76 results on '"BAILEY SD"'
Search Results
2. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy
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Mack, SC, Witt, H, Piro, RM, Gu, L, Zuyderduyn, S, Stütz, AM, Wang, X, Gallo, M, Garzia, L, Zayne, K, Zhang, X, Ramaswamy, V, Jäger, N, Jones, DTW, Sill, M, Pugh, TJ, Ryzhova, M, Wani, KM, Shih, DJH, Head, R, Remke, M, Bailey, SD, Zichner, T, Faria, CC, Barszczyk, M, Stark, S, Seker-Cin, H, Hutter, S, Johann, P, Bender, S, Hovestadt, V, Tzaridis, T, Dubuc, AM, Northcott, PA, Peacock, J, Bertrand, KC, Agnihotri, S, Cavalli, FMG, Clarke, I, Nethery-Brokx, K, Creasy, CL, Verma, SK, Koster, J, Wu, X, Yao, Y, Milde, T, Sin-Chan, P, Zuccaro, J, Lau, L, Pereira, S, Castelo-Branco, P, Hirst, M, Marra, MA, Roberts, SS, Fults, D, Massimi, L, Cho, YJ, Van Meter, T, Grajkowska, W, Lach, B, Kulozik, AE, von Deimling, A, Witt, O, Scherer, SW, Fan, X, Muraszko, KM, Kool, M, Pomeroy, SL, Gupta, N, Phillips, J, Huang, A, Tabori, U, Hawkins, C, Malkin, D, Kongkham, PN, Weiss, WA, Jabado, N, Rutka, JT, Bouffet, E, Korbel, JO, Lupien, M, Aldape, KD, Bader, GD, Eils, R, Lichter, P, Dirks, PB, Pfister, SM, Korshunov, A, and Taylor, MD
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Biological Sciences ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Pediatric ,Human Genome ,Rare Diseases ,Animals ,Brain Neoplasms ,CpG Islands ,DNA Methylation ,Embryonic Stem Cells ,Ependymoma ,Epigenesis ,Genetic ,Epigenomics ,Female ,Gene Expression Regulation ,Neoplastic ,Gene Silencing ,Histones ,Humans ,Infant ,Mice ,Mice ,Inbred NOD ,Mice ,SCID ,Mutation ,Phenotype ,Polycomb Repressive Complex 2 ,Prognosis ,Rhombencephalon ,Xenograft Model Antitumor Assays ,General Science & Technology - Abstract
Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
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- 2014
3. Erratum: Meta-analysis of dense genecentric association studies reveals common and uncommon variants associated with height ((The American Journal of Human Genetics (2010) 88 (6-18))
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Lanktree, MB, Guo, Y, Murtaza, M, Glessner, JT, Bailey, SD, Onland-Moret, NC, Lettre, G, Ongen, H, Rajagopalan, R, Johnson, T, Shen, H, Nelson, CP, Klopp, N, Baumert, J, Padmanabhan, S, Pankratz, N, Pankow, JS, Shah, S, Taylor, K, Barnard, J, Peters, BJ, Maloney, CM, Lobmeyer, MT, Stanton, A, Zafarmand, MH, Romaine, SPR, Mehta, A, Van Iperen, EPA, Gong, Y, Price, TS, Smith, EN, Kim, CE, Li, YR, Asselbergs, FW, Atwood, LD, Bailey, KM, Bhatt, D, Bauer, F, Behr, ER, Bhangale, T, Boer, JMA, Boehm, BO, Bradfield, JP, Brown, M, Braund, PS, Burton, PR, Carty, C, Chandrupatla, HR, Chen, W, Connell, J, Dalgeorgou, C, De Boer, A, Drenos, F, Elbers, CC, Fang, JC, Fox, CS, Frackelton, EC, Fuchs, B, Furlong, CE, Gibson, Q, Gieger, C, Goel, A, Grobbee, DE, Hastie, C, Howard, PJ, Huang, G-H, Johnson, WC, Li, Q, Kleber, ME, Klein, BEK, Klein, R, Kooperberg, C, Ky, B, Lacroix, A, Lanken, P, Lathrop, M, Li, M, Marshall, V, Melander, O, Mentch, FD, Meyer, NJ, Monda, KL, Montpetit, A, Murugesan, G, Nakayama, K, Nondahl, D, Onipinla, A, Rafelt, S, Newhouse, SJ, Otieno, FG, Patel, SR, Putt, ME, Rodriguez, S, Safa, RN, Sawyer, DB, Schreiner, PJ, Simpson, C, Sivapalaratnam, S, Srinivasan, SR, Suver, C, Swergold, G, Sweitzer, NK, Thomas, KA, Thorand, B, Timpson, NJ, Tischfield, S, Tobin, M, Tomaszewski, M, Verschuren, WMM, Wallace, C, Winkelmann, B, Zhang, H, Zheng, D, Zhang, L, Zmuda, JM, Clarke, R, Balmforth, AJ, Danesh, J, Day, IN, Schork, NJ, De Bakker, PIW, Delles, C, Duggan, D, Hingorani, AD, Hirschhorn, JN, Hofker, MH, Humphries, SE, Kivimaki, M, Lawlor, DA, Kottke-Marchant, K, Mega, JL, Mitchell, BD, Morrow, DA, Palmen, J, Redline, S, Shields, DC, Shuldiner, AR, Sleiman, PM, Smith, GD, Farrall, M, Jamshidi, Y, Christiani, DC, Casas, JP, Hall, AS, Doevendans, PA, Christie, JD, Berenson, GS, Murray, SS, Illig, T, Dorn, GW, Cappola, TP, Boerwinkle, E, Sever, P, Rader, DJ, Reilly, MP, Caulfield, M, Talmud, PJ, Topol, E, Engert, JC, Wang, K, Dominiczak, A, Hamsten, A, Curtis, SP, Silverstein, RL, Lange, LA, Sabatine, MS, Trip, M, Saleheen, D, Peden, JF, Cruickshanks, KJ, März, W, O'Connell, JR, Klungel, OH, Wijmenga, C, Maitland-Van Der Zee, AH, Schadt, EE, Johnson, JA, Jarvik, GP, Papanicolaou, GJ, Grant, SFA, Munroe, PB, North, KE, Samani, NJ, Koenig, W, Gaunt, TR, Anand, SS, Van Der Schouw, YT, Soranzo, N, Fitzgerald, GA, Reiner, A, Hegele, RA, Hakonarson, H, and Keating, BJ
- Published
- 2012
4. External exercise information provides no immediate additional performance benefit to untrained individuals in time trial cycling.
