphoblastic leukemia and bulk RNA-sequencing gene expression dataset of benign hyperplastic polyps and potentially malignant sessile serrated adenoma/polyps. One or both of the two compared phenotypes in each of these datasets have distinct molecular subtypes that contribute to within phenotype variability and to heterogeneous differences between two compared phenotypes. Our results show that methods designed to detect differential sample variance provide meaningful biological interpretations by detecting specific hallmark gene sets associated with the two compared phenotypes as documented in available literature. CONCLUSIONS The results of this study demonstrate the usefulness of methods designed to detect differential sample variance in providing biological interpretations when biologically relevant but heterogeneous changes between two phenotypes are prevalent in specific signaling pathways. Software implementation of the methods is available with detailed documentation from Bioconductor package GSAR. The available methods are applicable to gene expression datasets in a normalized matrix form and could be used with other omics datasets in a normalized matrix form with available collection of feature sets.
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Affiliation(s)
- Yasir Rahmatallah
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
| | - Galina Glazko
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
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Silva KCDS, Oliveira GEB, Amarante MK, Panis C. Evidence concerning parental exposure to pesticides and the occurrence of leukemia in offspring: a systematic review. Front Pediatr 2025; 13:1560678. [PMID: 40276105 PMCID: PMC12018327 DOI: 10.3389/fped.2025.1560678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 03/24/2025] [Indexed: 04/26/2025] Open
Abstract
Leukemias are among the most common childhood cancers. Although its causes are still unclear, parents' environmental exposure to carcinogenic risk factors may have considerable potential. In this context, we revised the literature concerning parental exposure to pesticides, the development of leukemia in offspring, and the underlying molecular mechanisms involved. This systematic review was based on the PRISMA methodology. Only original studies were included; review articles and case reports were excluded. In total, 312 articles were screened. Of the 29 articles selected and 14 were included in this review. The main findings described in the studies above raise the hypothesis that parental pesticide exposure may be related to the development of leukemia in offspring. However, the literature reinforces the lack of well-designed studies highlighting the mechanism triggered by this exposure and its relationship with childhood cancer. The revised literature provides strong evidence supporting the relationship between parental exposure to pesticides and leukemia development in offspring. While gaps remain in understanding the precise mechanisms involved, the findings emphasize the potential risk posed by pesticide exposure and highlight the need for well-designed studies to clarify the underlying biological pathways.
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Affiliation(s)
- Kennia Cristine de Souza Silva
- Programa de Pós-Graduação em Fisiopatologia Clínica e Laboratorial, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
- Laboratório de Biologia de Tumores, Universidade Estadual do Oeste do Paraná, Campus de Francisco Beltrão, Francisco Beltrão, Brazil
| | - Geise Ellen Broto Oliveira
- Programa de Pós-Graduação em Fisiopatologia Clínica e Laboratorial, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
- Laboratório de Biologia de Tumores, Universidade Estadual do Oeste do Paraná, Campus de Francisco Beltrão, Francisco Beltrão, Brazil
| | - Marla Karine Amarante
- Programa de Pós-Graduação em Fisiopatologia Clínica e Laboratorial, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
| | - Carolina Panis
- Programa de Pós-Graduação em Fisiopatologia Clínica e Laboratorial, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
- Laboratório de Biologia de Tumores, Universidade Estadual do Oeste do Paraná, Campus de Francisco Beltrão, Francisco Beltrão, Brazil
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Bin T, Tang J, Lu B, Xu XJ, Lin C, Wang Y. Construction of AML prognostic model with CYP2E1 and GALNT12 biomarkers based on golgi- associated genes. Ann Hematol 2024:10.1007/s00277-024-06119-7. [PMID: 39604595 DOI: 10.1007/s00277-024-06119-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 11/21/2024] [Indexed: 11/29/2024]
Abstract
Acute myeloid leukaemia (AML) was originally an aggressive malignancy of the bone marrow and one of the deadliest forms of acute leukaemia. The 5-year mortality benefit for patients with AML was only 28.3%. Moreover, a large proportion of patients experienced frequent relapses even after remission, thus predicting a bleak prognosis. This research employed differential expression analysis of AML and normal samples sourced from the GSE30029 database, as well as weighted gene co-expression network analysis (WGCNA). We discovered differential golgi apparatus-related genes (DGARGs) specifically associated with AML. Via regressivity analysis and machine learning algorithm, the cancer genome atlas-acute myeloid leukemia (TCGA-AML) cohort developed a prognostic model using characteristic prognostic genes. The performance value of risk score was analysed using Kaplan-Meier (KM) curves and Cox regression. A predictive nomogram was developed to assess the outcome. The association between prognostic trait genes and the immune microenvironment was examined. Finally, immunoactivity and drug susceptibilities were evaluated in various risk groups identified by prognostic signature genes. A total of 77 DGARGs were obtained by differential expression analysis with WGCNA analysis. Following univariate Cox regression and LASSO regression, six prognostic signature genes (ARL5B, GALNT12, MANSC1, PDE4DIP, NCALD and CYP2E1) were utilized to develop a prognostic model. This model was calibrated via KM survival and receiver operating characteristic (ROC) curves, which concluded that it had a predictive impact on the prognosis of AML. Further analysis of the tumour microenvironment in AML patients demonstrated notable variances in immune cell APC_co_inhibition, CCR, Parainflammation, Type_I_IFN_Response, and Type_II_IFN_Response between the high-risk and low-risk groups. A prognostic model was devised in this study using six prognostic genes linked to the Golgi apparatus. The exactness of the model in guiding the prognosis of AML was established. As a result of expression validation, CYP2E1 and GALNT12 will be used as biomarkers to offer fresh insights into the prognosis and treatment of AML patients.
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Affiliation(s)
- Ting Bin
- Department of Haematology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China
| | - Jing Tang
- Department of Haematology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China
| | - Bo Lu
- Department of Haematology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China
| | - Xiao-Jun Xu
- Department of Haematology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China.
| | - Chao Lin
- Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China.
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, 410000, China.
| | - Ying Wang
- Department of Haematology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China.
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Rahmatallah Y, Glazko G. Improving data interpretability with new differential sample variance gene set tests. RESEARCH SQUARE 2024:rs.3.rs-4888767. [PMID: 39315246 PMCID: PMC11419169 DOI: 10.21203/rs.3.rs-4888767/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Background Gene set analysis methods have played a major role in generating biological interpretations from omics data such as gene expression datasets. However, most methods focus on detecting homogenous pattern changes in mean expression and methods detecting pattern changes in variance remain poorly explored. While a few studies attempted to use gene-level variance analysis, such approach remains under-utilized. When comparing two phenotypes, gene sets with distinct changes in subgroups under one phenotype are overlooked by available methods although they reflect meaningful biological differences between two phenotypes. Multivariate sample-level variance analysis methods are needed to detect such pattern changes. Results We use ranking schemes based on minimum spanning tree to generalize the Cramer-Von Mises and Anderson-Darling univariate statistics into multivariate gene set analysis methods to detect differential sample variance or mean. We characterize these methods in addition to two methods developed earlier using simulation results with different parameters. We apply the developed methods to microarray gene expression dataset of prednisolone-resistant and prednisolone-sensitive children diagnosed with B-lineage acute lymphoblastic leukemia and bulk RNA-sequencing gene expression dataset of benign hyperplastic polyps and potentially malignant sessile serrated adenoma/polyps. One or both of the two compared phenotypes in each of these datasets have distinct molecular subtypes that contribute to heterogeneous differences. Our results show that methods designed to detect differential sample variance are able to detect specific hallmark signaling pathways associated with the two compared phenotypes as documented in available literature. Conclusions The results in this study demonstrate the usefulness of methods designed to detect differential sample variance in providing biological interpretations when biologically relevant but heterogeneous changes between two phenotypes are prevalent in specific signaling pathways. Software implementation of the developed methods is available with detailed documentation from Bioconductor package GSAR. The available methods are applicable to gene expression datasets in a normalized matrix form and could be used with other omics datasets in a normalized matrix form with available collection of feature sets.
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Affiliation(s)
- Yasir Rahmatallah
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Galina Glazko
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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Frikha I, Frikha R, Medhaffer M, Charfi H, Turki F, Elloumi M. Impact of CYP1A1 variants on the risk of acute lymphoblastic leukemia: evidence from an updated meta-analysis. Blood Res 2024; 59:9. [PMID: 38485870 PMCID: PMC10917727 DOI: 10.1007/s44313-024-00007-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 01/24/2024] [Indexed: 03/18/2024] Open
Abstract
OBJECTIVE Our study aimed to investigate the association between cytochrome P450 1A1 (CYP1A1) polymorphisms (T3801C and A2455G) and acute lymphoblastic leukemia (ALL) risk, considering genetic models and ethnicity. MATERIALS AND METHODS PubMed, Embase, Web of Knowledge, Scopus, and the Cochrane electronic databases were searched using combinations of keywords related to CYP1A1 polymorphisms and the risk of ALL. Studies retrieved from the database searches underwent screening based on strict inclusion and exclusion criteria. RESULTS In total, 2822 cases and 4252 controls, as well as 1636 cases and 2674 controls of the C3801T and A2455G variants of CYP1A1, respectively, were included in this meta-analysis. The T3801C polymorphism of CYP1A1 significantly increases the risk of ALL, particularly those observed in Asian and Hispanic populations, independent of age. Similarly, the A2455G polymorphism of CYP1A1 plays a significant role in the susceptibility to ALL in all genetic models, except the heterozygous form. This association was observed mainly in mixed populations and in both children and adults (except in the heterozygous model). CONCLUSION Our comprehensive analysis indicates that the T3801 and A2455G polymorphisms of CYP1A1 may increase the risk of ALL depending on ethnicity. Therefore, both variants should be considered promising biomarkers for ALL risk. Further large-scale investigations are necessary to assess other factors, such as gene-gene or gene-environment interactions.
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Affiliation(s)
- Imen Frikha
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
- Department of Hematology, Hedi Chaker Hospital, Sfax, Tunisia
| | - Rim Frikha
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia.
- Department of Medical Genetics, Hedi Chaker Hospital, Sfax, Tunisia.
| | - Moez Medhaffer
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
- Department of Hematology, Hedi Chaker Hospital, Sfax, Tunisia
| | - Hanen Charfi
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
- Department of Hematology, Hedi Chaker Hospital, Sfax, Tunisia
| | - Fatma Turki
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
- Department of Medical Genetics, Hedi Chaker Hospital, Sfax, Tunisia
| | - Moez Elloumi
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
- Department of Hematology, Hedi Chaker Hospital, Sfax, Tunisia
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Sandoval C, Calle Y, Godoy K, Farías J. An Updated Overview of the Role of CYP450 during Xenobiotic Metabolization in Regulating the Acute Myeloid Leukemia Microenvironment. Int J Mol Sci 2023; 24:6031. [PMID: 37047003 PMCID: PMC10094375 DOI: 10.3390/ijms24076031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/08/2023] [Accepted: 03/16/2023] [Indexed: 04/14/2023] Open
Abstract
Oxidative stress is associated with several acute and chronic disorders, including hematological malignancies such as acute myeloid leukemia, the most prevalent acute leukemia in adults. Xenobiotics are usually harmless compounds that may be detrimental, such as pharmaceuticals, environmental pollutants, cosmetics, and even food additives. The storage of xenobiotics can serve as a defense mechanism or a means of bioaccumulation, leading to adverse effects. During the absorption, metabolism, and cellular excretion of xenobiotics, three steps may be distinguished: (i) inflow by transporter enzymes, (ii) phases I and II, and (iii) phase III. Phase I enzymes, such as those in the cytochrome P450 superfamily, catalyze the conversion of xenobiotics into more polar compounds, contributing to an elevated acute myeloid leukemia risk. Furthermore, genetic polymorphism influences the variability and susceptibility of related myeloid neoplasms, infant leukemias associated with mixed-lineage leukemia (MLL) gene rearrangements, and a subset of de novo acute myeloid leukemia. Recent research has shown a sustained interest in determining the regulators of cytochrome P450, family 2, subfamily E, member 1 (CYP2E1) expression and activity as an emerging field that requires further investigation in acute myeloid leukemia evolution. Therefore, this review suggests that CYP2E1 and its mutations can be a therapeutic or diagnostic target in acute myeloid leukemia.
