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Gallardo-Blanco HL, Garza-Rodríguez MDL, Pérez-Ibave DC, Burciaga-Flores CH, Salinas-Torres VM, González-Escamilla M, Piñeiro-Retif R, Cerda-Flores RM, Vidal-Gutiérrez O, Sanchez-Dominguez CN. Genetic Insights into Breast Cancer in Northeastern Mexico: Unveiling Gene-Environment Interactions and Their Links to Obesity and Metabolic Diseases. Cancers (Basel) 2025; 17:982. [PMID: 40149317 PMCID: PMC11940701 DOI: 10.3390/cancers17060982] [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: 01/21/2025] [Revised: 03/02/2025] [Accepted: 03/05/2025] [Indexed: 03/29/2025] Open
Abstract
Background: Breast cancer (BC), one of the most common cancers, has increased in Mexico during the past decade, along with other chronic and metabolic diseases. Methods: Herein, we analyzed 121 SNPs (85 SNPs related to BC and/or glucose-associated metabolic pathways and 36 SNP classified as ancestry markers) in 92 confirmed BC cases and 126 unaffected BC women from Northeastern Mexico. The relationship of these 121 SNPs with BC, considering BMI, menopause status, and age as cofactors, was explored using a gene-environment (G × E) interaction multi-locus model. Results: Twelve gene variants were significantly associated with BC: three located in exome (rs3856806 PPARG, rs12792229 MMP8, and rs5218 KCNJ11-ABCC8), and nine in non-coding regions, which are involved in accelerated decay of the mRNA transcripts, regulatory regions, and flanking regions (rs3917542 PON1; rs3750804 and rs3750805 TCF7L2; rs1121980 and rs3751812 FTO; rs12946618 RPTOR; rs2833483 SCAF4; rs11652805 AMZ2P1-GNA13; and rs1800955 SCT-DEAF1-DRD4). Conclusions: This study identified an association between BC and menopause, age (above 45), obesity, and overweight status with gene variants implicated in diabetes mellitus, obesity, insulin resistance, inflammation, and remodeling of the extracellular matrix.
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Affiliation(s)
- Hugo Leonid Gallardo-Blanco
- Servicio de Oncología, Centro Universitario Contra el Cáncer (CUCC), Hospital Universitario “Dr. José Eleuterio González”, Universidad Autónoma de Nuevo León, Monterrey 66451, NL, Mexico; (H.L.G.-B.); (M.d.L.G.-R.); (D.C.P.-I.); (C.H.B.-F.); (M.G.-E.); (R.P.-R.); (O.V.-G.)
| | - María de Lourdes Garza-Rodríguez
- Servicio de Oncología, Centro Universitario Contra el Cáncer (CUCC), Hospital Universitario “Dr. José Eleuterio González”, Universidad Autónoma de Nuevo León, Monterrey 66451, NL, Mexico; (H.L.G.-B.); (M.d.L.G.-R.); (D.C.P.-I.); (C.H.B.-F.); (M.G.-E.); (R.P.-R.); (O.V.-G.)
| | - Diana Cristina Pérez-Ibave
- Servicio de Oncología, Centro Universitario Contra el Cáncer (CUCC), Hospital Universitario “Dr. José Eleuterio González”, Universidad Autónoma de Nuevo León, Monterrey 66451, NL, Mexico; (H.L.G.-B.); (M.d.L.G.-R.); (D.C.P.-I.); (C.H.B.-F.); (M.G.-E.); (R.P.-R.); (O.V.-G.)
| | - Carlos Horacio Burciaga-Flores
- Servicio de Oncología, Centro Universitario Contra el Cáncer (CUCC), Hospital Universitario “Dr. José Eleuterio González”, Universidad Autónoma de Nuevo León, Monterrey 66451, NL, Mexico; (H.L.G.-B.); (M.d.L.G.-R.); (D.C.P.-I.); (C.H.B.-F.); (M.G.-E.); (R.P.-R.); (O.V.-G.)
| | - Víctor Michael Salinas-Torres
- Departamento de Medicina Genómica, Hospital General Culiacán “Dr. Bernardo J. Gastélum”, Servicios de Salud del Instituto Mexicano del Seguro Social para el Bienestar, Culiacán 80064, SIN, Mexico;
- Facultad de Medicina, Universidad Autónoma de Sinaloa, Culiacán 80019, SIN, Mexico
| | - Moisés González-Escamilla
- Servicio de Oncología, Centro Universitario Contra el Cáncer (CUCC), Hospital Universitario “Dr. José Eleuterio González”, Universidad Autónoma de Nuevo León, Monterrey 66451, NL, Mexico; (H.L.G.-B.); (M.d.L.G.-R.); (D.C.P.-I.); (C.H.B.-F.); (M.G.-E.); (R.P.-R.); (O.V.-G.)
| | - Rafael Piñeiro-Retif
- Servicio de Oncología, Centro Universitario Contra el Cáncer (CUCC), Hospital Universitario “Dr. José Eleuterio González”, Universidad Autónoma de Nuevo León, Monterrey 66451, NL, Mexico; (H.L.G.-B.); (M.d.L.G.-R.); (D.C.P.-I.); (C.H.B.-F.); (M.G.-E.); (R.P.-R.); (O.V.-G.)
| | | | - Oscar Vidal-Gutiérrez
- Servicio de Oncología, Centro Universitario Contra el Cáncer (CUCC), Hospital Universitario “Dr. José Eleuterio González”, Universidad Autónoma de Nuevo León, Monterrey 66451, NL, Mexico; (H.L.G.-B.); (M.d.L.G.-R.); (D.C.P.-I.); (C.H.B.-F.); (M.G.-E.); (R.P.-R.); (O.V.-G.)
| | - Celia N. Sanchez-Dominguez
- Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey 64460, NL, Mexico
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Rosales-Reynoso MA, Rosas-Enríquez V, Saucedo-Sariñana AM, Pérez-Coria M, Gallegos-Arreola MP, Salas-González E, Barros-Núñez P, Juárez-Vázquez CI, Flores-Martínez SE, Sánchez-Corona J. Genotypes and Haplotypes in the AXIN2 and TCF7L2 Genes are Associated With Susceptibility and With Clinicopathological Characteristics in Breast Cancer Patients. Br J Biomed Sci 2022; 79:10211. [PMID: 35996498 PMCID: PMC8915722 DOI: 10.3389/bjbs.2021.10211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 12/23/2021] [Indexed: 12/09/2022]
Abstract
Background: Breast cancer is a multifactorial disease whose genetic susceptibility is related to polymorphic variants of cell proliferation and migration pathways. Variants in AXIN2 and TCF7L2 in the Wnt-β catenin pathway have been associated with different types of cancer; however, little is known about its role in breast cancer. This study tests the hypothesis of links between AXIN2 rs1133683 and rs2240308, and TCF7L2 rs7903146 and rs12255372 variants in breast cancer.Methods: Peripheral blood samples were obtained from 404 women (202 patients and 202 control females). The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology was used to identify the gene variants.Results: The AXIN2 rs2240308 (C > T), and TCF7L2 rs7903146 (C > T) and rs12255372 (G > T) variants were associated with breast cancer and with age, TNM stage, and histologic-molecular subtype (p = 0.001). Likewise, the haplotype T-T in the TCF7L2 gene (rs7903146-rs12253372) was significantly related with breast cancer (OR = 2.66, 95%, CI = 1.64–4.30, p = 0.001).Conclusion: Our data show a link between AXIN2 rs2240308 and TCF7L2 rs7903146 and rs12255372 variants in breast cancer, and speculate this may be important in pathogenesis.