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Williams CA, Bailey SD, and Mauger AR
- Abstract
Objective To determine the importance of the provision of external exercise information to the setting of the pacing strategy, in subjects unfamiliar with a cycling task. Design Twenty-two healthy, untrained cyclists (VO(2max), 50±9 mL-(1)·kg-(1)·min-(1)) were randomly assigned to a control (CON) group or an experimental (EXP) group and two successive 4 km time trials (TT) were performed, separated by a 17 min recovery. The CON group received distance knowledge and distance feedback; the EXP group received neither, but knew that each TT was to be of the same distance Results No significant difference in completion time (p>0.05) was observed between the groups for either time to complete TT one (TT1) (CON=443±33 s versus EXP=471±63 s) or time to complete TT two (time trial 2) (CON=461 ±37 s versus EXP=501±94 s). No significant difference in the final RPE was observed between groups. However, a significant interaction for RPE (rating of perceived exertion)xTT in the CON was observed (F7,70=5.32, p<0.05), with significantly higher RPE values in the final kilometre of TT2 (p<0.05). Conclusion The lack of any performance improvement in either group, despite the differences in exercise information received, indicates both a reliance on the afferent feedback for setting a pacing strategy and slow learning effect from practice in subjects unfamiliar with the task. The modification in RPE profile observed in the CON, despite no performance improvement, suggests exercise perception based changes may pre-empt work rate based changes and thus not immediately translate to improved performance. [ABSTRACT FROM AUTHOR]
- Published
- 2012
5. Intimate partner aggression perpetrated and sustained by male Afghanistan, Iraq, and Vietnam veterans with and without posttraumatic stress disorder.
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Teten AL, Schumacher JA, Taft CT, Stanley MA, Kent TA, Bailey SD, Dunn NJ, and White DL
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- 2010
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6. Empathic deficits and alexithymia in trauma-related impulsive aggression.
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Teten AL, Miller LA, Bailey SD, Dunn NJ, and Kent TA
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- 2008
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7. The effect of chromosome 9p21 variants on cardiovascular disease may be modified by dietary intake: evidence from a case/control and a prospective study.
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Do R, Xie C, Zhang X, Männistö S, Harald K, Islam S, Bailey SD, Rangarajan S, McQueen MJ, Diaz R, Lisheng L, Wang X, Silander K, Peltonen L, Yusuf S, Salomaa V, Engert JC, Anand SS, INTERHEART investigators, and Do, Ron
- Abstract
Background: One of the most robust genetic associations for cardiovascular disease (CVD) is the Chromosome 9p21 region. However, the interaction of this locus with environmental factors has not been extensively explored. We investigated the association of 9p21 with myocardial infarction (MI) in individuals of different ethnicities, and tested for an interaction with environmental factors.Methods and Findings: We genotyped four 9p21 SNPs in 8,114 individuals from the global INTERHEART study. All four variants were associated with MI, with odds ratios (ORs) of 1.18 to 1.20 (1.85×10(-8)≤p≤5.21×10(-7)). A significant interaction (p = 4.0×10(-4)) was observed between rs2383206 and a factor-analysis-derived "prudent" diet pattern score, for which a major component was raw vegetables. An effect of 9p21 on MI was observed in the group with a low prudent diet score (OR = 1.32, p = 6.82×10(-7)), but the effect was diminished in a step-wise fashion in the medium (OR = 1.17, p = 4.9×10(-3)) and high prudent diet scoring groups (OR = 1.02, p = 0.68) (p = 0.014 for difference). We also analyzed data from 19,129 individuals (including 1,014 incident cases of CVD) from the prospective FINRISK study, which used a closely related dietary variable. In this analysis, the 9p21 risk allele demonstrated a larger effect on CVD risk in the groups with diets low or average for fresh vegetables, fruits, and berries (hazard ratio [HR] = 1.22, p = 3.0×10(-4), and HR = 1.35, p = 4.1×10(-3), respectively) compared to the group with high consumption of these foods (HR = 0.96, p = 0.73) (p = 0.0011 for difference). The combination of the least prudent diet and two copies of the risk allele was associated with a 2-fold increase in risk for MI (OR = 1.98, p = 2.11×10(-9)) in the INTERHEART study and a 1.66-fold increase in risk for CVD in the FINRISK study (HR = 1.66, p = 0.0026).Conclusions: The risk of MI and CVD conferred by Chromosome 9p21 SNPs appears to be modified by a prudent diet high in raw vegetables and fruits. Please see later in the article for the Editors' Summary. [ABSTRACT FROM AUTHOR]- Published
- 2011
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8. Characterizing aggression and its association to anger and hostility among male veterans with post-traumatic stress disorder.