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Affiliation(s)
- Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras 753, Osorno 5310431, Chile
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile
- Departamento de Ciencias Preclínicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Yolanda Calle
- School of Life and Health Sciences, University of Roehampton, London SW15 4JD, UK;
| | - Karina Godoy
- Núcleo Científico y Tecnológico en Biorecursos (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile;
| | - Jorge Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile
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Zhang S, Mi Y, Ye T, Lu X, Liu L, Qian J, Fan X. Carbohydrates and ginsenosides in shenmai injection jointly improve hematopoietic function during chemotherapy-induced myelosuppression in mice. Chin Med 2022; 17:124. [DOI: 10.1186/s13020-022-00678-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022] Open
Abstract
Abstract
Background
Shenmai injection (SMI), a traditional Chinese medicine (TCM) injection prepared from Red ginseng and Ophiopogon japonicus, is widely used in clinics to treat chemotherapy-induced myelosuppression. Similar to other TCM injections, SMI contains a high amount of carbohydrates (fructose, sucrose, and maltose) in addition to the bioactive substances, specifically ginsenosides (Rg1, Re, and Rb1). To date, the role of these carbohydrates in the hematopoietic function of SMI remains unclear.
Purpose
We aimed to investigate the hematopoietic effects and potential mechanisms of SMI and its components, focusing on the carbohydrates present in SMI.
Experimental design/methods
First, we evaluated the hematopoietic effect of SMI on 5-fluorouracil (5-FU)-induced myelotoxicity in a tumor-bearing mouse model. Then we prepared mixtures of ginsenosides and carbohydrates according to their proportions in SMI and evaluated their hematopoietic function in mice with 5-FU-induced myelosuppression. Finally, hematopoiesis-related molecular networks were built based on RNA sequencing (RNA-seq) of the bone marrow stromal cells (BMSCs), and the potential mechanisms of carbohydrates and ginsenosides were evaluated.
Results
SMI attenuated 5-FU-induced myelotoxicity in tumor-bearing mice. Both ginsenosides and carbohydrates increased the bone marrow nucleated cell (BMNC) count and improved the bone marrow morphology in myelosuppressive mice; they promoted the proliferation of BMSCs derived from those myelosuppressive mice. Bioinformatics analyses revealed ECM-receptor interaction, Hippo signaling, and Wnt signaling are common pathways regulated by both ginsenosides and carbohydrates; Gstt1, Gstp2, Gsta4 and Oplah in Glutathione metabolism pathway and Cd19, Cd79a, and Cd79b in B cell receptor pathway are uniquely regulated genes related to carbohydrates but not ginsenosides.
Conclusions
Carbohydrates may collaborate with ginsenosides and contribute to the hematopoietic function of SMI. Carbohydrates could be considered as a bioactive component in this TCM injection.
Graphical Abstract
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Shapoo NS, Masood A, Bhat JR, Bhatia AS, Shah IA, Ganai BA. CYP2D6 rs35742686 and rs3892097 Gene Polymorphisms and Childhood Acute Lymphoblastic Leukemia: Relation to Disease Susceptibility in Kashmiri Children. J Pediatr Genet 2022; 11:213-220. [DOI: 10.1055/s-0041-1723975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 12/17/2020] [Indexed: 10/22/2022]
Abstract
Abstract
CYP2D6 is one of the most widely investigated CYPs in relation to gene polymorphism. This study analyzed the relationship between CYP2D6 rs35742686 and rs3892097 single-nucleotide polymorphisms (SNPs) and potential risk factors in the development of acute lymphoblastic leukemia (ALL) in Kashmiri children. We recruited 300 cases and 600 controls for genotyping and risk factors assessment. Genotypes of rs35742686 and rs3892097 were analyzed by polymerase chain reaction-restriction fragment length polymorphism method. CYP2D6 expression analysis was done by quantitative reverse transcription polymerase chain reaction in ALL cases. Conditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI). High risk of ALL was observed in cases who carried the mutant genotypes of rs35742686 (OR = 18.15; 95% CI = 4.13–79.66, p < 0.0001) or rs3892097 (OR = 24.06; 95% CI = 10.23–56.53, p < 0.0001). Significant interaction was observed between rs35742686 and rs3892097 SNPs (P interaction = 0.001). The risk associated with the variant genotypes of rs35742686 and rs3892097 was retained in the cases whose fathers were smokers or had maternal X-ray exposure (p < 0.001). Relative messenger ribonucleic acid expression across genotypes was significantly decreased in cases carrying rs357426863 (*3/*3) (n-fold = 0.37 ± 0.156, p < 0.0079) and rs3892097 SNPs (*4/*4) (n-fold = 0.02 ± 0.0075, p < 0.0001) suggesting these two events are independent in ALL cases. The study concluded that rs35742686 and rs3892097 SNPs are significantly associated with ALL risk in Kashmiri children.
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Affiliation(s)
- Nidha Sadiq Shapoo
- Department of Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Akbar Masood
- Department of Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Javid R. Bhat
- Department of Clinical Haematology, Sher-e-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
| | - A. S. Bhatia
- Department of Biochemistry, Government Medical College, Jammu, Jammu and Kashmir, India
| | - Idrees A. Shah
- Department of Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Bashir A. Ganai
- Centre of Research for Development, University of Kashmir, Srinagar, Jammu and Kashmir, India
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Hu T, Zhou G, Li W. Association Between the Individual and Combined Effects of the GSTM1 and GSTT1 Polymorphisms and Risk of Leukemia: A Meta-Analysis. Front Genet 2022; 13:898937. [PMID: 35938012 PMCID: PMC9355274 DOI: 10.3389/fgene.2022.898937] [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: 03/18/2022] [Accepted: 06/06/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Fourteen meta-analyses reported the individual effects of the GSTM1 and GSTT1 polymorphisms on leukemia risk. However, over 40 studies were not included in previously published meta-analyses. Moreover, one key aspect was that previous meta-analyses did not conduct the false-positive test on the aforementioned issues. Furthermore, previous meta-analyses did not observe the combined effects of GSTM1 present/null and GSTT1 present/null polymorphism with leukemia risk. Therefore, we conducted the current study to further analyze these associations. Objectives: This study aimed to investigate the association between the individual and combined effects of the GSTM1 present/null and GSTT1 present/null polymorphisms and the risk of leukemia. Methods: A meta-analysis was performed applying Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. Moreover, false-positive report probability (FPRP) and Bayesian false discovery probability (BFDP) were applied to investigate the false-positive results. Results: The individual GSTM1 and GSTT1 null genotypes and combined effects of the two genes were associated with a significantly increased leukemia risk in overall and several subgroup analyses, such as Asians, Caucasians, and so on. Then, further analysis was conducted using FPRP and BFDP. Significant associations were considered as "positive" results on the GSTM1 null genotype with leukemia risk in overall populations (FPRP < 0.001 and BFDP = 0.006), Asians (FPRP < 0.001 and BFDP < 0.001), and East Asian population (FPRP < 0.001 and BFDP = 0.002). For the GSTT1 null genotype, significant associations were regarded "positive" results in overall populations, acute myeloid leukemia (AML), Asians, and East Asian population. For the combined effects of the GSTM1 and GSTT1 polymorphisms, significant associations were also considered "positive" results in the overall analysis of Asians, Indians, and East Asian population. Conclusion: This study strongly indicates that the individual GSTM1 and GSTT1 null genotypes and combined effects of the two genes are associated with increased leukemia risk in Asians, especially in the East Asian population; the GSTT1 null genotype is associated with increased AML risk; the combined effects of the two genes are associated with increased leukemia risk in Indians.
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Affiliation(s)
- Ting Hu
- Department of Hematology, Pingxiang People’s Hospital, Pingxiang, China
| | - Guozhong Zhou
- Department of Cardiology, Pingxiang People’s Hospital, Pingxiang, China
| | - Wenjin Li
- Department of Hematology, Pingxiang People’s Hospital, Pingxiang, China
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Usman M, Priya K, Pandit S, Gupta P. Cancer risk and nullity of Glutathione-S-transferase mu and theta 1 in occupational pesticide workers. Curr Pharm Biotechnol 2021; 23:932-945. [PMID: 34375184 DOI: 10.2174/1389201022666210810092342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 06/16/2021] [Accepted: 06/16/2021] [Indexed: 12/08/2022]
Abstract
Occupational exposure to pesticides has been associated with adverse health conditions, including genotoxicity and cancer. Nullity of GSTT1/GSTM1 increases the susceptibility of pesticide workers to these adverse health effects due to lack of efficient detoxification process created by the absence of these key xenobiotic metabolizing enzymes. However, this assertion does not seem to maintain its stance at all the time; some pesticide workers with the null genotypes do not present the susceptibility. This suggests the modulatory role of other confounding factors, genetic and environmental conditions. Pesticides, aggravated by the null GSTT1/GSTM1, cause genotoxicity and cancer through oxidative stress and miRNA dysregulation. Thus, the absence of these adverse health effects together with the presence of null GSTT1/GSTM1 genotypes demands further explanation. Also, understanding the mechanism behind the protection of cells - that are devoid of GSTT1/GSTM1 - from oxidative stress constitutes a great challenge and potential research area. Therefore, this review article highlights the recent advancements in the presence and absence of cancer risk in occupational pesticide workers with GSTT1 and GSTM1 null genotypes.
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Affiliation(s)
- Muhammad Usman
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, KP-III, Greater Noida- 201310 [U.P.], India
| | - Kanu Priya
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, KP-III, Greater Noida- 201310 [U.P.], India
| | - Soumya Pandit
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, KP-III, Greater Noida- 201310 [U.P.], India
| | - Piyush Gupta
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, KP-III, Greater Noida- 201310 [U.P.], India
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11
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The impact of CYP2D6*4 and GSTP1 Ile105Val polymorphisms on the susceptibility to develop BCR-ABL1 negative myeloproliferative neoplasms. Mol Biol Rep 2020; 47:7413-7420. [PMID: 32918123 DOI: 10.1007/s11033-020-05796-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 08/28/2020] [Indexed: 10/23/2022]
Abstract
Inter-individual variations in the genes encoding xenobiotic-metabolizing enzymes have been reported to alter susceptibility to various diseases involving hematological disorders. The purpose of this case-control study was to investigate the relationship between CYP2D6*4 and GSTP1 Ile105Val polymorphisms and the risk of developing BCR-ABL1 negative myeloproliferative neoplasms (MPN). PCR-RFLP was used for genotyping single nucleotide polymorphisms (SNP) in CYP2D6 and GSTP1 in 139 patients with MPN and 126 controls. There was a significantly increased risk for developing BCR-ABL1 negative MPN for the group bearing the CYP2D6*4 variant allele (X2: 4.487; OR 1.738; 95% CI 1.040-2.904; p = 0.034). The platelet count was higher in CYP2D6*4 allele carriers (p = 0.047). There was no association between the GSTP1 Ile105Val polymorphism and the risk of developing MPNs. MPN patients bearing the GSTP1 Ile105Val variant allele had a higher prevalence of bleeding complications (X2: 7.510; OR 4.635; 95% CI 1.466-14.650; p = 0.006). Our study provides new data that the CYP2D6*4 polymorphism may be associated with an increased risk to develop MPNs while the GSTP1 Ile105Val polymorphism does not show such an association. To our knowledge, the current study is the first to investigate the relationship between CYP2D6*4 and GSTP1 Ile105Val polymorphisms and the risk of developing MPNs in the Turkish population. Further studies with more patients and controls are needed to support our data.