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Affiliation(s)
- M. A. Rosales-Reynoso
- Division of Molecular Medicine, Center for Western Biomedical Research (CIBO), Guadalajara, Mexico
- *Correspondence: M. A. Rosales-Reynoso,
| | - V. Rosas-Enríquez
- Service of Medical Oncology, High Specialty Medical Unit, Hospital of Gynecology and Obstetrics, Guadalajara, Mexico
| | - A. M. Saucedo-Sariñana
- Division of Molecular Medicine, Center for Western Biomedical Research (CIBO), Guadalajara, Mexico
| | - M. Pérez-Coria
- Division of Molecular Medicine, Center for Western Biomedical Research (CIBO), Guadalajara, Mexico
| | - M. P. Gallegos-Arreola
- Division of Genetics, Center for Western Biomedical Research (CIBO), Guadalajara, Mexico
| | - E. Salas-González
- Service of Medical Oncology, High Specialty Medical Unit, Hospital of Gynecology and Obstetrics, Guadalajara, Mexico
| | - P. Barros-Núñez
- Unit of Follow-up Research of Metabolic Diseases, UMAE Pediatrics, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Mexico
| | - C. I. Juárez-Vázquez
- Academic Directorate Devices and Systems I, Faculty of Medicine, Dean of Health Sciences, Autonomous University of Guadalajara (UAG), Guadalajara, Mexico
| | - S. E. Flores-Martínez
- Division of Molecular Medicine, Center for Western Biomedical Research (CIBO), Guadalajara, Mexico
| | - J. Sánchez-Corona
- Division of Molecular Medicine, Center for Western Biomedical Research (CIBO), Guadalajara, Mexico
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Jablonski KP, Pirkl M, Ćevid D, Bühlmann P, Beerenwinkel N. Identifying cancer pathway dysregulations using differential causal effects. Bioinformatics 2021; 38:1550-1559. [PMID: 34927666 PMCID: PMC8896597 DOI: 10.1093/bioinformatics/btab847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 11/05/2021] [Accepted: 12/14/2021] [Indexed: 02/03/2023] Open
Abstract
MOTIVATION Signaling pathways control cellular behavior. Dysregulated pathways, for example, due to mutations that cause genes and proteins to be expressed abnormally, can lead to diseases, such as cancer. RESULTS We introduce a novel computational approach, called Differential Causal Effects (dce), which compares normal to cancerous cells using the statistical framework of causality. The method allows to detect individual edges in a signaling pathway that are dysregulated in cancer cells, while accounting for confounding. Hence, technical artifacts have less influence on the results and dce is more likely to detect the true biological signals. We extend the approach to handle unobserved dense confounding, where each latent variable, such as, for example, batch effects or cell cycle states, affects many covariates. We show that dce outperforms competing methods on synthetic datasets and on CRISPR knockout screens. We validate its latent confounding adjustment properties on a GTEx (Genotype-Tissue Expression) dataset. Finally, in an exploratory analysis on breast cancer data from TCGA (The Cancer Genome Atlas), we recover known and discover new genes involved in breast cancer progression. AVAILABILITY AND IMPLEMENTATION The method dce is freely available as an R package on Bioconductor (https://bioconductor.org/packages/release/bioc/html/dce.html) as well as on https://github.com/cbg-ethz/dce. The GitHub repository also contains the Snakemake workflows needed to reproduce all results presented here. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
| | | | - Domagoj Ćevid
- Seminar for Statistics, ETH Zürich, 8092 Zürich, Switzerland
| | - Peter Bühlmann
- Seminar for Statistics, ETH Zürich, 8092 Zürich, Switzerland
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Wang Y, Men X, Gu Y, Wang H, Xu Z. Haplotype analysis on correlation between transcription factor 7-like 2 gene polymorphism and breast cancer risk. BMC Cancer 2021; 21:885. [PMID: 34340678 PMCID: PMC8327437 DOI: 10.1186/s12885-021-08571-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 06/02/2021] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Up to now, limited researches focused on the association between transcription factor 7-like 2 gene (TF7L2) gene single nucleotide polymorphisms (SNPs) and breast cancer (BC) risk. The aim of this study was to evaluate the associations between TF7L2 and BC risk in Chinese Han population. METHODS Logistic regression model was used to test the correlation between polymorphisms and BC risk. Strength of association was evaluated by odds ratio (OR) and 95% confidence interval (CI). Generalized multifactor dimensionality reduction (GMDR) was applied to analyze the SNP-SNP and gene-environment interaction. RESULTS Logistic regression analysis indicated that the BC risk was obviously higher in carriers of rs1225404 polymorphism C allele than that in TT genotype carriers (TC or CC versus TT), adjusted OR (95%CI) =1.40 (1.09-1.72). Additionally, we also discovered that people with rs7903146- T allele had an obviously higher risk of BC than people with CC allele (CT or TT versus CC), adjusted OR (95%CI) =1.44 (1.09-1.82). GMDR model was used to research the effect of interaction among 4 SNPs and environmental factors on BC risk. We discovered an important two-locus model (p = 0.0100) including rs1225404 and abdominal obesity, suggesting a potential gene-environment correlation between rs1225404 and abdominal obesity. In general, the cross-validation consistency of two-locus model was 10 of 10, and the testing accuracy was 0.632. Compared with subjects with normal waist circumference (WC) value and rs1225404 TT genotype, abdominal obese subjects with rs1225404 TC or CC genotype had the highest BC risk. After covariate adjustment, OR (95%CI) was 2.23 (1.62-2.89). Haplotype analysis indicated that haplotype containing rs1225404-T and rs7903146-C alleles were associated with higher BC risk. CONCLUSIONS C allele of rs1225404 and T allele of rs7903146, interaction between rs1225404 and abdominal obesity, rs1225404-T and rs7903146-C haplotype were all related to increased BC risk.
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Affiliation(s)
- Yang Wang
- Department of Galactophore Surgery, Weifang People's Hospital, No.151 Guangwen Street, Kuiwen District, Weifang, 261041, Shandong Province, People's Republic of China
| | - Xiaojuan Men
- Department of Galactophore Surgery, Weifang People's Hospital, No.151 Guangwen Street, Kuiwen District, Weifang, 261041, Shandong Province, People's Republic of China
| | - Yongxue Gu
- Department of Galactophore Surgery, Weifang People's Hospital, No.151 Guangwen Street, Kuiwen District, Weifang, 261041, Shandong Province, People's Republic of China
| | - Huidong Wang
- Department of Galactophore Surgery, Weifang People's Hospital, No.151 Guangwen Street, Kuiwen District, Weifang, 261041, Shandong Province, People's Republic of China
| | - Zhicai Xu
- Department of Galactophore Surgery, Weifang People's Hospital, No.151 Guangwen Street, Kuiwen District, Weifang, 261041, Shandong Province, People's Republic of China.