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Teten AL, Miller LA, Stanford MS, Petersen NJ, Bailey SD, Collins RL, Dunn NJ, Kent TA, Teten, Andra L, Miller, Lisa A, Stanford, Matthew S, Petersen, Nancy J, Bailey, Sara D, Collins, Robert L, Dunn, Nancy Jo, and Kent, Thomas A
- Abstract
Objectives: The basis for the associations among anger, hostility, aggressive behavior, and post-traumatic stress disorder (PTSD) remains unclear. We suggest classifying aggressive behavior may elucidate the associations among these factors. On the basis of diagnostic and neurobiological similarities between impulsive aggression (IA) and PTSD, we proposed that IA was the predominant form of aggression in PTSD and that anger and hostility would not significantly predict PTSD when IA was also included as a predictor.Methods: We used cross-sectional self-report data obtained from two samples of male veterans (N = 136).Results: Over 70% of veterans with PTSD reported IA compared to 29% of those without PTSD. IA, not anger, hostility, or premeditated aggression significantly predicted a diagnosis of PTSD.Conclusions: Associations between anger and PTSD may be unique to individuals with IA, and considering impulsive and premeditated aggressors separately may account for the heterogeneity found within samples of aggressive veterans with PTSD. [ABSTRACT FROM AUTHOR]- Published
- 2010
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9. Chromatin interaction maps identify oncogenic targets of enhancer duplications in cancer.
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Song Y, Li F, Wang S, Wang Y, Lai C, Chen L, Jiang N, Li J, Chen X, Bailey SD, and Zhang X
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As a major type of structural variants, tandem duplication plays a critical role in tumorigenesis by increasing oncogene dosage. Recent work has revealed that noncoding enhancers are also affected by duplications leading to the activation of oncogenes that are inside or outside of the duplicated regions. However, the prevalence of enhancer duplication and the identity of their target genes remains largely unknown in the cancer genome. Here, by analyzing whole-genome sequencing data in a non-gene-centric manner, we identify 881 duplication hotspots in 13 major cancer types, most of which do not contain protein-coding genes. We show that the hotspots are enriched with distal enhancer elements and are highly lineage-specific. We develop a HiChIP-based methodology that navigates enhancer-promoter contact maps to prioritize the target genes for the duplication hotspots harboring enhancer elements. The methodology identifies many novel enhancer duplication events activating oncogenes such as ESR1 , FOXA1 , GATA3, GATA6, TP63 , and VEGFA , as well as potentially novel oncogenes such as GRHL2, IRF2BP2 , and CREB3L1 In particular, we identify a duplication hotspot on Chromosome 10p15 harboring a cluster of enhancers, which skips over two genes, through a long-range chromatin interaction, to activate an oncogenic isoform of the NET1 gene to promote migration of gastric cancer cells. Focusing on tandem duplications, our study substantially extends the catalog of noncoding driver alterations in multiple cancer types, revealing attractive targets for functional characterization and therapeutic intervention., (© 2024 Song et al.; Published by Cold Spring Harbor Laboratory Press.)
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- 2024
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10. 3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression.
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Mortenson KL, Dawes C, Wilson ER, Patchen NE, Johnson HE, Gertz J, Bailey SD, Liu Y, Varley KE, and Zhang X
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- Humans, Cell Line, Tumor, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology, Enhancer Elements, Genetic genetics, Promoter Regions, Genetic genetics, Oncogenes, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Gene Expression Regulation, Neoplastic, Genomics methods, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism
- Abstract
Cancer genomes are composed of many complex structural alterations on chromosomes and extrachromosomal DNA (ecDNA), making it difficult to identify non-coding enhancer regions that are hijacked to activate oncogene expression. Here, we describe a 3D genomics-based analysis called HAPI (Highly Active Promoter Interactions) to characterize enhancer hijacking. HAPI analysis of HiChIP data from 34 cancer cell lines identified enhancer hijacking events that activate both known and potentially novel oncogenes such as MYC, CCND1, ETV1, CRKL, and ID4. Furthermore, we found enhancer hijacking among multiple oncogenes from different chromosomes, often including MYC, on the same complex amplicons such as ecDNA. We characterized a MYC-ERBB2 chimeric ecDNA, in which ERBB2 heavily hijacks MYC's enhancers. Notably, CRISPRi of the MYC promoter led to increased interaction of ERBB2 with MYC enhancers and elevated ERBB2 expression. Our HAPI analysis tool provides a robust strategy to detect enhancer hijacking and reveals novel insights into oncogene activation., (© 2024. The Author(s).)
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- 2024
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11. HiChIP-Based Epigenomic Footprinting Identifies a Promoter Variant of UXS1 That Confers Genetic Susceptibility to Gastroesophageal Cancer.