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12
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Wang Y, Hu F, Li JY, Nie RC, Chen SL, Cai YY, Shu LL, Deng DJ, Xu JB, Liang Y. Systematic Construction and Validation of a Metabolic Risk Model for Prognostic Prediction in Acute Myelogenous Leukemia. Front Oncol 2020; 10:540. [PMID: 32373530 PMCID: PMC7186449 DOI: 10.3389/fonc.2020.00540] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Accepted: 03/25/2020] [Indexed: 01/11/2023] Open
Abstract
Background: Acute myelogenous leukemia (AML) is a heterogeneous disease with recurrent gene mutations and variations in disease-associated gene expression, which may be useful for prognostic prediction. Methods: RNA matrix and clinical data of AML were downloaded from GEO, TCGA, and TARGET databases. Prognostic metabolic genes were identified by LASSO analysis to establish a metabolic model. Prognostic accuracy of the model was quantified by time-dependent receiver operating characteristic curves and the area under the curve (AUC). Survival analysis was performed by log-rank tests. Enriched pathways in different metabolic risk statuses were evaluated by gene set enrichment analyses (GSEA). Results: We identified nine genes to construct a prognostic model of shorter survival in the high-risk vs. low-risk group. The prognostic model showed good predictive efficacy, with AUCs for 5-year overall survival of 0.78 (0.73-0.83), 0.76 (0.62-0.89), and 0.66 (0.57-0.75) in the training, adult external, and pediatric external cohorts, respectively. Multivariable analysis demonstrated that the metabolic signature had independent prognostic value with hazard ratios of 2.75 (2.06-3.66), 1.89 (1.09-3.29), and 1.96 (1.00-3.84) in the training, adult external, and pediatric external cohorts, respectively. Combining metabolic signatures and classic prognostic factors improved 5-year overall survival prediction compared to the prediction by classic prognostic factors (p < 0.05). GSEA revealed that most pathways were metabolism-related, indicating potential mechanisms. Conclusion: We identified dysregulated metabolic features in AML and constructed a prognostic model to predict the survival of patients with AML.
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Affiliation(s)
- Yun Wang
- Sate key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Fang Hu
- Sate key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jin-Yuan Li
- Sate key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Run-Cong Nie
- Sate key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Si-Liang Chen
- Sate key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yan-Yu Cai
- Sate key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ling-Ling Shu
- Sate key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - De-Jun Deng
- Department of Oncology and Hematology, Shenzhen Luohu District Hospital of Traditional Chinese Medicine, Shenzhen, China
| | - Jing-Bo Xu
- Department of Hematology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Yang Liang
- Sate key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
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13
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Khalaj Z, Baratieh Z, Nikpour P, Khanahmad H, Mokarian F, Salehi R, Salehi M. Distribution of CYP2D6 polymorphism in the Middle Eastern region. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2019; 24:61. [PMID: 31523247 PMCID: PMC6670283 DOI: 10.4103/jrms.jrms_1076_18] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/04/2019] [Accepted: 04/10/2019] [Indexed: 12/12/2022]
Abstract
Cytochrome P450 2D6 (CYP2D6) is an important drug-metabolizing enzyme involved in the pharmacokinetic metabolism of drugs. CYP2D6 gene is highly polymorphic, and the combination of its different alleles yields different phenotypes including extensive metabolizer (EM), intermediate metabolizer (IM), poor metabolizer (PM), and ultrarapid metabolizer (UM). Genotyping of the important alleles for this gene in different ethnicities is of particular importance for assessing the efficacy of various drugs. In this study, we reviewed the CYP2D6 allele and phenotype frequencies predicted from the genotypes of CYP2D6 in the Middle East area. Regardless of different ethnicities, the CYP2D6*41 allele frequency was shown to be higher than that of other reduced functional alleles. In addition, CYP2D6*4 was the most frequent nonfunctional allele in all studied populations in the Middle East. Taken together, our findings illustrated that the frequencies of PM or IM alleles and different genotypes harboring these alleles are relatively high in the Middle Eastern countries. Therefore, the study of CYP2D6 alleles for each patient to detect those that are at risk is of great importance to prevent adverse drug reactions through individualization therapy.
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Affiliation(s)
- Zahra Khalaj
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zohreh Baratieh
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parvaneh Nikpour
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.,Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein Khanahmad
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fariborz Mokarian
- Cancer Prevention Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rasoul Salehi
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.,Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mansoor Salehi
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.,Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.,Cellular, Molecular and Genetics Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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14
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CYP 2D6* 4 polymorphism in Polycythemia vera patients in Turkish population. MARMARA MEDICAL JOURNAL 2018. [DOI: 10.5472/marumj.430790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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15
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Zehra A, Zehra S, Ismail M, Azhar A. Glutathione S-Transferase M1 and T1 Gene Deletions and Susceptibility to Acute Lymphoblastic Leukemia (ALL) in adults. Pak J Med Sci 2018; 34:666-670. [PMID: 30034435 PMCID: PMC6041525 DOI: 10.12669/pjms.343.14911] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Objective: Biotransformation of xenobiotics are critical for their metabolism and removal from the body which is carried out by xenobiotic metabolizing enzymes. Individuals carrying variants of genes that encode these enzymes have an altered ability to metabolize xenobiotics which may lead to an increased risk of acute lymphoblastic leukemia. The current study aimed to investigate the impact of GSTM1 and GSTT1 gene deletions in causing predisposition to adult ALL. Methods: The current case-control study involved 62 adult ALL patients and 62 age and gender matched healthy controls. Whole blood samples processed with standard phenol chloroform protocol for DNA isolation were genotyped using multiplex PCR approach for simultaneous identification of GSTM1 and GSTT1 deletions. The genotype frequency obtained for patients was compared to controls using odds ratio and chi-square. Results: The null genotype frequency of GSTM1 and GSTT1 in a group of adult ALL patients from Pakistan were 47% and 11% respectively. Deletion of GSTM1 and GSTT1 did not show statistically significant association with adult ALL (p=0.86 and p=0.35 respectively). The combined GSTM1/GSTT1 deletion was observed in 2% patients and was not significantly associated with ALL in adults (p=0.85). Conclusions: The results reveal that homozygous null polymorphism of GSTM1 and GSTT1genes does not influence ALL susceptibility among adult patients. Cancer susceptibility associated with GST polymorphism varies with ethnic and geographic differences. Therefore, further investigation on different populations is needed to understand the role of these genetic variations in modifying adult ALL risk.
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Affiliation(s)
- Alveena Zehra
- Alveena Zehra, PhD Student (MSc). The Karachi Institute of Biotechnology and Genetic Engineering (KIBGE), University of Karachi, Karachi, Pakistan
| | - Sitwat Zehra
- Sitwat Zehra, PhD. The Karachi Institute of Biotechnology and Genetic Engineering (KIBGE), University of Karachi, Karachi, Pakistan
| | - Muhammad Ismail
- Muhammad Ismail, PhD. Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan
| | - Abid Azhar
- Abid Azhar, DSc, PhD. The Karachi Institute of Biotechnology and Genetic Engineering (KIBGE), University of Karachi, Karachi, Pakistan
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16
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Maternal Exposure to Pesticides, Paternal Occupation in the Army/Police Force, and CYP2D6*4 Polymorphism in the Etiology of Childhood Acute Leukemia. J Pediatr Hematol Oncol 2018; 40:e207-e214. [PMID: 29432309 DOI: 10.1097/mph.0000000000001105] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Epidemiologic studies have suggested that parental occupations, pesticide use, environmental factors, and genetic polymorphism are involved in the etiology of childhood acute leukemia (CAL). In total, 116 cases of CAL and 162 controls were recruited and submitted to blood drawing to assess the presence of genetic polymorphisms. Parental occupations, pesticides exposure, and other potential determinants were investigated. Increased risk for CAL was associated with prenatal maternal use of insecticides/rodenticides (odds ratio [OR]=1.87; 95% confidence intervals [CI], 1.04-3.33), with subjects living <100 m from pesticide-treated fields (OR=3.21; 95% CI, 1.37-7.53) and with a paternal occupation as traffic warden/policeman (OR=4.02; 95% CI, 1.63-9.87). Associations were found between CAL and genetic polymorphism of CYP2D6*4 for homozygous alleles (mutant type/mutant type: OR=6.39; 95% CI, 1.17-34.66). In conclusion, despite the small sample size, maternal prenatal exposure to pesticides, paternal occupation as a traffic warden/police officer, and CYP2D6*4 polymorphism could play a role in the etiology of CAL.
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17
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Brisson GD, de Almeida Lopes B, Andrade FG, Dos Santos Bueno FV, Sardou-Cezar I, de Aguiar Gonçalves BA, Terra-Granado E, Paraguassú-Braga FH, Pombo-de-Oliveira MS. EPHX1 rs1051740 T>C (Tyr113His) is strongly associated with acute myeloid leukemia and KMT2A rearrangements in early age. Arch Toxicol 2018; 92:2001-2012. [PMID: 29605894 DOI: 10.1007/s00204-018-2198-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 03/21/2018] [Indexed: 01/18/2023]
Abstract
Experimental and epidemiological data have shown that acute myeloid leukemia in early-age (i-AML) originates prenatally. The risk association between transplacental exposure to benzene metabolites and i-AML might be influenced by genetic susceptibility. In this study, we investigated the relationship between genetic polymorphisms in CYP2E1, EPHX1, MPO, NQO1, GSTM1 and GSTT1 genes, and i-AML risk. The study included 101 i-AMLs and 416 healthy controls. Genomic DNA from study subjects was purified from bone marrow or peripheral blood aspirates and genotyped for genetic polymorphisms by real-time PCR allelic discrimination, Sanger sequencing and multiplex PCR. Crude and adjusted odds ratios (OR, adjOR, respectively) with 95% confidence intervals (95% CI) were assessed using unconditional logistic regression to estimate the magnitude of risk associations. EPHX1 rs1051740 T>C was associated with i-AML risk under the co-dominant (adjOR 3.04, P = 0.003) and recessive (adjOR 2.99, P = 0.002) models. In stratified analysis, EPHX1 rs1051740 was associated with increased risk for i-AML with KMT2A rearrangement (adjOR 3.06, P = 0.045), i-AML with megakaryocytic differentiation (adjOR 5.10, P = 0.008), and i-AML with type I mutation (adjOR 2.02, P = 0.037). EPHX1 rs1051740-rs2234922 C-G haplotype was also associated with increased risk for i-AML (adjOR 2.55, P = 0.043), and for i-AML with KMT2A rearrangement (adjOR 3.23, P = 0.034). Since EPHX1 enzyme is essential in cellular defense against epoxides, the diminished enzymatic activity conferred by the variant allele C could explain the risk associations found for i-AML. In conclusion, EPHX1 rs1051740 plays an important role in i-AML's genetic susceptibility by modulating the carcinogenic effects of epoxide exposures in the bone marrow.
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Affiliation(s)
- Gisele Dallapicola Brisson
- Pediatric Hematology-Oncology Research Program, Research Center, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti 37, Rio de Janeiro, RJ, Brazil
| | - Bruno de Almeida Lopes
- Pediatric Hematology-Oncology Research Program, Research Center, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti 37, Rio de Janeiro, RJ, Brazil
| | - Francianne Gomes Andrade
- Pediatric Hematology-Oncology Research Program, Research Center, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti 37, Rio de Janeiro, RJ, Brazil
| | - Filipe Vicente Dos Santos Bueno
- Pediatric Hematology-Oncology Research Program, Research Center, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti 37, Rio de Janeiro, RJ, Brazil
| | - Ingrid Sardou-Cezar
- Pediatric Hematology-Oncology Research Program, Research Center, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti 37, Rio de Janeiro, RJ, Brazil
| | - Bruno Alves de Aguiar Gonçalves
- Pediatric Hematology-Oncology Research Program, Research Center, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti 37, Rio de Janeiro, RJ, Brazil
| | - Eugênia Terra-Granado
- Pediatric Hematology-Oncology Research Program, Research Center, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti 37, Rio de Janeiro, RJ, Brazil
| | - Flávio Henrique Paraguassú-Braga
- Centro de Processamento e Armazenamento Celular, Banco de Sangue de Cordão Umbilical, Centro de Transplante e Terapia Celular, Instituto Nacional de Câncer (INCA), Praça da Cruz Vermelha 23, Rio de Janeiro, RJ, Brazil
| | - Maria S Pombo-de-Oliveira
- Pediatric Hematology-Oncology Research Program, Research Center, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti 37, Rio de Janeiro, RJ, Brazil.