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Tang W, Liu J, Zhong Z, Qiu H, Kang M. Association of metabolism-related genes polymorphisms with adenocarcinoma of the oesophagogastric junction: Evidence from 2261 subjects. J Cell Biochem 2019; 120:18689-18701. [PMID: 31211453 PMCID: PMC6771939 DOI: 10.1002/jcb.29167] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 05/17/2019] [Accepted: 05/23/2019] [Indexed: 01/26/2023]
Abstract
The etiology of adenocarcinoma of the esophagogastric junction (AEG) remains unclear. It is believed that the increasing of AEG may be correlated with the elevated ratio of obesity and overweight. Thus, metabolism‐related genes and variants may play important roles in the occurrence and progress of AEG. The current investigation involved 720 patients with AEG and 1541 healthy controls. We selected transcription factor 7‐like 2 (TCF7L2) rs7903146 and rs290481, INS rs689 and INSR rs1799817 single‐nucleotide polymorphisms (SNPs), and explored the association of these SNPs with lymph node status and risk of AEG. The polymerase chain reaction was harnessed to identify the genotyping of four polymorphisms. We found that TCF7L2 rs290481 (T > C) and INSR rs1799817 (G > A) polymorphisms were associated with the increased susceptibility of AEG (P = .007 and 0.004 for TCF7L2 rs290481 in TC vs TT and TC/CC vs TT models, and P = .040 for INSR rs1799817 in GA/AA vs GG model). We also conducted a subgroup analysis by different cancer stage. We identified that TCF7L2 rs290481, INS rs689, and INSR rs1799817 SNPs increased the susceptibility of AEG in different cancer stage subgroups. In addition, we found that rs290481 SNP in TCF7L2 gene increased the risk of lymph node metastasis in drinking patients with AEG. However, the association of INSR rs1799817 SNP with a decreased risk of lymph node metastasis in smoking patients with AEG was found. Our findings highlight that TCF7L2 rs290481, INS rs689, and INSR rs1799817 polymorphisms may increase the risk of AEG. In addition, TCF7L2 rs290481 and INSR rs1799817 SNPs may influence the lymph node metastasis in patients with AEG.
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Affiliation(s)
- Weifeng Tang
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jun Liu
- Department of Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Zhihui Zhong
- Department of Orthopaedics, The Fuzhou Second Hospital, Affiliated Hospital of Xiamen University, Fuzhou, Fujian, China
| | - Hao Qiu
- Department of Immunology, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Mingqiang Kang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
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Geoghegan G, Simcox J, Seldin MM, Parnell TJ, Stubben C, Just S, Begaye L, Lusis AJ, Villanueva CJ. Targeted deletion of Tcf7l2 in adipocytes promotes adipocyte hypertrophy and impaired glucose metabolism. Mol Metab 2019; 24:44-63. [PMID: 30948248 PMCID: PMC6531814 DOI: 10.1016/j.molmet.2019.03.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 03/02/2019] [Accepted: 03/09/2019] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Activation of the Wnt-signaling pathway is known to inhibit differentiation in adipocytes. However, there is a gap in our understanding of the transcriptional network regulated by components of the Wnt-signaling pathway during adipogenesis and in adipocytes during postnatal life. The key intracellular effectors of the Wnt-signaling pathway occur through TCF transcription factors such as TCF7L2 (transcription factor-7-like 2). Several genetic variants in proximity to TCF7L2 have been linked to type 2 diabetes through genome-wide association studies in various human populations. Our work aims to functionally characterize the adipocyte specific gene program regulated by TCF7L2 and understand how this program regulates metabolism. METHODS We generated Tcf7l2F/F mice and assessed TCF7L2 function in isolated adipocytes and adipose specific knockout mice. ChIP-sequencing and RNA-sequencing was performed on the isolated adipocytes with control and TCF7L2 knockout cells. Adipose specific TCF7L2 knockout mice were challenged with high fat diet and assessed for body weight, glucose tolerance, and lipolysis. RESULTS Here we report that TCF7L2 regulates adipocyte size, endocrine function, and glucose metabolism. Tcf7l2 is highly expressed in white adipose tissue, and its expression is suppressed in genetic and diet-induced models of obesity. Genome-wide distribution of TCF7L2 binding and gene expression analysis in adipocytes suggests that TCF7L2 directly regulates genes implicated in cellular metabolism and cell cycle control. When challenged with a high-fat diet, conditional deletion of TCF7L2 in adipocytes led to impaired glucose tolerance, impaired insulin sensitivity, promoted weight gain, and increased adipose tissue mass. This was accompanied by reduced expression of triglyceride hydrolase, reduced fasting-induced free fatty acid release, and adipocyte hypertrophy in subcutaneous adipose tissue. CONCLUSIONS Together our studies support that TCF7L2 is a central transcriptional regulator of the adipocyte metabolic program by directly regulating the expression of genes involved in lipid and glucose metabolism.
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Affiliation(s)
- Gisela Geoghegan
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Judith Simcox
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Marcus M Seldin
- Department of Human Genetics/Medicine, University of California, Los Angeles, CA, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA
| | - Timothy J Parnell
- Bioinformatics Shared Resources, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Chris Stubben
- Bioinformatics Shared Resources, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Steven Just
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Lori Begaye
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Aldons J Lusis
- Department of Human Genetics/Medicine, University of California, Los Angeles, CA, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA
| | - Claudio J Villanueva
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA.