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Gnanapragasam A, Kirbizakis E, Li A, White KH, Mortenson KL, Cavalcante de Moura J, Jawhar W, Yan Y, Falter R, Russett C, Giannias B, Camilleri-Broët S, Bertos N, Cools-Lartigue J, Garzia L, Sangwan V, Ferri L, Zhang X, and Bailey SD
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- Humans, Histones genetics, Histones metabolism, Cell Line, Tumor, Stomach Neoplasms genetics, Stomach Neoplasms pathology, Promoter Regions, Genetic, Genetic Predisposition to Disease, Esophageal Neoplasms genetics, Esophageal Neoplasms pathology, Polymorphism, Single Nucleotide, Genome-Wide Association Study methods, Epigenomics methods
- Abstract
Genome-wide association studies (GWAS) have identified more than a hundred single nucleotide variants (SNV) associated with the risk of gastroesophageal cancer (GEC). The majority of the identified SNVs map to noncoding regions of the genome. Uncovering the causal SNVs and genes they modulate could help improve GEC prevention and treatment. Herein, we used HiChIP against histone 3 lysine 27 acetylation (H3K27ac) to simultaneously annotate active promoters and enhancers, identify the interactions between them, and detect nucleosome-free regions (NFR) harboring potential causal SNVs in a single assay. The application of H3K27ac HiChIP in GEC relevant models identified 61 potential functional SNVs that reside in NFRs and interact with 49 genes at 17 loci. The approach led to a 67% reduction in the number of SNVs in linkage disequilibrium at these 17 loci, and at 7 loci, a single putative causal SNV was identified. One SNV, rs147518036, located within the promoter of the UDP-glucuronate decarboxylase 1 (UXS1) gene, seemed to underlie the GEC risk association captured by the rs75460256 index SNV. The rs147518036 SNV creates a GABPA DNA recognition motif, resulting in increased promoter activity, and CRISPR-mediated inhibition of the UXS1 promoter reduced the viability of the GEC cells. These findings provide a framework that simplifies the identification of potentially functional regulatory SNVs and target genes underlying risk-associated loci. In addition, the study implicates increased expression of the enzyme UXS1 and activation of its metabolic pathway as a predisposition to gastric cancer, which highlights potential therapeutic avenues to treat this disease. Significance: Epigenomic footprinting using a histone posttranslational modification targeted 3D genomics methodology elucidates functional noncoding sequence variants and their target genes at cancer risk loci., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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12. Multidimensional biomarker predicts disease control in response to immunotherapy in recurrent or metastatic head and neck squamous-cell carcinoma.
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Flanagan KC, Earls J, Schillebeeckx I, Hiken J, Wellinghoff RL, LaFranzo NA, Bradley ZS, Babbitt J, Westra WH, Hsu R, Nadauld L, Mcleod H, Firth SD, Sharp B, Fuller J, Vavinskaya V, Sutton L, Deichaite I, Bailey SD, Sandulache VC, Rendo MJ, Macdonald OK, Welaya K, Wade JL 3rd, Pippas AW, Slim J, Bank B, Saccaro SJ, Sui X, Akhtar A, Balaraman S, Kossman SE, Sonnier SA, Shenkenberg TD, Alexander WL, Price KA, Bane CL, Ley J, Messina DN, Glasscock JI, Cohen EEW, Adkins DR, and Duncavage EJ
- Abstract
Purpose: Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity., Methods: Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods., Results: The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p < 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009)., Conclusion: This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy., (© 2023. The Author(s).)
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- 2023
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13. Tumour extracellular vesicles induce neutrophil extracellular traps to promote lymph node metastasis.
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Su X, Brassard A, Bartolomucci A, Dhoparee-Doomah I, Qiu Q, Tsering T, Rohanizadeh R, Koufos O, Giannias B, Bourdeau F, Feng L, Messina-Pacheco J, Leo S, Sangwan V, Quail D, Tankel J, Spicer J, Burnier JV, Bailey SD, Ferri L, and Cools-Lartigue J
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- Animals, Lymphatic Metastasis pathology, Endothelial Cells, Lymph Nodes pathology, Extracellular Traps, Extracellular Vesicles
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Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastatic status. However, there is evidence suggesting that LN metastasis is facilitated by the formation of a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. Earlier work has demonstrated that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition diminishes LN metastases in animal models. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Finally, we showed that lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings reveal the role of EV-induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities that may occur early in the metastatic cascade., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)
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- 2023
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14. Soluble factors in malignant ascites promote the metastatic adhesion of gastric adenocarcinoma cells.
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Al-Marzouki L, Stavrakos VS, Pal S, Giannias B, Bourdeau F, Rayes R, Bertos N, Najmeh S, Spicer JD, Cools-Lartigue J, Bailey SD, Ferri L, and Sangwan V
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- Humans, Animals, Mice, Ascites pathology, Vascular Endothelial Growth Factor A metabolism, Cell Line, Tumor, Peritoneal Neoplasms secondary, Stomach Neoplasms pathology, Adenocarcinoma
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Background: Adenocarcinoma of the proximal stomach is the fastest rising malignancy in North America. It is commonly associated with peritoneal accumulation of malignant ascites (MA), a fluid containing cancer and inflammatory cells and soluble proteins. Peritoneal metastasis (PM) is the most common site of gastric cancer (GC) progression after curative-intent surgery and is the leading cause of death among GC patients., Methods/results: Using a panel of gastric adenocarcinoma cell lines (human: MKN 45, SNU-5; murine: NCC-S1M), we demonstrate that prior incubation of GC cells with MA results in a significant (> 1.7-fold) increase in the number of cells capable of adhering to human peritoneal mesothelial cells (HPMC) (p < 0.05). We then corroborate these findings using an ex vivo PM model and show that MA also significantly enhances the ability of GC cells to adhere to strips of human peritoneum (p < 0.05). Using a multiplex ELISA, we identify MIF and VEGF as consistently elevated across MA samples from GC patients (p < 0.05). We demonstrate that agents that block the effects of MIF or VEGF abrogate the ability of MA to stimulate the adhesion of GC cells to adhere to human peritoneum and promote both ex vivo and in vivo metastases., Conclusion: Agents targeting MIF or VEGF may be relevant to the treatment or prevention of PM in GC patients., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)
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- 2023
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15. Author Correction: Failure of human rhombic lip differentiation underlies medulloblastoma formation.