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18
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Li WX, Li YK, Lin HT. Correlation between survivin polymorphism and acute leukemia of children. Exp Ther Med 2018; 15:2941-2945. [PMID: 29456699 PMCID: PMC5795526 DOI: 10.3892/etm.2018.5740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 12/12/2017] [Indexed: 12/13/2022] Open
Abstract
The correlation between the variations in the polymorphic sites of survivin, rs9904341C/G and rs8073069C/G, and the pathogenesis of acute leukemia, as well as the guiding significance in clinical practice were investigated. We enrolled a total of 182 children with acute leukemia and 200 healthy children as the subjects. In accordance with the case-control method, the polymerase chain reaction was carried out for genetic typing of the two polymorphic sites, rs9904341C/G and rs8073069C/G. In the case group and the healthy group, the frequencies of C and G alleles in rs9904341C/G of survivin were 59.3 and 41.7%, and 46.7 and 50.3%, respectively, and the pairwise comparison showed statistically significant differences (P=0.008). Additionally, the frequencies of genotypes, C/C, C/G and G/G, were 38.5 and 41.7%; 19.8 and 26.5%; 16.5 and 27.0% in the case group and the healthy group, respectively, and the differences in comparisons showed statistical significance (P=0.033). The genotype frequency of C/C in the case group was 38.5%, significantly higher than that in the healthy group (26.5%). Compared with C/C, the risk coefficient of leukemia in patients with genotypes of C/G or G/G was significantly decreased. In the case group and the healthy group, the frequencies of C and G alleles in rs8073069C/G of survivin were 30.5 and 69.5%; 27.7 and 72.3%, respectively, and the pairwise comparison showed no statistically significant differences (P=0.404). Additionally, the frequencies of genotypes, C/C, C/G and G/G, were 11 and 39.0%; 50.0 and 9.0%; 37.5 and 53.5% in the case group and the healthy group, respectively, and the differences in comparisons showed no statistical significance (P=0.62). Compared with the genotype of C/C, we found that the risk of leukemia was not affected in patients with genotypes of C/G and G/G. In conclusion, the SNP of rs9904341C/G in survivin may be correlated with the risk of acute leukemia, and compared with C/C genotype, patients with C/G or G/G may have a decreased risk of acute leukemia. In survivin, rs8073069C/G may have no correlation with the risk of acute leukemia.
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Affiliation(s)
- Wei-Xi Li
- School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510000, P.R. China.,Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan 650000, P.R. China
| | - Yong-Kun Li
- Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan 650000, P.R. China
| | - Hai-Tao Lin
- Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan 650000, P.R. China
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19
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Choi EM, Suh KS, Jung WW, Park SY, Chin SO, Rhee SY, Pak YK, Chon S. Actein alleviates 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated cellular dysfunction in osteoblastic MC3T3-E1 cells. ENVIRONMENTAL TOXICOLOGY 2017; 32:2455-2470. [PMID: 28836330 DOI: 10.1002/tox.22459] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 07/30/2017] [Accepted: 08/06/2017] [Indexed: 06/07/2023]
Abstract
The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to affect bone metabolism. We evaluated the protective effects of the triterpene glycoside actein from the herb black cohosh against TCDD-induced toxicity in MC3T3-E1 osteoblastic cells. We found that TCDD significantly reduced cell viability and increased apoptosis and autophagy in MC3T3-E1 osteoblastic cells (P < .05). In addition, TCDD treatment resulted in a significant increase in intracellular calcium concentration, mitochondrial membrane potential collapse, reactive oxygen species (ROS) production, and cardiolipin peroxidation, whereas pretreatment with actein significantly mitigated these effects (P < .05). The effects of TCDD on extracellular signal-related kinase (ERK), aryl hydrocarbon receptor, aryl hydrocarbon receptor repressor, and cytochrome P450 1A1 levels in MC3T3-E1 cells were significantly inhibited by actein. The levels of superoxide dismutase, ERK1, and nuclear factor kappa B mRNA were also effectively restored by pretreatment with actein. Furthermore, actein treatment resulted in a significant increase in alkaline phosphatase (ALP) activity and collagen content, as well as in the expression of genes associated with osteoblastic differentiation (ALP, type I collagen, osteoprotegerin, bone sialoprotein, and osterix). This study demonstrates the underlying molecular mechanisms of cytoprotection exerted by actein against TCDD-induced oxidative stress and osteoblast damage.
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Affiliation(s)
- Eun Mi Choi
- Department of Endocrinology & Metabolism, School of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Kwang Sik Suh
- Department of Endocrinology & Metabolism, School of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Woon-Won Jung
- Department of Biomedical Laboratory Science, College of Health Sciences, Cheongju University, Cheongju, Chungbuk, 28503, Republic of Korea
| | - So Young Park
- Department of Medicine, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Sang Ouk Chin
- Department of Endocrinology & Metabolism, School of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Sang Youl Rhee
- Department of Endocrinology & Metabolism, School of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Youngmi Kim Pak
- Department of Physiology, School of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Suk Chon
- Department of Endocrinology & Metabolism, School of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
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20
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Pombo-de-Oliveira MS, Andrade FG, Brisson GD, Dos Santos Bueno FV, Cezar IS, Noronha EP. Acute myeloid leukaemia at an early age: Reviewing the interaction between pesticide exposure and KMT2A-rearrangement. Ecancermedicalscience 2017; 11:782. [PMID: 29225689 PMCID: PMC5718248 DOI: 10.3332/ecancer.2017.782] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Indexed: 12/29/2022] Open
Abstract
Acute myeloid leukaemia (AML) in early childhood is characterised by a high frequency of recurrent genomic aberrations associated with distinct myeloid subtypes, clinical outcomes and pathogenesis. Genomic instability is the first step of pathogenic mechanism in early childhood AML. A sum of adverse events is necessary to the development of infant AML (i-AML), which includes latency of biochemical-molecular and cellular effects. Inherited genetic susceptibility associated with exposures to biotransformation substances can modulate the risk of DNA damage and it is a very important piece in the pathogenic puzzle. In this review, we have aimed to explore the chain of events in the time-points of the natural history of i-AML, which includes maternal exposures during pregnancy, the speculations about the formation of somatic mutations during foetal life and the secondary genomic aberrations associated with i-AML. The modulation of risk conferred by xenobiotic metabolism´s genes variants is the bottom line of the pathogenic process. Since we have conducted observational and molecular investigations in early childhood leukaemia, the data focused here is based on Brazilian findings with summarised results of our experience with epidemiological and molecular studies in early-age leukaemia.
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Affiliation(s)
- Maria S Pombo-de-Oliveira
- Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil
| | - Francianne Gomes Andrade
- Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil
| | - Gisele Dallapicola Brisson
- Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil
| | - Filipe Vicente Dos Santos Bueno
- Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil
| | - Ingrid Sardou Cezar
- Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil
| | - Elda Pereira Noronha
- Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil
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21
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Rahmani M, Talebi M, Hagh MF, Feizi AAH, Solali S. Aberrant DNA methylation of key genes and Acute Lymphoblastic Leukemia. Biomed Pharmacother 2017; 97:1493-1500. [PMID: 29793312 DOI: 10.1016/j.biopha.2017.11.033] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 10/27/2017] [Accepted: 11/03/2017] [Indexed: 02/06/2023] Open
Abstract
DNA methylation is a dynamic process influencing gene expression by altering either coding or non-coding loci. Despite advances in treatment of Acute Lymphoblastic Leukemia (ALL); relapse occurs in approximately 20% of patients. Nowadays, epigenetic factors are considered as one of the most effective mechanisms in pathogenesis of malignancies. These factors are reversible elements which can be potentially regarded as therapy targets and disease prognosis. DNA methylation, which primarily serves as transcriptional suppressor, mostly occurs in CpG islands of the gene promoter regions. This was shown as a key epigenetic factor in inactivating various tumor suppressor genes during cancer initiation and progression. We aimed to review methylation status of key genes involved in hematopoietic malignancies such as IKZF1, CDKN2B, TET2, CYP1B1, SALL4, DLC1, DLX family, TP73, PTPN6, and CDKN1C; and their significance in pathogenesis of ALL. The DNA methylation alterations in promoter regions of the genes have been shown to play crucial roles in tumorigenesis. Methylation -based inactivation of these genes has also been reported as associated with prognosis in acute leukemia. In this review, we also addressed the association of gene expression and methylation pattern in ALL patients.
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Affiliation(s)
- Mina Rahmani
- Department of Immunology, Division of Hematology and Transfusion Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Stem cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Talebi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Farshdousti Hagh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Saeed Solali
- Department of Immunology, Division of Hematology and Transfusion Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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22
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Palma-Cano LE, Córdova EJ, Orozco L, Martínez-Hernández A, Cid M, Leal-Berumen I, Licón-Trillo A, Lechuga-Valles R, González-Ponce M, González-Rodríguez E, Moreno-Brito V. GSTT1 and GSTM1 null variants in Mestizo and Amerindian populations from northwestern Mexico and a literature review. Genet Mol Biol 2017; 40:727-735. [PMID: 29111561 PMCID: PMC5738617 DOI: 10.1590/1678-4685-gmb-2016-0142] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 04/05/2017] [Indexed: 12/21/2022] Open
Abstract
The GSTT1 and GSTM1 genes are key molecules in
cellular detoxification. Null variants in these genes are associated with
increase susceptibility to developing different types of cancers. The aim of
this study was to determine the prevalence of GSTT1 and
GSTM1 null genotypes in Mestizo and Amerindian individuals
from the Northwestern region of Mexico, and to compare them with those reported
worldwide. GSTT1 and GSTM1 null variants were
genotyped by multiplex PCR in 211 Mestizos and 211 Amerindian individuals.
Studies reporting on frequency of GSTT1 and
GSTM1 null variants worldwide were identified by a PubMed
search and their geographic distribution were analyzed. We found no significant
differences in the frequency of the null genotype for GSTT1 and
GSM1 genes between Mestizo and Amerindian individuals.
Worldwide frequencies of the GSTT1 and GSTM1
null genotypes ranges from 0.10 to 0.51, and from 0.11 to 0.67, respectively.
Interestingly, in most countries the frequency of the GSTT1
null genotype is common or frequent (76%), whereas the frequency of the
GSMT1 null genotype is very frequent or extremely frequent
(86%). Thus, ethnic-dependent differences in the prevalence of
GSTT1 and GSTM1 null variants may
influence the effect of environmental carcinogens in cancer risk.
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Affiliation(s)
- Luz Elena Palma-Cano
- Department of Biochemistry, Faculty of Medicine and Biomedical Science, Autonomus University of Chihuahua, Chihuahua, Chihuahua, Mexico
| | - Emilio J Córdova
- Department of Clinical Research, National Institute of Genomic Medicine, Mexico City, Mexico
| | - Lorena Orozco
- Department of Clinical Research, National Institute of Genomic Medicine, Mexico City, Mexico
| | | | - Miguel Cid
- Department of Clinical Research, National Institute of Genomic Medicine, Mexico City, Mexico
| | - Irene Leal-Berumen
- Department of Biochemistry, Faculty of Medicine and Biomedical Science, Autonomus University of Chihuahua, Chihuahua, Chihuahua, Mexico
| | - Angel Licón-Trillo
- Department of Biochemistry, Faculty of Medicine and Biomedical Science, Autonomus University of Chihuahua, Chihuahua, Chihuahua, Mexico
| | - Ruth Lechuga-Valles
- Department of Molecular Biology, Faculty of Zootechnics and Ecology, Autonomus University of Chihuahua, Chihuahua, Chihuahua, Mexico
| | - Mauricio González-Ponce
- Department of Biochemistry, Faculty of Medicine and Biomedical Science, Autonomus University of Chihuahua, Chihuahua, Chihuahua, Mexico
| | - Everardo González-Rodríguez
- Department of Molecular Biology, Faculty of Zootechnics and Ecology, Autonomus University of Chihuahua, Chihuahua, Chihuahua, Mexico
| | - Verónica Moreno-Brito
- Department of Biochemistry, Faculty of Medicine and Biomedical Science, Autonomus University of Chihuahua, Chihuahua, Chihuahua, Mexico
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Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy. Pharmacol Rep 2017; 69:504-511. [DOI: 10.1016/j.pharep.2017.01.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 01/10/2017] [Accepted: 01/16/2017] [Indexed: 12/11/2022]
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Abstract
In first part of this study, a systematic review was designed to explore the involvement of CYP1A1 and GSTP1 genes in breast cancerogenesis. Based on systematic review, we designed a study to screen CYP1A1 and GSTP1 genes for mutation and their possible association with breast carcinogenesis. A total of 400 individuals were collected and analyzed by PCR-SSCP. After sequence analysis of coding region of CYP1A1 we identified eleven mutations in different exons of respective gene. Among these eleven mutations, ~3 folds increased breast cancer risk was found associated with Asp82Glu mutation (OR 2.99; 95% CI 1.26-7.09), with Ser83Thr mutation (OR 2.99; 95% CI 1.26-7.09) and with Glu86Ala mutation (OR 3.18; 95% CI 1.27-7.93) in cancer patients compared to controls. Furthermore, ~4 folds increase in breast cancer risk was found associated with Asp347Glu, Phe398Tyr and 5178delT mutations (OR 3.92; 95% CI 1.35-11.3) in patients compared to controls. The sequence analysis of GSTP1 resulted in identification of total five mutations. Among these five mutations, ~3 folds increase in breast cancer risk was observed associated with 1860G>A mutation, with 1861-1876delCAGCCCTCTGGAGTGG mutation (OR 2.70; 95% CI 1.10-6.62) and with 1861C>A mutation (OR 2.97; 95% CI 1.01-8.45) in cancer patients compared to controls. Furthermore, ~5 folds increase in breast cancer risk was associated with 1883G>T mutation (OR 4.75; 95% CI 1.46-15.3) and ~6 folds increase in breast cancer risk was found associated with Iso105Val mutation (OR 6.43; 95% CI 1.41-29.3) in cancer patients compared to controls. Our finding, based on systematic review and experimental data suggest that the polymorphic CYP1A1 and GSTP1 genes may contribute to risk of developing breast cancer.