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Investigation of TCF7L2, LEP and LEPR polymorphisms with esophageal squamous cell carcinomas. Oncotarget 2017; 8:109107-109119. [PMID: 29312594 PMCID: PMC5752507 DOI: 10.18632/oncotarget.22619] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 08/26/2017] [Indexed: 12/31/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) in energy metabolism related gene may be key agents in the development of human malignancies. In this study, we aimed to examine the association of transcription factor 7-like 2, Leptin (LEP) and LEP receptor (LEPR) polymorphisms with esophageal squamous cell carcinoma (ESCC). A total of 507 ESCC cases and 1,496 controls were enrolled. We found that LEPR rs6588147 AA genotype was associated with ESCC risk (AA vs. GG/GA: adjusted OR=1.90, 95%CI=1.00-3.61, P=0.049). In the stratified analyses, LEPR rs6588147 G>A polymorphism increased the risk of ESCC (<63 years subgroup: AA vs. GG: adjusted OR=2.58, 95%CI=1.00-6.62, P=0.049 and AA vs. GA/GG: adjusted OR=2.71, 95%CI=1.06-6.91, P=0.038; male subgroup: AA vs. GG: adjusted OR=2.19, 95%CI=1.02-4.67, P=0.044 and AA vs. GA/GG: adjusted OR=2.26, 95%CI=1.06-4.80, P=0.035). However, LEP rs7799039 A>G decreased the risk of ESCC (≥63 years subgroup: GG vs. AA: adjusted OR=0.47, 95%CI=0.23-0.95, P=0.035 and GG vs. AA/AG: adjusted OR=0.48, 95%CI=0.24-0.96, P=0.038; BMI≥24 kg/m2 subgroup: AG vs. AA: adjusted OR=0.66, 95%CI=0.45-0.99, P=0.044). In addition, LEPR rs1137101 G>A polymorphism decreased ESCC risk in some subgroups (ever smoking subgroup: GA vs. GG: adjusted OR=0.66, 95%CI=0.44-1.00, P=0.049; ever drinking subgroup: GA vs. GG: adjusted OR=0.54, 95%CI=0.31-0.95, P=0.031 and GA/AA vs. GG: adjusted OR=0.54, 95%CI=0.31-0.93, P=0.027). Our findings suggest that LEPR rs6588147 G>A polymorphism is associated with the increased risk of ESCC; however, LEP rs7799039 A>G and LEPR rs1137101 G>A polymorphisms may be protective factors for ESCC.
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Szabo M, Máté B, Csép K, Benedek T. Genetic Approaches to the Study of Gene Variants and Their Impact on the Pathophysiology of Type 2 Diabetes. Biochem Genet 2017; 56:22-55. [DOI: 10.1007/s10528-017-9827-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 10/06/2017] [Indexed: 12/18/2022]
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Masoudkabir F, Sarrafzadegan N, Gotay C, Ignaszewski A, Krahn AD, Davis MK, Franco C, Mani A. Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention. Atherosclerosis 2017; 263:343-351. [PMID: 28624099 PMCID: PMC6207942 DOI: 10.1016/j.atherosclerosis.2017.06.001] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 05/08/2017] [Accepted: 06/01/2017] [Indexed: 12/21/2022]
Abstract
Cardiovascular disease (CVD) and cancer are leading causes of mortality and morbidity worldwide. Strategies to improve their treatment and prevention are global priorities and major focus of World Health Organization's joint prevention programs. Emerging evidence suggests that modifiable risk factors including diet, sedentary lifestyle, obesity and tobacco use are central to the pathogenesis of both diseases and are reflected in common genetic, cellular, and signaling mechanisms. Understanding this important biological overlap is critical and may help identify novel therapeutic and preventative strategies for both disorders. In this review, we will discuss the shared genetic and molecular factors central to CVD and cancer and how the strategies commonly used for the prevention of atherosclerotic vascular disease can be applied to cancer prevention.
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Affiliation(s)
- Farzad Masoudkabir
- Cardiac Primary Prevention Research Center, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nizal Sarrafzadegan
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran; School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.
| | - Carolyn Gotay
- School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada; Cancer Control Research Program, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada
| | - Andrew Ignaszewski
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Andrew D Krahn
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Margot K Davis
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Christopher Franco
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Arya Mani
- Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
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Abana CO, Bingham BS, Cho JH, Graves AJ, Koyama T, Pilarski RT, Chakravarthy AB, Xia F. IL-6 variant is associated with metastasis in breast cancer patients. PLoS One 2017; 12:e0181725. [PMID: 28732081 PMCID: PMC5521838 DOI: 10.1371/journal.pone.0181725] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 07/06/2017] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Although tumor metastases remain significant drivers of mortality, the genetic factors that increase the risks of metastases are not fully identified. Interleukin 6 (IL-6) has emerged as an important factor in breast cancer progression with IL-6 single nucleotide polymorphism (SNP) variants shown to affect survival. We hypothesized that SNPs of the IL-6 promoter at rs1800795 in breast cancer patients are associated with distant metastases. METHODS We performed an initial case-control study using Vanderbilt University Medical Center's BioVU, a genomic biobank linked to de-identified electronic medical records in the Synthetic Derivative database, to identify germline SNPs that may predict the development of metastatic disease to any site from any solid tumor including breast cancer. We identified a SNP in IL-6: rs1800795 to be of significance and evaluated this finding using a separate, matched-pair cohort of breast cancer patients with and without metastases from The Ohio State University Wexner Medical Center. RESULTS The initial study suggested that GG relative to CG at rs1800795 (OR 1.52; 95% CI 1.14-2.02; p = 0.004) was significantly associated with the development of metastases. This association was also observed in the Ohio State University cohort (OR 2.23; 95% CI 1.06-4.71; p = 0.001). There were no significant relationships between rs1800795 status and any patient or tumor characteristics, including estrogen receptor status. CONCLUSIONS These findings suggest that GG SNP at IL-6: rs1800795 may indicate an increased risk of metastasis of primary breast cancer. Further studies in larger population sets are warranted as advanced screening and prophylactic intervention might be employed in GG carriers.
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Affiliation(s)
- Chike O. Abana
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Brian S. Bingham
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Ju Hwan Cho
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, Ohio, United States of America
| | - Amy J. Graves
- Department of Urologic Surgery and Center for Quantitative Science, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
- Center for Quantitative Science, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Tatsuki Koyama
- Center for Quantitative Science, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Robert T. Pilarski
- Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - A. Bapsi Chakravarthy
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Fen Xia
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
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Lynce F, Graves KD, Jandorf L, Ricker C, Castro E, Moreno L, Augusto B, Fejerman L, Vadaparampil ST. Genomic Disparities in Breast Cancer Among Latinas. Cancer Control 2017; 23:359-372. [PMID: 27842325 DOI: 10.1177/107327481602300407] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Breast cancer is the most common cancer diagnosed among Latinas in the United States and the leading cause of cancer-related death among this population. Latinas tend to be diagnosed at a later stage and have worse prognostic features than their non-Hispanic white counterparts. Genetic and genomic factors may contribute to observed breast cancer health disparities in Latinas. METHODS We provide a landscape of our current understanding and the existing gaps that need to be filled across the cancer prevention and control continuum. RESULTS We summarize available data on mutations in high and moderate penetrance genes for inherited risk of breast cancer and the associated literature on disparities in awareness of and uptake of genetic counseling and testing in Latina populations. We also discuss common genetic polymorphisms and risk of breast cancer in Latinas. In the treatment setting, we examine tumor genomics and pharmacogenomics in Latina patients with breast cancer. CONCLUSIONS As the US population continues to diversify, extending genetic and genomic research into this underserved and understudied population is critical. By understanding the risk of breast cancer among ethnically diverse populations, we will be better positioned to make treatment advancements for earlier stages of cancer, identify more effective and ideally less toxic treatment regimens, and increase rates of survival.
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Affiliation(s)
- Filipa Lynce
- Health Outcomes and Behavior Program, Moffitt Cancer Center, Tampa, FL, USA.