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Hendrikse LD, Haldipur P, Saulnier O, Millman J, Sjoboen AH, Erickson AW, Ong W, Gordon V, Coudière-Morrison L, Mercier AL, Shokouhian M, Suárez RA, Ly M, Borlase S, Scott DS, Vladoiu MC, Farooq H, Sirbu O, Nakashima T, Nambu S, Funakoshi Y, Bahcheli A, Diaz-Mejia JJ, Golser J, Bach K, Phuong-Bao T, Skowron P, Wang EY, Kumar SA, Balin P, Visvanathan A, Lee JJY, Ayoub R, Chen X, Chen X, Mungall KL, Luu B, Bérubé P, Wang YC, Pfister SM, Kim SK, Delattre O, Bourdeaut F, Doz F, Masliah-Planchon J, Grajkowska WA, Loukides J, Dirks P, Fèvre-Montange M, Jouvet A, French PJ, Kros JM, Zitterbart K, Bailey SD, Eberhart CG, Rao AAN, Giannini C, Olson JM, Garami M, Hauser P, Phillips JJ, Ra YS, de Torres C, Mora J, Li KKW, Ng HK, Poon WS, Pollack IF, López-Aguilar E, Gillespie GY, Van Meter TE, Shofuda T, Vibhakar R, Thompson RC, Cooper MK, Rubin JB, Kumabe T, Jung S, Lach B, Iolascon A, Ferrucci V, de Antonellis P, Zollo M, Cinalli G, Robinson S, Stearns DS, Van Meir EG, Porrati P, Finocchiaro G, Massimino M, Carlotti CG, Faria CC, Roussel MF, Boop F, Chan JA, Aldinger KA, Razavi F, Silvestri E, McLendon RE, Thompson EM, Ansari M, Garre ML, Chico F, Eguía P, Pérezpeña M, Morrissy AS, Cavalli FMG, Wu X, Daniels C, Rich JN, Jones SJM, Moore RA, Marra MA, Huang X, Reimand J, Sorensen PH, Wechsler-Reya RJ, Weiss WA, Pugh TJ, Garzia L, Kleinman CL, Stein LD, Jabado N, Malkin D, Ayrault O, Golden JA, Ellison DW, Doble B, Ramaswamy V, Werbowetski-Ogilvie TE, Suzuki H, Millen KJ, and Taylor MD
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- 2022
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16. To bind or not to bind: Cistromic reprogramming in prostate cancer.
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Shen M, Demers LK, Bailey SD, and Labbé DP
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The term "cistrome" refers to the genome-wide location of regulatory elements associated with transcription factor binding-sites. The cistrome of key regulatory factors in prostate cancer etiology are substantially reprogrammed and altered during prostatic transformation and disease progression. For instance, the cistrome of the androgen receptor (AR), a ligand-inducible transcription factor central in normal prostate epithelium biology, is directly impacted and substantially reprogrammed during malignant transformation. Accumulating evidence demonstrates that additional transcription factors that are frequently mutated, or aberrantly expressed in prostate cancer, such as the pioneer transcription factors Forkhead Box A1 (FOXA1), the homeobox protein HOXB13, and the GATA binding protein 2 (GATA2), and the ETS-related gene (ERG), and the MYC proto-oncogene, contribute to the reprogramming of the AR cistrome. In addition, recent findings have highlighted key roles for the SWI/SNF complex and the chromatin-modifying helicase CHD1 in remodeling the epigenome and altering the AR cistrome during disease progression. In this review, we will cover the role of cistromic reprogramming in prostate cancer initiation and progression. Specifically, we will discuss the impact of key prostate cancer regulators, as well as the role of epigenetic and chromatin regulators in relation to the AR cistrome and the transformation of normal prostate epithelium. Given the importance of chromatin-transcription factor dynamics in normal cellular differentiation and cancer, an in-depth assessment of the factors involved in producing these altered cistromes is of great relevance and provides insight into new therapeutic strategies for prostate cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shen, Demers, Bailey and Labbé.)
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- 2022
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17. Failure of human rhombic lip differentiation underlies medulloblastoma formation.
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Hendrikse LD, Haldipur P, Saulnier O, Millman J, Sjoboen AH, Erickson AW, Ong W, Gordon V, Coudière-Morrison L, Mercier AL, Shokouhian M, Suárez RA, Ly M, Borlase S, Scott DS, Vladoiu MC, Farooq H, Sirbu O, Nakashima T, Nambu S, Funakoshi Y, Bahcheli A, Diaz-Mejia JJ, Golser J, Bach K, Phuong-Bao T, Skowron P, Wang EY, Kumar SA, Balin P, Visvanathan A, Lee JJY, Ayoub R, Chen X, Chen X, Mungall KL, Luu B, Bérubé P, Wang YC, Pfister SM, Kim SK, Delattre O, Bourdeaut F, Doz F, Masliah-Planchon J, Grajkowska WA, Loukides J, Dirks P, Fèvre-Montange M, Jouvet A, French PJ, Kros JM, Zitterbart K, Bailey SD, Eberhart CG, Rao AAN, Giannini C, Olson JM, Garami M, Hauser P, Phillips JJ, Ra YS, de Torres C, Mora J, Li KKW, Ng HK, Poon WS, Pollack IF, López-Aguilar E, Gillespie GY, Van Meter TE, Shofuda T, Vibhakar R, Thompson RC, Cooper MK, Rubin JB, Kumabe T, Jung S, Lach B, Iolascon A, Ferrucci V, de Antonellis P, Zollo M, Cinalli G, Robinson S, Stearns DS, Van Meir EG, Porrati P, Finocchiaro G, Massimino M, Carlotti CG, Faria CC, Roussel MF, Boop F, Chan JA, Aldinger KA, Razavi F, Silvestri E, McLendon RE, Thompson EM, Ansari M, Garre ML, Chico F, Eguía P, Pérezpeña M, Morrissy AS, Cavalli FMG, Wu X, Daniels C, Rich JN, Jones SJM, Moore RA, Marra MA, Huang X, Reimand J, Sorensen PH, Wechsler-Reya RJ, Weiss WA, Pugh TJ, Garzia L, Kleinman CL, Stein LD, Jabado N, Malkin D, Ayrault O, Golden JA, Ellison DW, Doble B, Ramaswamy V, Werbowetski-Ogilvie TE, Suzuki H, Millen KJ, and Taylor MD
- Subjects
- Cell Lineage, Cerebellum embryology, Cerebellum pathology, Core Binding Factor alpha Subunits genetics, Hedgehog Proteins metabolism, Histone Demethylases, Humans, Ki-67 Antigen metabolism, Muscle Proteins, Mutation, Otx Transcription Factors deficiency, Otx Transcription Factors genetics, Repressor Proteins, T-Box Domain Proteins metabolism, Transcription Factors, Cell Differentiation genetics, Cerebellar Neoplasms classification, Cerebellar Neoplasms genetics, Cerebellar Neoplasms pathology, Medulloblastoma classification, Medulloblastoma genetics, Medulloblastoma pathology, Metencephalon embryology, Metencephalon pathology
- Abstract
Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain
1-4 . Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8 . By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10 . However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4 . Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+ KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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18. A predominant enhancer co-amplified with the SOX2 oncogene is necessary and sufficient for its expression in squamous cancer.