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Polymorphisms and haplotypes of the CYP2B6 detoxification gene in the predisposition of Acute Myeloid Leukemia (AML) and induction of its cytogenetic abnormalities. Cancer Genet 2016; 209:525-533. [PMID: 27865701 DOI: 10.1016/j.cancergen.2016.10.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 10/25/2016] [Accepted: 10/26/2016] [Indexed: 12/13/2022]
Abstract
CYP2B6 is a polymorphic detoxification gene which plays a vital role in the degradation of genotoxic compounds. In this study we hypothesized that inadequate detoxification due to CYP2B6 polymorphisms may contribute to AML. To evaluate the potential impact of CYP2B6 polymorphisms on AML development and induction of its specific chromosomal abnormalities we studied C777A and A785G polymorphisms for the first time in AML. Furthermore, we investigated the co-existence of the above polymorphisms with G516T polymorphism to determine the CYP2B6 high-risk haplotypes in AML susceptibility. Our study included 619 AML patients and 430 healthy donors. Concerning C777A CYP2B6 polymorphism, no significant difference was found between patients and controls. However, A785G CYP2B6 polymorphism showed a statistically higher frequency of the variant genotypes in patients (48.2%), mainly in secondary AML patients (49.1%) than in controls (26.1%). Moreover, an increased frequency of the variant genotypes was found in those with abnormal karyotypes, especially with -7/del(7q), -5/del(5q), +8, inv(16) and t(8;21). The combination of the three CYP2B6 polymorphisms (G516T, C777A & A785G) revealed seven haplotypes. Four out of six haplotypes with at least one mutant allele were significantly associated with an increased risk for AML. Interestingly, T516A777G785 haplotype, where the three mutant alleles co-existed, had ~3-fold increased risk to be found in patients than controls. The association between haplotypes and cytogenetic aberrations revealed a positive correlation between specific CYP2B6 haplotypes and AML cytogenetic abnormalities. Our data suggest that A785G CYP2B6 gene polymorphism and specific CYP2B6 haplotypes may contribute to AML and its specific chromosomal aberrations.
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26
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Cerliani MB, Pavicic W, Gili JA, Klein G, Saba S, Richard S. Cigarette smoking, dietary habits and genetic polymorphisms in GSTT1, GSTM1 and CYP1A1 metabolic genes: A case-control study in oncohematological diseases. World J Clin Oncol 2016; 7:395-405. [PMID: 27777882 PMCID: PMC5056331 DOI: 10.5306/wjco.v7.i5.395] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 09/02/2016] [Accepted: 09/22/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To analyze the association between oncohematological diseases and GSTT1/GSTM1/CYP1A1 polymorphisms, dietary habits and smoking, in an argentine hospital-based case-control study.
METHODS This hospital-based case-control study involved 125 patients with oncohematological diseases and 310 control subjects. A questionnaire was used to obtain sociodemographic data and information about habits. Blood samples were collected, and DNA was extracted using salting out methods. Deletions in GSTT1 and GSTM1 (null genotypes) were addressed by PCR. CYP1A1 MspI polymorphism was detected by PCR-RFLP. Odds ratio (OR) and 95%CI were calculated to estimate the association between each variable studied and oncohematological disease.
RESULTS Women showed lower risk of disease compared to men (OR 0.52, 95%CI: 0.34-0.82, P = 0.003). Higher levels of education (> 12 years) were significantly associated with an increased risk, compared to complete primary school or less (OR 3.68, 95%CI: 1.82-7.40, P < 0.001 adjusted for age and sex). With respect to tobacco, none of the smoking categories showed association with oncohematological diseases. Regarding dietary habits, consumption of grilled/barbecued meat 3 or more times per month showed significant association with an increased risk of disease (OR 1.72, 95%CI: 1.08-2.75, P = 0.02). Daily consumption of coffee also was associated with an increased risk (OR 1.77, 95%CI: 1.03-3.03, P = 0.03). Results for GSTT1, GSTM1 and CYP1A1 polymorphisms showed no significant association with oncohematological diseases. When analyzing the interaction between polymorphisms and tobacco smoking or dietary habits, no statistically significant associations that modify disease risk were found.
CONCLUSION We reported an increased risk of oncohematological diseases associated with meat and coffee intake. We did not find significant associations between genetic polymorphisms and blood cancer.
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Lu J, Zhao Q, Zhai YJ, He HR, Yang LH, Gao F, Zhou RS, Zheng J, Ma XC. Genetic polymorphisms of CYP1A1 and risk of leukemia: a meta-analysis. Onco Targets Ther 2015; 8:2883-2902. [PMID: 26491362 PMCID: PMC4608596 DOI: 10.2147/ott.s92259] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The associations between CYP1A1 polymorphisms and risk of leukemia have been studied extensively, but the results have been inconsistent. Therefore, in this study, we performed a meta-analysis to clarify associations of three CYP1A1 polymorphisms (T3801C, A2455G, and C4887A) with the risks of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Medline, EMBASE, and China National Knowledge Infrastructure databases were searched to collect relevant studies published up to April 20, 2015. The extracted data were analyzed statistically, and pooled odds ratios with 95% confidence intervals were calculated to quantify the associations. Overall, 26 publications were included. Finally, T3801C was associated with an increased risk of AML in Asians under the dominant model. For A2455G, the risk of ALL was increased among Caucasians in the recessive model and the allele-contrast model; A2455G was also associated with an increased risk of CML among Caucasians under the recessive model, dominant model, and allele-contrast model. For C4887A, few of the included studies produced data. In conclusion, the results suggest that Asians carrying the T3801C C allele might have an increased risk of AML and that Caucasians with the A2455G GG genotype might have an increased risk of ALL. Further investigations are needed to confirm these associations.
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Affiliation(s)
- Jun Lu
- Clinical Research Center, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Qian Zhao
- Clinical Research Center, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
- College of Pharmacy, Xi’an Medical University, Xi’an, Shaanxi, People’s Republic of China
| | - Ya-Jing Zhai
- Department of Pharmacy, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Hai-Rong He
- Clinical Research Center, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Li-Hong Yang
- Clinical Research Center, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Fan Gao
- Clinical Research Center, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Rong-Sheng Zhou
- Department of Anesthesiology, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Jie Zheng
- Clinical Research Center, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Xian-Cang Ma
- Clinical Research Center, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
- Department of Psychiatry, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
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Carvalho DC, Wanderley AV, Amador MAT, Fernandes MR, Cavalcante GC, Pantoja KBCC, Mello FAR, de Assumpção PP, Khayat AS, Ribeiro-Dos-Santos Â, Santos S, Dos Santos NPC. Amerindian genetic ancestry and INDEL polymorphisms associated with susceptibility of childhood B-cell Leukemia in an admixed population from the Brazilian Amazon. Leuk Res 2015; 39:S0145-2126(15)30361-1. [PMID: 26321572 DOI: 10.1016/j.leukres.2015.08.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 07/14/2015] [Accepted: 08/15/2015] [Indexed: 12/29/2022]
Abstract
Acute lymphoblastic leukemia (ALL) is a malignant tumor common in children. Studies of genetic susceptibility to cancer using biallelic insertion/deletion (INDEL) type polymorphisms associated with cancer development pathways may help to clarify etymology of ALL. In this study, we investigate the role of eight functional INDEL polymorphisms and influence of genetic ancestry to B-cell ALL susceptibility in children of Brazilian Amazon population, which has a high degree of inter-ethnic admixture. Ancestry analysis was estimated using a panel of 48 autosomal ancestry informative markers. 130 B-cell ALL patients and 125 healthy controls were included in this study. The odds ratios and 95% confidence intervals were adjusted for confounders. The results indicated an association between the investigated INDEL polymorphisms in CASP8 (rs3834129), CYP19A1 (rs11575899) e XRCC1 (rs3213239) genes in the development of B-cell ALL. The carriers of Insertion/Insertion (Ins/Ins) genotype of the polymorphism in CASP8 gene presented reduced chances of developing B-cell ALL (P=0.001; OR=0.353; 95% CI=0.192-0.651). The Deletion/Deletion (Del/Del) genotype of the polymorphism in CYP19A1 gene was associated to a lower chance of developing B-cell ALL (P=3.35×10-6; OR=0.121; 95% CI=0.050-0.295), while Del/Del genotype of the polymorphism in XRCC1 gene was associated to a higher chance of developing B-cell ALL (P=2.01×10-4; OR=6.559; 95% CI=2.433-17.681). We also found that Amerindian ancestry correlates with the risk of B-cell ALL. For each increase of 10% in the Amerindian ancestry results in 1.4-fold chances of developing B-cell ALL (OR=1.406; 95% IC=1.123-1.761), while each increase of 10% in the European ancestry presents a protection effect in the development of B-cell ALL (OR=0.666; 95% IC=0.536-0.827). The results suggest that genetic factors influence leukemogenesis and might be explored in the stratification of B-cell ALL risk in admixed populations.
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Affiliation(s)
- Darlen C Carvalho
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, PA, Brazil; Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Belém, Pará, PA, Brazil.
| | - Alayde V Wanderley
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, PA, Brazil; Hospital Ophir Loyola, Departamento de Pediatria, Belém, Pará, PA, Brazil.
| | - Marcos A T Amador
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Belém, Pará, PA, Brazil.
| | - Marianne R Fernandes
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, PA, Brazil; Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Belém, Pará, PA, Brazil.
| | - Giovanna C Cavalcante
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, PA, Brazil; Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Belém, Pará, PA, Brazil.
| | - Karla B C C Pantoja
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, PA, Brazil; Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Belém, Pará, PA, Brazil.
| | - Fernando A R Mello
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, PA, Brazil.
| | - Paulo P de Assumpção
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, PA, Brazil; Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil.
| | - André S Khayat
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, PA, Brazil.
| | - Ândrea Ribeiro-Dos-Santos
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, PA, Brazil; Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Belém, Pará, PA, Brazil.
| | - Sidney Santos
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, PA, Brazil; Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Belém, Pará, PA, Brazil.
| | - Ney P C Dos Santos
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, PA, Brazil; Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Belém, Pará, PA, Brazil.
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Guven M, Unal S, Erhan D, Ozdemir N, Baris S, Celkan T, Bostancı M, Batar B. Role of glutathione S-transferase M1, T1 and P1 gene polymorphisms in childhood acute lymphoblastic leukemia susceptibility in a Turkish population. Meta Gene 2015; 5:115-9. [PMID: 26137447 PMCID: PMC4484718 DOI: 10.1016/j.mgene.2015.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 05/29/2015] [Accepted: 06/06/2015] [Indexed: 11/15/2022] Open
Abstract
The variations between different individuals in the xenobiotic metabolizing enzymes' activity were shown to modify susceptibility to childhood acute lymphoblastic leukemia (ALL). Polymorphisms associated with genes coding for the glutathione S-transferase (GST) enzyme were known to affect the metabolism of different carcinogens. The aim of this study was to evaluate the influence of the GSTM1 and GSTT1 deletion polymorphisms, and the GSTP1 Ile105Val single nucleotide polymorphism (SNP) on the susceptibility to childhood ALL. The study was conducted in 95 children with ALL and 190 healthy control subjects from the Turkish population. The data revealed no difference in the prevalence of the GSTM1 and GSTT1 null genotypes between the childhood ALL patients and the controls. No association was found between GSTP1 Ile105Val variants and the susceptibility to childhood ALL, separately or in combination. Our findings suggested that the status of heritable GST polymorphism might not influence the risk of developing childhood ALL. Studies with a larger sample size are needed to evaluate and confirm the validity of our results.