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12
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Min W, Liu X, Lu Y, Gong Z, Wang M, Lin S, Kang H, Jin T, Wang X, Ma X, Liu K, Dai C, Zheng Y, Li S, Ma Q, Dai Z. Association of transcription factor 7-like 2 gene polymorphisms with breast cancer risk in northwest Chinese women. Oncotarget 2016; 7:77175-77182. [PMID: 27738320 PMCID: PMC5363578 DOI: 10.18632/oncotarget.12591] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 09/29/2016] [Indexed: 01/08/2023] Open
Abstract
Genetic variations in transcription factor 7-like 2 (TCF7L2) are associated with cancer risk. This study was conducted to establish the relationship between TCF7L2 polymorphisms (rs1225404, rs7003146, and rs7903146) and clinical features and risk of breast cancer in Northwest Chinese Han women. In this study, three polymorphisms of TCF7L2 (rs1225404, rs7003146, and rs7903146) were genotyped in 458 patients with breast cancer and 500 healthy controls using the Sequenom MassARRAY-iPLEX system. We evaluated the associations between the polymorphisms and breast cancer using odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs). The C allele of rs1225404 was associated with increased breast cancer risk (OR = 1.58, P = 0.0004, PC= 0.0012), whereas the G allele of rs7003146 was associated with decreased breast cancer risk (OR = 0.71, P = 0.01, PC= 0.03). Furthermore, the rs1225404 polymorphism positively correlated with negative progesterone receptor status. A positive correlation with positive estrogen receptor (ER) status was observed for the rs7003146 polymorphism. Our results suggest that TCF7L2 polymorphisms rs1225404 and rs7003146, but not rs7903146, may affect breast cancer risk in Northwest Chinese women. Additionally, the tag polymorphisms in TCF7L2 are associated with the clinical features of breast cancer, which may provide us novel insight into the pathogenesis of breast cancer.
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Affiliation(s)
- Weili Min
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Xinghan Liu
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Ye Lu
- Department of Student Affairs, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Zhuoqing Gong
- Department of Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Meng Wang
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Shuai Lin
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Huafeng Kang
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Tianbo Jin
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Xijing Wang
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Xiaobin Ma
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Kang Liu
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Cong Dai
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Yi Zheng
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Shanli Li
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Zhijun Dai
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
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Torres K, Labrador L, Valderrama E, Chiurillo MA. TCF7L2 rs7903146 polymorphism is associated with gastric cancer: A case-control study in the Venezuelan population. World J Gastroenterol 2016; 22:6520-6526. [PMID: 27605886 PMCID: PMC4968131 DOI: 10.3748/wjg.v22.i28.6520] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 05/25/2016] [Accepted: 06/13/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the association between TCF7L2 rs12255372 and rs7903146 single nucleotide polymorphisms (SNPs) and gastric cancer risk in Venezuelan patients.
METHODS We performed a case-control study including 122 paraffin-embedded archived intestinal-type gastric cancer samples and 129 biopsies obtained by superior endoscopy from chronic gastritis patients. Gastric cancer samples were classified according the degree of carcinoma differentiation. Genomic DNA was extracted from tissues, and the two SNPs of TCF7L2 gene (rs12255372 and rs7903146) were genotyped by polymerase chain reaction-restriction fragment length polymorphism reactions. Multiple regression analysis with adjustments for age and gender were performed and best-fitting models of inheritance were determined. Statistic powers were post-hoc calculated.
RESULTS After adjusting for age and sex the TCF7L2 rs7903146 TT genotype was associated with gastric cancer risk under the recessive genetic model (OR = 3.11, 95%CI: 1.22-7.92, P = 0.017). We further investigated the distribution of rs12255372 and rs7903146 genotypes according gastric cancer stratified by degree of differentiation, and we observed that carriers of rs7903146 T allele (CT + TT vs CC) had a significantly increased risk of moderate/well differentiated gastric cancer (dominant model, OR = 2.55, 95%CI: 1.35-4.80, P = 0.004), whereas the rs7903146 TT genotype was associated with poorly differentiated gastric cancer in the recessive model (OR = 3.65, 95%CI: 1.25-10.62, P = 0.018). We did not find association between rs12255372 SNP and the susceptibility of developing gastric cancer.
CONCLUSION TCF7L2 rs7903146 polymorphism is associated with gastric cancer risk in the Venezuelan population, and could be related to determine the degree of differentiation of tumor cells.
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Mucaki EJ, Caminsky NG, Perri AM, Lu R, Laederach A, Halvorsen M, Knoll JHM, Rogan PK. A unified analytic framework for prioritization of non-coding variants of uncertain significance in heritable breast and ovarian cancer. BMC Med Genomics 2016; 9:19. [PMID: 27067391 PMCID: PMC4828881 DOI: 10.1186/s12920-016-0178-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 03/15/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sequencing of both healthy and disease singletons yields many novel and low frequency variants of uncertain significance (VUS). Complete gene and genome sequencing by next generation sequencing (NGS) significantly increases the number of VUS detected. While prior studies have emphasized protein coding variants, non-coding sequence variants have also been proven to significantly contribute to high penetrance disorders, such as hereditary breast and ovarian cancer (HBOC). We present a strategy for analyzing different functional classes of non-coding variants based on information theory (IT) and prioritizing patients with large intragenic deletions. METHODS We captured and enriched for coding and non-coding variants in genes known to harbor mutations that increase HBOC risk. Custom oligonucleotide baits spanning the complete coding, non-coding, and intergenic regions 10 kb up- and downstream of ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, and TP53 were synthesized for solution hybridization enrichment. Unique and divergent repetitive sequences were sequenced in 102 high-risk, anonymized patients without identified mutations in BRCA1/2. Aside from protein coding and copy number changes, IT-based sequence analysis was used to identify and prioritize pathogenic non-coding variants that occurred within sequence elements predicted to be recognized by proteins or protein complexes involved in mRNA splicing, transcription, and untranslated region (UTR) binding and structure. This approach was supplemented by in silico and laboratory analysis of UTR structure. RESULTS 15,311 unique variants were identified, of which 245 occurred in coding regions. With the unified IT-framework, 132 variants were identified and 87 functionally significant VUS were further prioritized. An intragenic 32.1 kb interval in BRCA2 that was likely hemizygous was detected in one patient. We also identified 4 stop-gain variants and 3 reading-frame altering exonic insertions/deletions (indels). CONCLUSIONS We have presented a strategy for complete gene sequence analysis followed by a unified framework for interpreting non-coding variants that may affect gene expression. This approach distills large numbers of variants detected by NGS to a limited set of variants prioritized as potential deleterious changes.
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Affiliation(s)
- Eliseos J Mucaki
- Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 2C1, Canada
| | - Natasha G Caminsky
- Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 2C1, Canada
| | - Ami M Perri
- Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 2C1, Canada
| | - Ruipeng Lu
- Department of Computer Science, Faculty of Science, Western University, London, N6A 2C1, Canada
| | - Alain Laederach
- Department of Biology, University of North Carolina, Chapel Hill, NC, 27599-3290, USA
| | - Matthew Halvorsen
- Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, 10032, USA
| | - Joan H M Knoll
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, N6A 2C1, Canada
- Cytognomix Inc., London, Canada
| | - Peter K Rogan
- Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 2C1, Canada.