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Liu Y, Wu Z, Zhou J, Ramadurai DKA, Mortenson KL, Aguilera-Jimenez E, Yan Y, Yang X, Taylor AM, Varley KE, Gertz J, Choi PS, Cherniack AD, Chen X, Bass AJ, Bailey SD, and Zhang X
- Subjects
- CRISPR-Cas Systems, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Proliferation, Chromatin, Enhancer Elements, Genetic, Epigenomics, Female, Gene Knockout Techniques, Heterografts, Humans, Oncogenes genetics, Transcription Factors genetics, Transcription Factors metabolism, Carcinoma, Squamous Cell genetics, Gene Expression Regulation, Neoplastic, Neoplasms, Squamous Cell genetics, SOXB1 Transcription Factors genetics, SOXB1 Transcription Factors metabolism
- Abstract
Amplification and overexpression of the SOX2 oncogene represent a hallmark of squamous cancers originating from diverse tissue types. Here, we find that squamous cancers selectively amplify a 3' noncoding region together with SOX2, which harbors squamous cancer-specific chromatin accessible regions. We identify a single enhancer e1 that predominantly drives SOX2 expression. Repression of e1 in SOX2-high cells causes collapse of the surrounding enhancers, remarkable reduction in SOX2 expression, and a global transcriptional change reminiscent of SOX2 knockout. The e1 enhancer is driven by a combination of transcription factors including SOX2 itself and the AP-1 complex, which facilitates recruitment of the co-activator BRD4. CRISPR-mediated activation of e1 in SOX2-low cells is sufficient to rebuild the e1-SOX2 loop and activate SOX2 expression. Our study shows that squamous cancers selectively amplify a predominant enhancer to drive SOX2 overexpression, uncovering functional links among enhancer activation, chromatin looping, and lineage-specific copy number amplifications of oncogenes., (© 2021. The Author(s).)
- Published
- 2021
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19. The transcriptional landscape of Shh medulloblastoma.
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Skowron P, Farooq H, Cavalli FMG, Morrissy AS, Ly M, Hendrikse LD, Wang EY, Djambazian H, Zhu H, Mungall KL, Trinh QM, Zheng T, Dai S, Stucklin ASG, Vladoiu MC, Fong V, Holgado BL, Nor C, Wu X, Abd-Rabbo D, Bérubé P, Wang YC, Luu B, Suarez RA, Rastan A, Gillmor AH, Lee JJY, Zhang XY, Daniels C, Dirks P, Malkin D, Bouffet E, Tabori U, Loukides J, Doz FP, Bourdeaut F, Delattre OO, Masliah-Planchon J, Ayrault O, Kim SK, Meyronet D, Grajkowska WA, Carlotti CG, de Torres C, Mora J, Eberhart CG, Van Meir EG, Kumabe T, French PJ, Kros JM, Jabado N, Lach B, Pollack IF, Hamilton RL, Rao AAN, Giannini C, Olson JM, Bognár L, Klekner A, Zitterbart K, Phillips JJ, Thompson RC, Cooper MK, Rubin JB, Liau LM, Garami M, Hauser P, Li KKW, Ng HK, Poon WS, Yancey Gillespie G, Chan JA, Jung S, McLendon RE, Thompson EM, Zagzag D, Vibhakar R, Ra YS, Garre ML, Schüller U, Shofuda T, Faria CC, López-Aguilar E, Zadeh G, Hui CC, Ramaswamy V, Bailey SD, Jones SJ, Mungall AJ, Moore RA, Calarco JA, Stein LD, Bader GD, Reimand J, Ragoussis J, Weiss WA, Marra MA, Suzuki H, and Taylor MD
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Gene Regulatory Networks, Genetic Variation, Humans, Infant, Male, Middle Aged, Signal Transduction genetics, Young Adult, Cerebellar Neoplasms genetics, Gene Expression Regulation, Neoplastic, Hedgehog Proteins genetics, Medulloblastoma genetics, Transcriptome
- Abstract
Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
- Published
- 2021
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20. Chromatin Looping Shapes KLF5-Dependent Transcriptional Programs in Human Epithelial Cancers.