There was no association between any of the GST variants and the risk of childhood ALL in Turkish Population The alleles of GST P1 were similar in cases and controls for childhood ALL There was not statistically significant relationship between the combined GSTM1, GSTP1, and GSTT1 genotypes and the risk of childhood ALL
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Key Words
- ALL, acute lymphoblastic leukemia
- AML, acute myeloid leukemia
- CI, confidence interval
- CLL, chronic lymphocytic leukemia
- Childhood ALL
- Disease susceptibility
- FAB, French–American–British
- GST, glutathione S-transferase
- Genetic risk
- Glutathione S-transferase
- HWE, Hardy–Weinberg Equilibrium
- NHL, non-Hodgkin lymphoma
- OR, odds ratio
- PCR, polymerase chain reaction
- Polymorphism
- ROS, reactive oxygen species
- SD, mean and standard deviation
- SNP, single nucleotide polymorphism
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Affiliation(s)
- Mehmet Guven
- Department of Medical Biology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Selin Unal
- Department of Medical Biology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Duygu Erhan
- Department of Medical Biology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Nihal Ozdemir
- Department of Pediatric Hematology-Oncology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Safa Baris
- Department of Pediatric Hematology-Oncology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Tiraje Celkan
- Department of Pediatric Hematology-Oncology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Merve Bostancı
- Department of Medical Biology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Bahadir Batar
- Department of Medical Biology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
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Brisson GD, Alves LR, Pombo-de-Oliveira MS. Genetic susceptibility in childhood acute leukaemias: a systematic review. Ecancermedicalscience 2015; 9:539. [PMID: 26045716 PMCID: PMC4448992 DOI: 10.3332/ecancer.2015.539] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Indexed: 11/06/2022] Open
Abstract
Acute leukaemias (AL) correspond to 25-35% of all cancer cases in children. The aetiology is still sheltered, although several factors are implicated in causality of AL subtypes. Childhood acute leukaemias are associated with genetic syndromes (5%) and ionising radiation as risk factors. Somatic genomic alterations occur during fetal life and are initiating events to childhood leukaemia. Genetic susceptibility has been explored as a risk factor, since environmental exposure of the child to xenobiotics, direct or indirectly, can contribute to the accumulation of somatic mutations. Hence, a systematic review was conducted in order to understand the association between gene polymorphisms and childhood leukaemia risk. The search was performed in the electronic databases PubMed, Lilacs, and Scielo, selecting articles published between 1995 and 2013. This review included 90 case-control publications, which were classified into four groups: xenobiotic system (n = 50), DNA repair (n = 16), regulatory genes (n = 15), and genome wide association studies (GWAS) (n = 9). We observed that the most frequently investigated genes were: NQO1, GSTM1, GSTT1, GSTP1, CYP1A1, NAT2, CYP2D6, CYP2E1, MDR1 (ABCB1), XRCC1, ARID5B, and IKZF1. The collected evidence suggests that genetic polymorphisms in CYP2E1, GSTM1, NQO1, NAT2, MDR1, and XRCC1 are capable of modulating leukaemia risk, mainly when associated with environmental exposures, such as domestic pesticides and insecticides, smoking, trihalomethanes, alcohol consumption, and x-rays. More recently, genome wide association studies identified significant associations between genetic polymorphisms in ARID5B e IKZF1 and acute lymphoblastic leukaemia, but only a few studies have replicated these results until now. In conclusion, genetic susceptibility contributes to the risk of childhood leukaemia through the effects of gene-gene and gene-environment interactions.
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Affiliation(s)
- Gisele D Brisson
- Paediatric Haematology-Oncology Programme, Research Centre, Instituto Nacional de Câncer, Rio de Janeiro, Brazil, 20231050
| | - Liliane R Alves
- Pharmacy Service, Multiprofessional Residency Programme, Instituto Nacional de Câncer, Rio de Janeiro, Brazil, 20231050
| | - Maria S Pombo-de-Oliveira
- Paediatric Haematology-Oncology Programme, Research Centre, Instituto Nacional de Câncer, Rio de Janeiro, Brazil, 20231050
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31
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Weich N, Nuñez MC, Galimberti G, Elena G, Acevedo S, Larripa I, Fundia AF. Polymorphic variants of GSTM1, GSTT1, and GSTP1 genes in childhood acute leukemias: A preliminary study in Argentina. ACTA ACUST UNITED AC 2015; 20:511-6. [PMID: 25799091 DOI: 10.1179/1607845415y.0000000007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND AND AIM Despite recent major advances in leukemia research, the etiopathogenesis of childhood leukemias remains far elusive. Individual predisposing factors, including polymorphisms in detoxification enzymes, have been implicated in the molecular pathogenesis and heterogeneity of the disease. Genetic polymorphisms of glutathione S-transferases (GSTs) that alter enzyme activity could be an additional factor that increases the risk of acute leukemia, but data are lacking in Argentina. We assessed the association of GST polymorphisms and the susceptibility to childhood leukemia in Argentina by conducting an exploratory case-control study and correlated patients' genotype to clinical and biological features. METHODS Deletion polymorphisms in GSTM1 and GSTT1 genes and the single nucleotide polymorphism in GSTP1 c.313A>G (rs1695; p.105Ile>Val) were genotyped by PCR-RFLP in 36 patients and 133 healthy individuals. RESULTS GSTM1-null genotype was associated with a lower risk of developing acute leukemia (P = 0.013; OR: 0.31; CI: 0.12-0.80), while GSTP1-GG variants displayed an increased risk (P = 0.01; OR: 3.9; CI: 1.85-8.2). However, no differences were found for GSTT1 gene. Conclusion These preliminary results, to be validated in a larger population from Argentina, suggest that the development of pediatric leukemia may be differentially influenced by polymorphic variants in GST genes.
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Tang ZH, Zhang C, Cheng P, Sun HM, Jin Y, Chen YJ, Huang F. Glutathione-S-transferase polymorphisms (GSTM1, GSTT1 and GSTP1) and acute leukemia risk in Asians: a meta-analysis. Asian Pac J Cancer Prev 2014; 15:2075-81. [PMID: 24716937 DOI: 10.7314/apjcp.2014.15.5.2075] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The association between glutathione-S-transferase polymorphisms (GSTM1, GSTT1 and GSTP1) and risk of acute leukemia in Asians remains controversial. This study was therefore designed to evaluate the precise association in 23 studies identified by a search of PubMed and several other databases, up to December 2013. Using random or fixed effects models odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. Heterogeneity across studies was assessed, and funnel plots were constructed to test for publication bias. The meta-analysis showed positive associations between GST polymorphisms (GSTM1 and GSTT1 but not GSTP1) and acute leukemia risk [(OR=1.47, 95% CI 1.18-1.83); (OR=1.32, 95% CI 1.07-1.62); (OR=1.01, 95% CI 0.84-1.23), respectively] and heterogeneity between the studies. The results suggested that the GSTM1 null genotype and GSTT1null genotype, but not the GSTP1 polymorphism, might be a potential risk factors for acute leukemia. Further well-designed studies are needed to confirm our findings.
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Affiliation(s)
- Zhen-Hai Tang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China E-mail :
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Seven M, Batar B, Unal S, Yesil G, Yuksel A, Guven M. The effect of genetic polymorphisms of cytochrome P450 CYP2C9, CYP2C19, and CYP2D6 on drug-resistant epilepsy in Turkish children. Mol Diagn Ther 2014; 18:229-36. [PMID: 24338437 DOI: 10.1007/s40291-013-0078-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVE Despite the availability of several antiepileptic drugs, drug resistance remains one of the major challenges in epilepsy therapy. Genetic factors are known to play a significant role in the prognosis and treatment of epilepsy. The aim of this study was to determine the frequencies of alleles for CYP2C9, CYP2C19, and CYP2D6 genes in Turkish children with epilepsy, and to investigate the relationship between the genetic polymorphism of these genes with multiple drug resistance in epilepsy patients. METHODS We genotyped 132 epileptic patients (60 drug resistant and 72 drug responsive) and 55 healthy controls for six single nucleotide polymorphisms (SNPs) in CYP2C9, CYP2C19, and CYP2D6. Genotype, allele, and haplotype frequencies were compared between groups. RESULTS The frequencies of CYP2C9*3/*3 genotype and CYP2C9*3 allele, and the haplotype CCGG (CYP2C9*2 C>T, CYP2C9*3 A>C, and CYP2C19*2 G>A, CYP2C19* G>A) were significantly higher in drug-resistant versus -responsive patients. CONCLUSION Our results demonstrated the important role of the CYP2C9*3 allelic variant in preventing epilepsy patients from developing drug resistance. These data suggest that CYP2C9, CYP2C19, and CYP2D6 SNPs and haplotypes may affect the response to antiepileptic drugs.
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Affiliation(s)
- Mehmet Seven
- Department of Medical Genetics, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
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He HR, You HS, Sun JY, Hu SS, Ma Y, Dong YL, Lu J. Glutathione S-transferase gene polymorphisms and susceptibility to acute myeloid leukemia: meta-analyses. Jpn J Clin Oncol 2014; 44:1070-1081. [PMID: 25145382 DOI: 10.1093/jjco/hyu121] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE A large body of evidence has shown the possible relevance of polymorphisms of the genes that encode glutathione S-transferase μ, π and θ (GSTM1, GSTP1 and GST1, respectively) to the susceptibility of acute myeloid leukemia, but the exact association still remains uncertain. Therefore, we performed a meta-analysis to derive a more precise estimation of the relationship. METHODS A comprehensive literature search of PubMed and Web of Knowledge electronic databases was conducted to collect relevant studies until 20 February 2014. References of the retrieved articles were also screened. The extracted data were statistically analyzed, and pooled odds ratios with 95% confidence intervals were calculated to estimate the association strength using Review Manager version 5.2. RESULTS Twenty-nine studies were included in the meta-analysis. The pooled analyses revealed that the GSTM1-null genotype was associated with an increased risk of acute myeloid leukemia in East Asians (P = 0.01; odds ratio = 1.22; 95% confidence interval = 1.05-1.42), and GSTT1-null genotype in Caucasians (P < 0.0001; odds ratio = 1.48; 95% confidence interval = 1.29-1.69). There was also a predilection towards the female gender for both of these polymorphisms. For GSTP1 Ile105Val polymorphism, no significant association was found under any contrast model. In addition, the presence of the double-null genotypes increased the risk of acute myeloid leukemia in both Caucasians and East Asians. CONCLUSIONS This meta-analysis suggested that heritable GST status could influence the risk of developing acute myeloid leukemia.
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Affiliation(s)
- Hai-Rong He
- Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Hai-Sheng You
- Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Jin-Yue Sun
- Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Sa-Sa Hu
- Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Ying Ma
- Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Ya-Lin Dong
- Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Jun Lu
- Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, People's Republic of China
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Glutathione-S-transferase polymorphism and acute lymphoblastic leukemia (ALL) in north Indian children: a case-control study and meta-analysis. J Hum Genet 2014; 59:529-35. [PMID: 25102096 DOI: 10.1038/jhg.2014.66] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 07/03/2014] [Accepted: 07/04/2014] [Indexed: 02/02/2023]
Abstract
Various studies on association of glutathione S-transferase (GST) polymorphisms and childhood acute lymphoblastic leukemia (ALL) have yielded conflicting results. We examined this association among north Indian children and conducted an updated meta-analysis to overcome sample size-related limitations. GSTM1, GSTP1 and GSTT1 genotypes in 100 children with ALL and 300 healthy controls were compared. GSTT1 null mutation (odds ratio (OR) 2.54, 95% confidence interval (CI) 1.50-4.32) and GSTP1 homozygous mutation (OR 3.13, 95%CI 1.48-6.59) were found to increase the risk of childhood ALL, while GSTM1 did not alter the risk. Meta-analysis included 22, 10 and 20 studies examining the association of childhood ALL with GSTM1, GSTP1 and GSTT1 genotypes, respectively. Only GSTM1 genotype (OR 1.29, 95%CI 1.10-1.62) was associated with increased risk in the overall analysis. However, both GSTM1 (OR 1.54, 95%CI 1.12-2.10) and GSTT1 (OR 1.63, 95%CI 1.32-1.99) null genotypes were associated with increased risk in Asian subjects. The risk of developing childhood ALL was not associated with GSTP1 genotype.