- Department of Computer Science, Faculty of Science, Western University, London, N6A 2C1, Canada.
- Cytognomix Inc., London, Canada.
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, N6A 2C1, Canada.
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Wang F, Jiang L, li J, Yu X, Li M, Wu G, Yu Z, Zhou K, Chu H, Zhai H. Association between TCF7L2 polymorphisms and breast cancer susceptibility: a meta-analysis. Int J Clin Exp Med 2015; 8:9355-9361. [PMID: 26309596 PMCID: PMC4537972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 05/21/2015] [Indexed: 06/04/2023]
Abstract
AIM Our aim was to investigate the relationship between transcription factor 7-like 2 (TCF7L2) polymorphisms and breast cancer susceptibility. METHODS PubMed, Embase and CNKI databases were used to search the related studies investigating the correlation between TCF7L2 polymorphisms and breast cancer susceptibility. Pooled ORs and 95% CIs, based on five genetic models, were applied to estimate the association betweenTCF7L2 polymorphisms and breast cancer. A fixed-effect model or a random-effect model was applied according to the between-study heterogeneity. RESULTS We analyzed six single nucleotide polymorphisms (SNPs) in TCF7L2 gene, namely rs12255372, rs7903146, rs7900150, rs3750805, rs1225404 and rs7003146. The increased risk of breast cancer was associated with TCF7L2 polymorphisms (22 vs. 11: OR=1.16, 95% CI=1.02-1.32; 22+12 vs. 11: OR=1.06, 95% CI=1.02-1.10; 22 vs. 11+12: OR=1.15, 95% CI=1.04-1.27; 2 vs. 1: OR=1.07, 95% CI=1.02-1.13; 12 vs. 11: OR=1.05, 95% CI=1.01-1.09). Among the locus, rs7903146 polymorphism was significantly associated with the risk for breast cancer under five genetic models (TT vs. CC: OR=1.29, 95% CI=1.08-1.53; TT+CT vs. CC: OR=1.09, 95% CI=1.01-1.18; TT vs. CC+CT: OR=1.24, 95% CI=1.05-1.48; T vs. C: OR=1.11, 95% CI=1.04-1.19; CT vs. CC: OR=1.08, 95% CI=1.00-1.17). Additionally, rs7900150 also showed effects on the susceptibility of breast cancer (TT vs. AA: OR=1.22, 95% CI=1.07-1.39; TT+AT vs. AA: OR=1.06, 95% CI=1.00-1.14; TT vs. AA+AT: OR=1.21, 95% CI=1.07-1.37; T vs. A: OR=1.09, 95% CI=1.02-1.15; AT vs. AA: OR=1.04, 95% CI=1.01-1.33). Meanwhile, we found that rs3750805 polymorphism could increased the risk for breast cancer (TT+AT vs. AA: OR=1.12, 95% CI=1.01-1.24). CONCLUSION Our meta-analysis demonstrates that TCF7L2 polymorphisms may increase the risk for breast cancer.
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Affiliation(s)
- Feng Wang
- Department of Breast Disease, The Second Hospital of Shandong University247 Beiyuan Street, Tianqiao District, Jinan 250033, Shandong, China
- Department of Breast Disease, Beijing Tiantan Hospital, Capital Medical UniversityBeijing 100050, China
| | - Lixin Jiang
- Department of Gastrointestinal Surgery, Yantai Yuhuangding Hospital20 Yuhuangding East Road, Yantai 264000, Shandong, China
| | - Jianlin li
- Image Diagnostic Center, Yantai Yuhuangding Hospital20 Yuhuangding East Road, Yantai 264000, Shandong, China
| | - Xiao Yu
- Department of Endocrinology, Yantai Yuhuangding Hospital20 Yuhuangding East Road, Yantai 264000, Shandong, China
| | - Mingchuan Li
- Department of Anesthesiology, Yantai Yuhuangding Hospital20 Yuhuangding East Road, Yantai 264000, Shandong, China
| | - Guochang Wu
- Department of Gastrointestinal Surgery, Yantai Yuhuangding Hospital20 Yuhuangding East Road, Yantai 264000, Shandong, China
| | - Zhenyu Yu
- Department of Anesthesiology, Yantai Yuhuangding Hospital20 Yuhuangding East Road, Yantai 264000, Shandong, China
| | - Kai Zhou
- Department of Gastrointestinal Surgery, Yantai Yuhuangding Hospital20 Yuhuangding East Road, Yantai 264000, Shandong, China
| | - Haidi Chu
- Department of Gastrointestinal Surgery, Yantai Yuhuangding Hospital20 Yuhuangding East Road, Yantai 264000, Shandong, China
| | - Huiyuan Zhai
- Department of Gastrointestinal Surgery, Yantai Yuhuangding Hospital20 Yuhuangding East Road, Yantai 264000, Shandong, China
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16
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Connor AE, Baumgartner RN, Baumgartner KB, Pinkston CM, Boone SD, John EM, Torres-Mejía G, Hines LM, Giuliano AR, Wolff RK, Slattery ML. Associations between ALOX, COX, and CRP polymorphisms and breast cancer among Hispanic and non-Hispanic white women: The breast cancer health disparities study. Mol Carcinog 2014; 54:1541-53. [PMID: 25339205 DOI: 10.1002/mc.22228] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Revised: 08/08/2014] [Accepted: 08/14/2014] [Indexed: 12/21/2022]
Abstract
Chronic inflammation is suggested to be associated with specific cancer sites, including breast cancer. Recent research has focused on the roles of genes involved in the leukotriene/lipoxygenase and prostaglandin/cyclooxygenase pathways in breast cancer etiology. We hypothesized that genes in ALOX/COX pathways and CRP polymorphisms would be associated with breast cancer risk and mortality in our sample of Hispanic/Native American (NA) (1430 cases, 1599 controls) and non-Hispanic white (NHW) (2093 cases, 2610 controls) women. A total of 104 Ancestral Informative Markers was used to distinguish European and NA ancestry. The adaptive rank truncated product (ARTP) method was used to determine the significance of associations for each gene and the inflammation pathway with breast cancer risk and by NA ancestry. Overall, the pathway was associated with breast cancer risk (PARTP = 0.01). Two-way interactions with NA ancestry (P(adj) < 0.05) were observed for ALOX12 (rs2292350, rs2271316) and PTGS1 (rs10306194). We observed increases in breast cancer risk in stratified analyses by tertiles of polyunsaturated fat intake for ALOX12 polymorphisms; the largest increase in risk was among women in the highest tertile with ALOX12 rs9904779CC (Odds Ratio (OR), 1.49; 95% Confidence Interval (CI) 1.14-1.94, P(adj) = 0.01). In a sub-analysis stratified by NSAIDs use, two-way interactions with NSAIDs use were found for ALOX12 rs9904779 (P(adj) = 0.02), rs434473 (P(adj ) = 0.02), and rs1126667 (P(adj) = 0.01); ORs for ALOX12 polymorphisms ranged from 1.55 to 1.64 among regular users. Associations were not observed with breast cancer mortality. These findings could support advances in the discovery of new pathways related to inflammation for breast cancer treatment.