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Liu Y, Guo B, Aguilera-Jimenez E, Chu VS, Zhou J, Wu Z, Francis JM, Yang X, Choi PS, Bailey SD, and Zhang X
- Subjects
- CRISPR-Cas Systems, Cell Line, Tumor, Cell Lineage genetics, Cell Proliferation genetics, Gene Expression, Gene Expression Regulation, Neoplastic, Humans, Kruppel-Like Transcription Factors genetics, Neoplasms, Glandular and Epithelial pathology, Phenotype, Promoter Regions, Genetic, Protein Binding genetics, Chromatin metabolism, Epithelial Cells metabolism, Kruppel-Like Transcription Factors metabolism, Neoplasms, Glandular and Epithelial metabolism, Transcription, Genetic genetics
- Abstract
Activation of transcription factors is a key driver event in cancer. We and others have recently reported that the Krüppel-like transcription factor KLF5 is activated in multiple epithelial cancer types including squamous cancer and gastrointestinal adenocarcinoma, yet the functional consequences and the underlying mechanisms of this activation remain largely unknown. Here we demonstrate that activation of KLF5 results in strongly selective KLF5 dependency for these cancer types. KLF5 bound lineage-specific regulatory elements and activated gene expression programs essential to cancer cells. HiChIP analysis revealed that multiple distal KLF5 binding events cluster and synergize to activate individual target genes. Immunoprecipitation-mass spectrometry assays showed that KLF5 interacts with other transcription factors such as TP63 and YAP1, as well as the CBP/EP300 acetyltransferase complex. Furthermore, KLF5 guided the CBP/EP300 complex to increase acetylation of H3K27, which in turn enhanced recruitment of the bromodomain protein BRD4 to chromatin. The 3D chromatin architecture aggregated KLF5-dependent BRD4 binding to activate polymerase II elongation at KLF5 target genes, which conferred a transcriptional vulnerability to proteolysis-targeting chimera-induced degradation of BRD4. Our study demonstrates that KLF5 plays an essential role in multiple epithelial cancers by activating cancer-related genes through 3D chromatin loops, providing an evidence-based rationale for targeting the KLF5 pathway. SIGNIFICANCE: An integrative 3D genomics methodology delineates mechanisms underlying the function of KLF5 in multiple epithelial cancers and suggests potential strategies to target cancers with aberrantly activated KLF5., (©2020 American Association for Cancer Research.)
- Published
- 2020
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21. Author Correction: Human somatic cell mutagenesis creates genetically tractable sarcomas.
- Author
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Molyneux SD, Waterhouse PD, Shelton D, Shao YW, Watling CM, Tang QL, Harris IS, Dickson BC, Tharmapalan P, Sandve GK, Zhang X, Bailey SD, Berman H, Wunder JS, Izsvák Z, Lupien M, Mak TW, and Khokha R
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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22. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.
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Suzuki H, Kumar SA, Shuai S, Diaz-Navarro A, Gutierrez-Fernandez A, De Antonellis P, Cavalli FMG, Juraschka K, Farooq H, Shibahara I, Vladoiu MC, Zhang J, Abeysundara N, Przelicki D, Skowron P, Gauer N, Luu B, Daniels C, Wu X, Forget A, Momin A, Wang J, Dong W, Kim SK, Grajkowska WA, Jouvet A, Fèvre-Montange M, Garrè ML, Nageswara Rao AA, Giannini C, Kros JM, French PJ, Jabado N, Ng HK, Poon WS, Eberhart CG, Pollack IF, Olson JM, Weiss WA, Kumabe T, López-Aguilar E, Lach B, Massimino M, Van Meir EG, Rubin JB, Vibhakar R, Chambless LB, Kijima N, Klekner A, Bognár L, Chan JA, Faria CC, Ragoussis J, Pfister SM, Goldenberg A, Wechsler-Reya RJ, Bailey SD, Garzia L, Morrissy AS, Marra MA, Huang X, Malkin D, Ayrault O, Ramaswamy V, Puente XS, Calarco JA, Stein L, and Taylor MD
- Subjects
- Adolescent, Adult, Alternative Splicing, Hedgehog Proteins metabolism, Humans, Mutation, RNA Splice Sites, RNA Splicing, Cerebellar Neoplasms genetics, Hedgehog Proteins genetics, Medulloblastoma genetics, RNA, Small Nuclear genetics
- Abstract
In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes
1-3 . Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.- Published
- 2019
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23. C3D: a tool to predict 3D genomic interactions between cis-regulatory elements.
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Mehdi T, Bailey SD, Guilhamon P, and Lupien M
- Subjects
- Chromatin Immunoprecipitation, Regulatory Sequences, Nucleic Acid, Software, Genome, Genomics
- Abstract
Motivation: The 3D genome architecture influences the regulation of genes by facilitating chromatin interactions between distal cis-regulatory elements and gene promoters. We implement Cross Cell-type Correlation based on DNA accessibility (C3D), a customizable computational tool that predicts chromatin interactions using an unsupervised algorithm that utilizes correlations in chromatin measurements, such as DNaseI hypersensitivity signals., Results: C3D accurately predicts 32.7%, 18.3% and 24.1% of interactions, validated by ChIA-PET assays, between promoters and distal regions that overlie DNaseI hypersensitive sites in K562, MCF-7 and GM12878 cells, respectively., Availability and Implementation: Source code is open-source and freely available on GitHub (https://github.com/LupienLabOrganization/C3D) under the GNU GPLv3 license. C3D is implemented in Bash and R; it runs on any platform with Bash (≥4.0), R (≥3.1.1) and BEDTools (≥2.19.0). It requires the following R packages: GenomicRanges, Sushi, data.table, preprocessCore and dynamicTreeCut., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2019
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24. Publisher Correction: ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters.