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Daraki A, Zachaki S, Koromila T, Diamantopoulou P, Pantelias GE, Sambani C, Aleporou V, Kollia P, Manola KN. The G⁵¹⁶T CYP2B6 germline polymorphism affects the risk of acute myeloid leukemia and is associated with specific chromosomal abnormalities. PLoS One 2014; 9:e88879. [PMID: 24586425 PMCID: PMC3933334 DOI: 10.1371/journal.pone.0088879] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Accepted: 01/16/2014] [Indexed: 01/11/2023] Open
Abstract
The etiology of acute myeloid leukemia (AML) underlies the influence of genetic variants in candidate genes. The CYP2B6 enzyme detoxifies many genotoxic xenobiotics, protecting cells from oxidative damage. The CYP2B6 gene is subjected to a single-nucleotide polymorphism (G⁵¹⁶T) with heterozygotes (GT) and homozygotes (TT) presenting decreased enzymatic activity. This case-control study aimed to investigate the association of CYP2B6 G⁵¹⁶T polymorphism with the susceptibility of AML and its cytogenetic and clinical characteristics. Genotyping was performed on 619 AML patients and 430 healthy individuals using RCR-RFLP and a novel LightSNip assay. The major finding was a statistically higher frequency of the variant genotypes (GT and TT) in patients compared to the controls (GT:38.8% vs 29.8% and TT:9.3% vs 5.3% respectively) (p<0.001). More specifically, a significantly higher frequency of GT+TT genotypes in de novo AML patients (46.6%) and an immensely high frequency of TT in secondary AML (s-AML) (20.5%) were observed. The statistical analysis showed that the variant T allele was approximately 1.5-fold and 2.4-fold higher in de novo and s-AML respectively than controls. Concerning FAB subtypes, the T allele presented an almost 2-fold increased in AML-M2. Interestingly, a higher incidence of the TT genotype was observed in patients with abnormal karyotypes. In particular, positive correlations of the mutant allele were found in patients carrying specific chromosomal aberrations [-7/del(7q), -5/del(5q), +8, +21 or t(8;21)], complex or monosomal karyotypes. Finally, a strikingly higher frequency of TT genotype was also observed in patients stratified to the poor risk group. In conclusion, our results provide evidence for the involvement of the CYP2B6 polymorphism in AML susceptibility and suggest a possible role of the CYP2B6 genetic background on the development of specific chromosomal aberrations.
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Affiliation(s)
- Aggeliki Daraki
- Laboratory of Health Physics, Radiobiology & Cytogenetics, National Centre for Scientific Research (NCSR) “Demokritos”, Athens, Greece
- Department of Genetics & Biotechnology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Sophia Zachaki
- Laboratory of Health Physics, Radiobiology & Cytogenetics, National Centre for Scientific Research (NCSR) “Demokritos”, Athens, Greece
| | - Theodora Koromila
- Department of Genetics & Biotechnology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Paraskevi Diamantopoulou
- Laboratory of Health Physics, Radiobiology & Cytogenetics, National Centre for Scientific Research (NCSR) “Demokritos”, Athens, Greece
| | - Gabriel E. Pantelias
- Laboratory of Health Physics, Radiobiology & Cytogenetics, National Centre for Scientific Research (NCSR) “Demokritos”, Athens, Greece
| | - Constantina Sambani
- Laboratory of Health Physics, Radiobiology & Cytogenetics, National Centre for Scientific Research (NCSR) “Demokritos”, Athens, Greece
| | - Vasiliki Aleporou
- Department of Genetics & Biotechnology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagoula Kollia
- Department of Genetics & Biotechnology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Kalliopi N. Manola
- Laboratory of Health Physics, Radiobiology & Cytogenetics, National Centre for Scientific Research (NCSR) “Demokritos”, Athens, Greece
- * E-mail:
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Daraki A, Zachaki S, Stavropoulou C, Aleporou-Marinou V, Sambani C, Manola KN. Glutathione S-transferase P1 promoter hypermethylation in acute myeloid leukemia: association with A³¹³G germline polymorphism and chromosomal abnormalities. Leuk Lymphoma 2014; 55:2637-9. [PMID: 24547706 DOI: 10.3109/10428194.2014.894192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Aggeliki Daraki
- Laboratory of Health Physics, Radiobiology and Cytogenetics, National Center for Scientific Research (NCSR) "Demokritos" , Athens , Greece
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Association between the CYP1A1 T3801C polymorphism and risk of cancer: Evidence from 268 case–control studies. Gene 2014. [PMID: 24498651 DOI: 10.1016/j.gene.2013.10.025] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Tang Q, Li J, Zhang S, Yuan B, Sun H, Wu D, Lu C, Wu W, Xia Y, Ding H, Hu L, Chen D, Sha J, Wang X. GSTM1 and GSTT1 null polymorphisms and childhood acute leukemia risk: evidence from 26 case-control studies. PLoS One 2013; 8:e78810. [PMID: 24194954 PMCID: PMC3806859 DOI: 10.1371/journal.pone.0078810] [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: 06/13/2013] [Accepted: 09/16/2013] [Indexed: 12/12/2022] Open
Abstract
Several molecular epidemiological studies have been conducted to examine the association between glutathione S-transferase mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) null polymorphisms and childhood acute leukemia; however, the conclusions remain controversial. We performed an extensive meta-analysis on 26 published case-control studies with a total of 3252 cases and 5024 controls. Crude odds ratios (ORs) with 95% confidence interval were used to assess the strength of association between childhood acute leukemia risk and polymorphisms of GSTM1 and GSTT1. With respect to GSTM1 polymorphism, significantly increased risk of childhood acute leukemia was observed in the overall analysis (OR = 1.30; 95%CI, 1.11-1.51). Furthermore, a stratification analysis showed that the risk of GSTM1 polymorphism are associated with childhood acute leukemia in group of Asians (OR = 1.94; 95%CI, 1.53-2.46), Blacks (OR = 1.76; 95%CI, 1.07-2.91), ALL (OR = 1.33; 95%CI, 1.13-1.58), '< 100 cases and <100 controls' (OR = 1.79; 95%CI, 1.21-2.64), '≥ 100 cases and ≥ 100 controls' (OR = 1.25; 95%CI, 1.02-1.52), and population-based control source (OR = 1.40; 95%CI, 1.15-1.69). With respect to GSTT1 polymorphism, significant association with childhood acute leukemia risk was only found in subgroup of Asian. This meta-analysis supports that GSTM1 null polymorphism is capable of causing childhood acute leukemia susceptibility.
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Affiliation(s)
- Qiuqin Tang
- State Key Laboratory of Reproductive Medicine, Department of Obstetrics, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jing Li
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Public Health, Xuzhou Medical College, Xuzhou, Jiangsu, China
| | - Simin Zhang
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Beilei Yuan
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hong Sun
- Department of Microbial and Molecular SystemsLeuven, Leuven, Belgium
| | - Di Wu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chuncheng Lu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wei Wu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
- State Key Laboratory of Reproductive Medicine, Wuxi Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China
| | - Yankai Xia
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hongjuan Ding
- State Key Laboratory of Reproductive Medicine, Department of Obstetrics, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lingqing Hu
- State Key Laboratory of Reproductive Medicine, Wuxi Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China
| | - Daozhen Chen
- State Key Laboratory of Reproductive Medicine, Wuxi Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China
| | - Jiahao Sha
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xinru Wang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
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Zareifar S, Monabati A, Saeed A, Fakhraee F, Cohan N. The association of glutathione S-transferase gene mutations (including GSTT1 and GSTM1) with the prognostic factors and relapse in acute lymphoblastic leukemia. Pediatr Hematol Oncol 2013; 30:568-73. [PMID: 23444902 DOI: 10.3109/08880018.2013.773474] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. It accounts for one fourth of all childhood cancers and approximately 75% of all childhood leukemias. Some prognostic factors determine the outcome of therapy [e.g. age, sex, initial white blood cell count (WBC), etc.]; however, it is believed that other mechanisms such as glutathione S-transferase (GST) gene mutation, the expression of lung resistance protein (LRP), and multidrug resistance-associated protein (MRP) also plays a role in treatment failure. In this study, GST gene mutations including GSTM1 and GSTT1 were evaluated in patients with leukemia. Thirty newly diagnosed ALL patients younger than 15 years of age participated in the present study. Bone marrow aspiration and biopsy were evaluated for immune phenotyping and DNA was extracted for GST genotyping. All data plus sex, age, initial WBC count, central nervous system (CNS) or testicular involvement, immune phenotype, and outcome (relapse or not) were analyzed statistically. Genotyping showed that 46% were double null, 50% were M1 null and 93.3% were T1 null for GST mutations. There was no statistically significant relationship between GSTT1 and GSTM1 mutations, or between double null status, prognostic factors and relapse (P > .05). So, although the results of GST mutations were consistent, it seems that these mutations are not statistically significant.
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Affiliation(s)
- Soheila Zareifar
- Department of Pediatric Hematology/Oncology, Shiraz University of Medical Sciences, Iran.
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Han F, Tan Y, Cui W, Dong L, Li W. Novel insights into etiologies of leukemia: a HuGE review and meta-analysis of CYP1A1 polymorphisms and leukemia risk. Am J Epidemiol 2013; 178:493-507. [PMID: 23707957 DOI: 10.1093/aje/kwt016] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
We conducted a meta-analysis to investigate the association of 2 single nucleotide polymorphisms in the cytochrome P450, family 1, subfamily 1A1 gene (CYP1A1), CYP1A1*2A and CYP1A1*2C, with the risk of developing different subtypes of leukemia in adults and children. A total of 26 studies published between 1999 and 2011 were identified by searching the PubMed, EMBASE, Medline, and Web of Science databases. The odds ratios for the CYP1A1 polymorphisms and leukemia risk were calculated. The cumulative evidence in genetic associations was graded by using the Venice criteria of the Human Genome Epidemiology Network (Atlanta, Georgia). The results showed that the cumulative evidence was moderate for the association of the CYP1A1*2A variant with leukemia in Caucasians and with childhood acute lymphoid leukemia in Caucasians. In addition, there was moderate evidence that children who carry both the CYP1A1*2A variant and the glutathione S-transferase M1 null genotype have an increased risk of acute lymphoid leukemia. For the CYP1A1*2C polymorphism, the cumulative evidence of an association with leukemia risk was moderate for adults and weak for children. Logistic regression analysis demonstrated an interaction between the CYP1A1*2C polymorphism and age. This meta-analysis showed that the CYP1A1*2A and CYP1A1*2C polymorphisms were associated with an increased risk of leukemia, and that the associations might vary by ethnicity, gene-gene interactions, age, and leukemia subtype.
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Affiliation(s)
- Fujun Han
- Cancer Center, First Hospital of Jilin University, Changchun, China
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Agha A, Shabaan H, Abdel-Gawad E, El-Ghannam D. Polymorphism of CYP1A1 gene and susceptibility to childhood acute lymphoblastic leukemia in Egypt. Leuk Lymphoma 2013; 55:618-23. [PMID: 23725389 DOI: 10.3109/10428194.2013.809527] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The origin of acute lymphoblastic leukemia (ALL) may be explained by a combination of genetic susceptibility and environmental exposure. We aimed to study the frequency of CYP1A1 allelic variants in Egyptian patients with ALL, to evaluate their role in the development of ALL and to correlate these allelic variants with clinical and biological characteristics of the patients. Polymorphism of CYP1A1*2A, *2B and *4 alleles was examined in 186 Egyptian children with ALL and 200 normal individuals using polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP). A higher prevalence of the CYP1A1*4 allele was found in patients with ALL than in the normal population (19.4%vs. 10.0%, odds ratio [OR] = 2.160, 95% confidence interval [CI] = 1.200-3.89, p = 0.01), especially in the homozygous variant (OR = 6.6, 95% CI = 2.23-19.58, p = 0.001) and in male patients (p = 0.005), particularly those aged 2-10 years (OR = 5.214, 95% CI = 1.535-17.706, p = 0.008). CYP1A1*2A showed a significant difference between age groups (p = 0.046), with a higher incidence in the 10-17-year-old group (21.1%). Multivariate analysis showed that only the CYP1A1*4 allele remained as a probable independent risk factor for ALL development (OR = 2.250, 95% CI = 1.244-4.069; p = 0.007). Our results suggest that polymorphic variants in the CYP1A1*4 gene may increase the risk of childhood ALL, particularly in male patients aged 2-10 years.