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Affiliation(s)
- Avonne E Connor
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Richard N Baumgartner
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Kathy B Baumgartner
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Christina M Pinkston
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Stephanie D Boone
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Esther M John
- Cancer Prevention Institute of California, Fremont, California.,Division of Epidemiology, Department of Health Research and Policy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California
| | - Gabriela Torres-Mejía
- Instituto Nacional de Salud Pública, Centro de Investigación en Salud Poblacional, Cuernavaca, Morelos, Mexico
| | - Lisa M Hines
- Department of Biology, University of Colorado Colorado Springs, Colorado Springs, Colorado
| | - Anna R Giuliano
- H. Lee Moffit Cancer Center & Research Institute, Tampa, Florida
| | - Roger K Wolff
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
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Basile KJ, Johnson ME, Xia Q, Grant SFA. Genetic susceptibility to type 2 diabetes and obesity: follow-up of findings from genome-wide association studies. Int J Endocrinol 2014; 2014:769671. [PMID: 24719615 PMCID: PMC3955626 DOI: 10.1155/2014/769671] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 01/17/2014] [Accepted: 01/20/2014] [Indexed: 12/13/2022] Open
Abstract
Elucidating the underlying genetic variations influencing various complex diseases is one of the major challenges currently facing clinical genetic research. Although these variations are often difficult to uncover, approaches such as genome-wide association studies (GWASs) have been successful at finding statistically significant associations between specific genomic loci and disease susceptibility. GWAS has been especially successful in elucidating genetic variants that influence type 2 diabetes (T2D) and obesity/body mass index (BMI). Specifically, several GWASs have confirmed that a variant in transcription factor 7-like 2 (TCF7L2) confers risk for T2D, while a variant in fat mass and obesity-associated protein (FTO) confers risk for obesity/BMI; indeed both of these signals are considered the most statistically associated loci discovered for these respective traits to date. The discovery of these two key loci in this context has been invaluable for providing novel insight into mechanisms of heritability and disease pathogenesis. As follow-up studies of TCF7L2 and FTO have typically lead the way in how to follow up a GWAS discovery, we outline what has been learned from such investigations and how they have implications for the myriad of other loci that have been subsequently reported in this disease context.
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Affiliation(s)
- Kevin J. Basile
- Division of Human Genetics, The Children's Hospital of Philadelphia Research Institute, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Matthew E. Johnson
- Division of Human Genetics, The Children's Hospital of Philadelphia Research Institute, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Qianghua Xia
- Division of Human Genetics, The Children's Hospital of Philadelphia Research Institute, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Struan F. A. Grant
- Division of Human Genetics, The Children's Hospital of Philadelphia Research Institute, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
- Center for Applied Genomics, The Children's Hospital of Philadelphia Research Institute, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- 1216F Children's Hospital of Philadelphia Research Institute, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
- *Struan F. A. Grant:
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18
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Connor AE, Baumgartner RN, Baumgartner KB, Pinkston CM, John EM, Torres-Mejía G, Hines LM, Giuliano AR, Wolff RK, Slattery ML. Epidermal growth factor receptor (EGFR) polymorphisms and breast cancer among Hispanic and non-Hispanic white women: the Breast Cancer Health Disparities Study. INTERNATIONAL JOURNAL OF MOLECULAR EPIDEMIOLOGY AND GENETICS 2013; 4:235-249. [PMID: 24319539 PMCID: PMC3852643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 11/08/2013] [Indexed: 06/03/2023]
Abstract
The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, functions in cellular processes essential to the development of cancer. Overexpression of EGFR in primary breast tumors has been linked with poor prognosis. We investigated the associations between 34 EGFR tagging SNPs and breast cancer risk and breast cancer-specific mortality in 4,703 Hispanic and 3,030 non-Hispanic white women from the Breast Cancer Health Disparities Study. We evaluated associations with risk of breast cancer defined by estrogen/progesterone receptor (ER/PR) tumor phenotype. Only one association remained statistically significant after adjusting for multiple comparisons. Rs2075112GA/AA was associated with reduced risk for ER-/PR+ tumor phenotype (odds ratio (OR), 0.34; 95% confidence interval (CI) 0.18-0.63, p adj=0.01). All additional results were significant prior to adjustment for multiple comparisons. Two of the EGFR polymorphisms were associated with breast cancer risk in the overall study population (rs11770531TT: OR, 0.56, 95% CI 0.37-0.84; and rs2293348AA: OR, 1.20, 95% CI 1.04-1.38) and two polymorphisms were associated with risk among Hispanics: rs6954351AA: OR, 2.50, 95% CI 1.32-4.76; and rs845558GA/AA: OR, 1.15, 95% CI 1.01-1.30. With regard to breast cancer-specific mortality, we found positive associations with rs6978771TT hazard ratio (HR), 1.68; 95% CI 1.11-2.56; rs9642391CC HR, 1.64; 95% CI 1.04-2.58; rs4947979AG/GG HR, 1.36; 95% CI 1.03-1.79; and rs845552GG HR, 1.62; 95% CI 1.05-2.49. Our findings provide additional insight for the role of EGFR in breast cancer development and prognosis. Further research is needed to elucidate EGFR's contribution to ethnic disparities in breast cancer.
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Affiliation(s)
- Avonne E Connor
- Department of Epidemiology & Population Health, School of Public Health and Information Sciences, University of LouisvilleLouisville, KY, USA
| | - Richard N Baumgartner
- Department of Epidemiology & Population Health, School of Public Health and Information Sciences, University of LouisvilleLouisville, KY, USA
| | - Kathy B Baumgartner
- Department of Epidemiology & Population Health, School of Public Health and Information Sciences, University of LouisvilleLouisville, KY, USA
| | - Christina M Pinkston
- Department of Epidemiology & Population Health, School of Public Health and Information Sciences, University of LouisvilleLouisville, KY, USA
| | - Esther M John
- Cancer Prevention Institute of CaliforniaFremont, CA
- Division of Epidemiology, Department of Health Research and Policy, and Stanford Cancer Institute, Stanford University School of MedicineStanford, CA, USA
| | - Gabriela Torres-Mejía
- Instituto Nacional de Salud Pública, Centro de Investigación en Salud PoblacionalCuernavaca, Morelos, México
| | - Lisa M Hines
- Department of Biology, University of Colorado Springs, Colorado Springs, CO, USA
| | - Anna R Giuliano
- H.Lee Moffit Cancer Center & Research InstituteTampa, FL, USA
| | - Roger K Wolff
- Department of Internal Medicine, University of Utah, Salt Lake CityUT, USA
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake CityUT, USA
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Abstract
Type 2 diabetes (T2D) is the result of interaction between environmental factors and a strong hereditary component. We review the heritability of T2D as well as the history of genetic and genomic research in this area. Very few T2D risk genes were identified using candidate gene and linkage-based studies, but the advent of genome-wide association studies has led to the identification of multiple genes, including several that were not previously known to play any role in T2D. Highly replicated genes, for example TCF7L2, KCNQ1 and KCNJ11, are discussed in greater detail. Taken together, the genetic loci discovered to date explain only a small proportion of the observed heritability. We discuss possible explanations for this “missing heritability”, including the role of rare variants, gene-environment interactions and epigenetics. The clinical utility of current findings and avenues of future research are also discussed.
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Chen J, Yuan T, Liu M, Chen P. Association between TCF7L2 gene polymorphism and cancer risk: a meta-analysis. PLoS One 2013; 8:e71730. [PMID: 23951231 PMCID: PMC3739728 DOI: 10.1371/journal.pone.0071730] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Accepted: 07/09/2013] [Indexed: 01/14/2023] Open
Abstract
Objective The transcription factor 7-like 2 (TCF7L2) gene has been suggested to play an important role in the pathogenesis of cancer. However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the associations between TCF7L2 polymorphism and cancer risk. Methods Published literature from PubMed and EMBASE were retrieved. Pooled odds ratios (ORs) with 95% confidence interval (CIs) were calculated using fixed- or random-effects model. Results A total of 19 studies (14,814 cases and 33,856 controls) were identified for the analysis of the association between TCF7L2 polymorphism and cancer risk. The results showed that TCF7L2 polymorphism was associated with breast cancer (Homogeneous model: OR = 1.17, 95%CI = 1.02–1.35, I2 = 21.8%, p for heterogeneity = 0.276; Heterogeneous model: OR = 1.11, 95%CI = 1.03–1.20, I2 = 0.0%, p for heterogeneity = 0.543), prostate cancer (Homogeneous model: OR = 0.89, 95%CI = 0.84–0.96, I2 = 0.0%, p for heterogeneity = 0.640; Heterogeneous model: OR = 0.89, 95%CI = 0.84–0.95, I2 = 0.0%, p for heterogeneity = 0.871), and colon cancer (Heterogeneous model: OR = 1.15, 95%CI = 1.01–1.31, I2 = 0.0%, p for heterogeneity = 0.658), but not with colorectal cancer, lung cancer, and ovarian cancer. Conclusions The present meta-analysis indicated that there were significantly associations between the TCF7L2 rs7903146 polymorphism and risk of breast, prostate and colon cancers, rather than colorectal cancer, lung cancer, and ovarian cancer.
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Affiliation(s)
- Jingxiang Chen
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of the Third Military Medical University, Chongqing, China
- Department of Hepatobiliary Surgery, Jiangjin Central Hospital, Chongqing, China
| | - Tao Yuan
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of the Third Military Medical University, Chongqing, China
| | - Menggang Liu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of the Third Military Medical University, Chongqing, China
| | - Ping Chen
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of the Third Military Medical University, Chongqing, China
- * E-mail:
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Ling Q, Dong F, Geng L, Liu Z, Xie H, Xu X, Zheng S. Impacts of TCF7L2 gene polymorphisms on the susceptibility of hepatogenous diabetes and hepatocellular carcinoma in cirrhotic patients. Gene 2013; 522:214-218. [PMID: 23558246 DOI: 10.1016/j.gene.2013.03.089] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Revised: 02/15/2013] [Accepted: 03/16/2013] [Indexed: 01/19/2023]
Abstract
BACKGROUND Hepatogenous diabetes (HD) occurs as a complication of cirrhosis. Whether genetic factors, rather than only liver damage, play roles in the development of HD is unknown. TCF7L2 gene has been reported to be associated with type 2 diabetes and also cancer risks. We aim to evaluate the impact of TCF7L2 gene on the susceptibility of HD and hepatocellular carcinoma (HCC) in a Chinese Han population. PATIENTS AND METHODS A total of 367 adult liver transplant candidates with liver cirrhosis were included. Fifteen tag single nucleotide polymorphisms (SNPs) were selected from HapMap CHB database with a minor allele frequency of >0.2 and r(2) of >0.8. Another three SNPs were also chosen because of their close association with type 2 diabetes in East Asian. RESULTS Patients with HD presented significantly poorer liver function, higher incidence of cirrhotic complications and higher insulin resistance compared with non-HD patients. Three SNPs were differentially distributed between HD patients and non-HD patients. In multivariate logistic analysis, TCF7L2 rs290487 and rs6585194 polymorphisms were independently associated with HD after adjustment of clinical factors. The TCF7L2 rs290487 C/C variant homozygote showed much higher insulin resistance and significantly increased HD risk comparing with T/T and T/C genotypes, while the genetic variant of rs6585194 was protectively against HD. Three SNPs (rs290481, rs290487 and rs290489) located near the 3' end of TCF7L2 gene were associated with HCC risk with marginal significance. Patients carrying G-C-A haplotype had a significantly higher HCC risk than those with A-T-G. CONCLUSIONS TCF7L2 polymorphisms were associated with HD and maybe cancer risk as well. Further studies with large samples are needed to verify these results.
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Affiliation(s)
- Qi Ling
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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Association of single nucleotide polymorphisms in Wnt signaling pathway genes with breast cancer in Saudi patients. PLoS One 2013; 8:e59555. [PMID: 23516639 PMCID: PMC3597615 DOI: 10.1371/journal.pone.0059555] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2012] [Accepted: 02/15/2013] [Indexed: 12/28/2022] Open
Abstract
Breast cancer is a complex heterogeneous disease involving genetic and epigenetic alterations in genes encoding proteins that are components of various signaling pathways. Candidate gene approach have identified association of genetic variants in the Wnt signaling pathway genes and increased susceptibility to several diseases including breast cancer. Due to the rarity of somatic mutations in key genes of Wnt pathway, we investigated the association of genetic variants in these genes with predisposition to breast cancers. We performed a case-control study to identify risk variants by examining 15 SNPs located in 8 genes associated with Wnt signaling. Genotypic analysis of individual locus showed statistically significant association of five SNPs located in β-catenin, AXIN2, DKK3, SFRP3 and TCF7L2 with breast cancers. Increased risk was observed only with the SNP in β-catenin while the other four SNPs conferred protection against breast cancers. Majority of these associations persisted after stratification of the cases based on estrogen receptor status and age of on-set of breast cancer. The rs7775 SNP in exon 6 of SFRP3 gene that codes for either arginine or glycine exhibited very strong association with breast cancer, even after Bonferroni's correction. Apart from these five variants, rs3923086 in AXIN2 and rs3763511 in DKK4 that did not show any association in the overall population were significantly associated with early on-set and estrogen receptor negative breast cancers, respectively. This is the first study to utilize pathway based approach to identify association of risk variants in the Wnt signaling pathway genes with breast cancers. Confirmation of our findings in larger populations of different ethnicities would provide evidence for the role of Wnt pathway as well as screening markers for early detection of breast carcinomas.
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