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Affiliation(s)
- Adel Agha
- Clinical Pathology Department, Faculty of Medicine, Benha University , Banha , Egypt
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Zhou LP, Luan H, Dong XH, Jin GJ, Man DL, Shang H. Genetic variants of CYP2D6 gene and cancer risk: a HuGE systematic review and meta-analysis. Asian Pac J Cancer Prev 2013; 13:3165-72. [PMID: 22994728 DOI: 10.7314/apjcp.2012.13.7.3165] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE Genetic polymorphisms in metabolic enzymes are associated with numerous cancers. A large number of single nucleotide polymorphisms (SNPs) in the CYP2D6 gene have been reported to associate with cancer susceptibility. However, the results are controversial. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis was to summarize the evidence for associations. METHODS Studies focusing on the relationship between CYP2D6 gene polymorphisms and susceptibility to cancer were selected from the Pubmed, Cochrane library, Embase, Web of Science, Springerlink, CNKI and CBM databases. Data were extracted by two independent reviewers and the meta-analysis was performed with Review Manager Version 5.1.6 and STATA Version 12.0 software. Odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated. RESULTS According to the inclusion criteria, forty-three studies with a total of 7,009 cancer cases and 9,646 healthy controls, were included in the meta-analysis. The results showed that there was a positive association between heterozygote (GC) of rs1135840 and cancer risk (OR=1.92, 95%CI: 1.14-3.21, P=0.01). In addition, we found that homozygote (CC) of rs1135840 might be a protective factor for cancer (OR=0.58, 95%CI: 0.34-0.97, P=0.04). Similarly, the G allele and G carrier (AG + GG) of rs16947 and heterozygote (A/del) of rs35742686 had negative associations with cancer risk (OR=0.69, 95%CI: 0.48-0.99, P=0.04; OR=0.60, 95%CI: 0.38-0.94, P=0.03; OR=0.50, 95%CI: 0.26-0.95, P=0.03; respectively). CONCLUSION This meta-analysis suggests that CYP2D6 gene polymorphisms are involved in the pathogenesis of various cancers. The heterozygote (GC) of rs1135840 in CYP2D6 gene might increase the risk while the homozygote (CC) of rs1135840, G allele and G carrier (AG + GG) of rs16947 and heterozygote (A/del) of rs35742686 might be protective factors.
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Affiliation(s)
- Li-Ping Zhou
- Department of Laboratory Medicine, the First Affiliated Hospital of China Medical University, Shenyang, China
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Puumala SE, Ross JA, Aplenc R, Spector LG. Epidemiology of childhood acute myeloid leukemia. Pediatr Blood Cancer 2013; 60:728-33. [PMID: 23303597 PMCID: PMC3664189 DOI: 10.1002/pbc.24464] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Accepted: 12/10/2012] [Indexed: 11/05/2022]
Abstract
Although leukemia is the most common childhood cancer diagnosis, the subtype, acute myeloid leukemia (AML), is less common and fewer etiologic studies exist. This review summarizes the major risk factors for AML. We searched the literature using PubMed for articles on childhood AML and reviewed 180 articles. While few risk factors are definitive, we identified several with consistent evidence of a possible effect. Thorough analysis of genetic and epigenetic factors is missing from this literature and methodological issues are unresolved. Future studies should more closely examine causal mechanisms, improve exposure measurement, and include analysis using genetic and epigenetic factors.
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Affiliation(s)
- Susan E. Puumala
- Center for Health Outcomes and Prevention Research, Sanford Research, Sioux Falls, South Dakota,Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota
| | - Julie A. Ross
- Division of Pediatric Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota,University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota
| | - Richard Aplenc
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Logan G. Spector
- Division of Pediatric Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota,University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota
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Bonaventure A, Rudant J, Goujon-Bellec S, Orsi L, Leverger G, Baruchel A, Bertrand Y, Nelken B, Pasquet M, Michel G, Sirvent N, Bordigoni P, Ducassou S, Rialland X, Zelenika D, Hémon D, Clavel J. Childhood acute leukemia, maternal beverage intake during pregnancy, and metabolic polymorphisms. Cancer Causes Control 2013; 24:783-93. [DOI: 10.1007/s10552-013-0161-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Accepted: 01/23/2013] [Indexed: 11/24/2022]
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Does cytochrome P450 1A1 MspI polymorphism increase acute lymphoblastic leukemia risk? Evidence from 2013 cases and 2903 controls. Gene 2012; 510:14-21. [DOI: 10.1016/j.gene.2012.08.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Revised: 08/20/2012] [Accepted: 08/25/2012] [Indexed: 12/11/2022]
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Chauhan PS, Ihsan R, Mishra AK, Yadav DS, Saluja S, Mittal V, Saxena S, Kapur S. High order interactions of xenobiotic metabolizing genes and P53 codon 72 polymorphisms in acute leukemia. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2012; 53:619-630. [PMID: 22930568 DOI: 10.1002/em.21723] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2012] [Revised: 07/02/2012] [Accepted: 07/03/2012] [Indexed: 06/01/2023]
Abstract
Polymorphisms in xenobiotic metabolizing genes are associated with altered metabolism of carcinogens in acute leukemia (AL). This study applied two data mining approaches to explore potential interactions among P53 and xenobiotic metabolizing genes in 230 AL patients [131 acute myeloid leukemia (AML) and 99 acute lymphoblastic leukemia (ALL)] and 199 controls. Individually, none of the genotypes showed significant associations with AML risk. However, in ALL the CYP1A12A TC genotype was associated with increased risk (OR = 2.02; 95% CI = 1.14-3.58; P = 0.01), whereas the GSTM1 null genotype imparted reduced risk (OR = 0.55; 95% CI = 0.31-0.96; P = 0.03). In classification and regression tree analysis, combinations of GSTM1 present, CYP1A12C AA or GG, EPHX1 exon3 TC, and EPHX1 exon4 AA or GG genotype strongly enhanced the risk of AML (OR = 5.89; 95% CI = 1.40-26.62; P = 0.01). In ALL, combinations of CYP1A12A TT, P53 GG or CC and GSTP1 AG genotypes conferred the highest risk (OR = 4.19; 95% CI = 1.45-12.25; P = 0.004). In multifactor dimensionality reduction analysis, a four locus model (GSTP1, P53, EPHX1 exon3, and CYP1A12A) was the best predictor model for ALL risk. The association between this model and ALL risk remained true even at low prior probabilities of 0.01% (false positive report probability = 0.05). Interaction entropy interpretations of the best model of ALL revealed that two-way interactions were mostly synergistic. These results suggest that high order gene-gene interactions play an important role in AL risk.
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Affiliation(s)
- Pradeep Singh Chauhan
- Department of Tumour Biology, National Institute of Pathology Indian Council of Medical Research, Safdarjung Hospital Campus, New Delhi, India
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Over-expression of CYP2E1 mRNA and protein: implications of xenobiotic induced damage in patients with de novo acute myeloid leukemia with inv(16)(p13.1q22); CBFβ-MYH11. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2012; 9:2788-800. [PMID: 23066397 PMCID: PMC3447587 DOI: 10.3390/ijerph9082788] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 07/25/2012] [Accepted: 07/31/2012] [Indexed: 11/30/2022]
Abstract
Environmental exposure to benzene occurs through cigarette smoke, unleaded gasoline and certain types of plastic. Benzene is converted to hematotoxic metabolites by the hepatic phase-I enzyme CYP2E1, and these metabolites are detoxified by the phase-II enzyme NQO1. The genes encoding these enzymes are highly polymorphic and studies of these polymorphisms have shown different pathogenic and prognostic features in various hematological malignancies. The potential role of different cytochrome p450 metabolizing enzymes in the pathogenesis of acute myeloid leukemia (AML) in an area of active interest. In this study, we demonstrate aberrant CYP2E1 mRNA over-expression by quantitative real-time polymerase chain reaction in 11 cases of de novo AML with inv(16); CBFβ-MYH11. CYP2E1 mRNA levels correlated with CBFβ-MYH11 transcript levels and with bone marrow blast counts in all cases. CYP2E1 over-expression correlated positively with NQO1 mRNA levels (R2 = 0.934, n = 7). By immunohistochemistry, CYP2E1 protein was more frequently expressed in AML with inv(16) compared with other types of AML (p < 0.001). We obtained serial bone marrow samples from two patients with AML with inv(16) before and after treatment. CYP2E1 mRNA expression levels decreased in parallel with CBFβ-MYH11 transcript levels and blast counts following chemotherapy. In contrast, CYP1A2 transcript levels did not change in either patient. This is the first study to demonstrate concurrent over-expression of CYP2E1 and NQO1 mRNA in AML with inv(16). These findings also suggest that a balance between CYP2E1 and NQO1 may be important in the pathogenesis of AML with inv(16).
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Zhuo W, Zhang L, Wang Y, Zhu B, Chen Z. CYP1A1 MspI polymorphism and acute myeloid leukemia risk: meta-analyses based on 5018 subjects. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2012; 31:62. [PMID: 22846179 PMCID: PMC3444413 DOI: 10.1186/1756-9966-31-62] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Accepted: 07/13/2012] [Indexed: 12/11/2022]
Abstract
Background Evidence indicates that CYP1A1 MspI polymorphism might be a possible risk factor for several malignancies. A growing body of literature has been devoted to the association of CYP1A1 MspI polymorphism with acute myeloid leukemia (AML). However, the results remain conflicting. The aim of the present study was to derive a more precise estimation of the relationship. Methods Meta-analyses assessing the association of CYP1A1 MspI variation with AML were conducted and subgroup analyses on ethnicity and age groups were further performed. Eligible studies were identified for the period up to May 2012. Results A total of ten case–control studies including 1330 cases and 3688 controls were selected for analysis. The overall data failed to indicate a significant association of CYP1A1 MspI polymorphism with AML risk (C vs T: OR = 1.13; 95%CI = 0.87-1.48; CC vs TT: OR = 1.72; 95%CI = 0.99-3.01; CC + TC vs TT: OR = 1.16; 95%CI = 0.86-1.55). In subgroup analysis stratified by ethnicity, significant AML risk was shown among Asians (CC + TC vs TT: OR = 1.33; 95%CI = 1.09-1.62) but not Caucasians or mixed races. In subgroup analysis regarding age groups, no associations were observed in either the childhood AML or the adult AML subgroups. Conclusion The results of the present study suggested that CYP1A1 MspI polymorphism might be a risk factor for AML among Asians. Further investigations are needed to confirm the conclusions.
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Affiliation(s)
- Wenlei Zhuo
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
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Taspinar M, Aydos S, Sakiragaoglu O, Duzen IV, Yalcinkaya A, Oztuna D, Bardakci H, Tutar E, Sunguroglu A. Impact of Genetic Variations of theCYP1A1, GSTT1, andGSTM1Genes on the Risk of Coronary Artery Disease. DNA Cell Biol 2012; 31:211-8. [DOI: 10.1089/dna.2011.1252] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Mehmet Taspinar
- Department of Medical Biology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Sena Aydos
- Department of Medical Biology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Onur Sakiragaoglu
- Department of Medical Biology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Irfan Veysel Duzen
- Department of Cardiology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Adnan Yalcinkaya
- Department of Cardiovascular Surgery, Turkiye Yuksek Ihtisas Hospital, Ankara, Turkey
| | - Derya Oztuna
- Department of Biostatistics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Hasmet Bardakci
- Department of Cardiovascular Surgery, Turkiye Yuksek Ihtisas Hospital, Ankara, Turkey
| | - Eralp Tutar
- Department of Cardiology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Asuman Sunguroglu
- Department of Medical Biology, Faculty of Medicine, Ankara University, Ankara, Turkey
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