- Author
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Bailey SD, Zhang X, Desai K, Aid M, Corradin O, Cowper-Sal Lari R, Akhtar-Zaidi B, Scacheri PC, Haibe-Kains B, and Lupien M
- Abstract
This corrects the article DOI: 10.1038/ncomms7186.
- Published
- 2018
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25. Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer.
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Bailey SD, Desai K, Kron KJ, Mazrooei P, Sinnott-Armstrong NA, Treloar AE, Dowar M, Thu KL, Cescon DW, Silvester J, Yang SY, Wu X, Pezo RC, Haibe-Kains B, Mak TW, Bedard PL, Pugh TJ, Sallari RC, and Lupien M
- Subjects
- CRISPR-Cas Systems, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, MCF-7 Cells, Regulatory Sequences, Nucleic Acid, Transcription Factors metabolism, Breast Neoplasms genetics, Estrogen Receptor alpha genetics, Mutation, Polymorphism, Single Nucleotide
- Abstract
Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer risk-associated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.
- Published
- 2016
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26. Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer.
- Author
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Guo H, Ahmed M, Zhang F, Yao CQ, Li S, Liang Y, Hua J, Soares F, Sun Y, Langstein J, Li Y, Poon C, Bailey SD, Desai K, Fei T, Li Q, Sendorek DH, Fraser M, Prensner JR, Pugh TJ, Pomerantz M, Bristow RG, Lupien M, Feng FY, Boutros PC, Freedman ML, Walsh MJ, and He HH
- Subjects
- Animals, Cell Line, Tumor, Chromatin metabolism, Enhancer Elements, Genetic, Genome-Wide Association Study, Genotype, Humans, Male, Mice, Mice, Inbred NOD, Receptors, Androgen metabolism, Risk Factors, Signal Transduction, Transcription Factors metabolism, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Prostatic Neoplasms genetics, RNA, Long Noncoding genetics
- Abstract
Long noncoding RNAs (lncRNAs) represent an attractive class of candidates to mediate cancer risk. Through integrative analysis of the lncRNA transcriptome with genomic data and SNP data from prostate cancer genome-wide association studies (GWAS), we identified 45 candidate lncRNAs associated with risk to prostate cancer. We further evaluated the mechanism underlying the top hit, PCAT1, and found that a risk-associated variant at rs7463708 increases binding of ONECUT2, a novel androgen receptor (AR)-interacting transcription factor, at a distal enhancer that loops to the PCAT1 promoter, resulting in upregulation of PCAT1 upon prolonged androgen treatment. In addition, PCAT1 interacts with AR and LSD1 and is required for their recruitment to the enhancers of GNMT and DHCR24, two androgen late-response genes implicated in prostate cancer development and progression. PCAT1 promotes prostate cancer cell proliferation and tumor growth in vitro and in vivo. These findings suggest that modulating lncRNA expression is an important mechanism for risk-associated SNPs in promoting prostate transformation.
- Published
- 2016
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27. The Transcriptional Repressor Polycomb Group Factor 6, PCGF6, Negatively Regulates Dendritic Cell Activation and Promotes Quiescence.
- Author
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Boukhaled GM, Cordeiro B, Deblois G, Dimitrov V, Bailey SD, Holowka T, Domi A, Guak H, Chiu HH, Everts B, Pearce EJ, Lupien M, White JH, and Krawczyk CM
- Subjects
- Animals, Bone Marrow Cells cytology, Bone Marrow Cells drug effects, Bone Marrow Cells immunology, Cell Differentiation immunology, Chromatin chemistry, Chromatin metabolism, Dendritic Cells cytology, Dendritic Cells drug effects, Female, Gene Expression Regulation, Histone Demethylases, Histones metabolism, Lipopolysaccharides pharmacology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oxidoreductases, N-Demethylating immunology, Polycomb Repressive Complex 1 antagonists & inhibitors, Polycomb Repressive Complex 1 immunology, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Repressor Proteins immunology, Signal Transduction, Transcription, Genetic, Dendritic Cells immunology, Histones genetics, Oxidoreductases, N-Demethylating genetics, Polycomb Repressive Complex 1 genetics, Repressor Proteins genetics
- Abstract
Pro-inflammatory signals provided by the microenvironment are critical to activate dendritic cells (DCs), components of the innate immune system that shape both innate and adaptive immunity. However, to prevent inappropriate immune activation, mechanisms must be in place to restrain DC activation to ensure DCs are activated only once sufficient stimuli have been received. Here, we report that DC activation and immunogenicity are regulated by the transcriptional repressor Polycomb group factor 6 (PCGF6). Pcgf6 is rapidly downregulated upon stimulation, and this downregulation is necessary to permit full DC activation. Silencing PCGF6 expression enhanced both spontaneous and stimulated DC activation. We show that PCGF6 associates with the H3K4me3 demethylase JARID1c, and together, they negatively regulate H3K4me3 levels in DCs. Our results identify two key regulators, PCGF6 and JARID1c that temper DC activation and implicate active transcriptional silencing via histone demethylation as a previously unappreciated mechanism for regulating DC activation and quiescence., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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28. Pre-neoplastic epigenetic disruption of transcriptional enhancers in chronic inflammation.
- Author
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Planello AC, Singhania R, Kron KJ, Bailey SD, Roulois D, Lupien M, Line SR, de Souza AP, and De Carvalho DD
- Subjects
- Adult, Carcinoma, Squamous Cell genetics, DNA Methylation, Epigenesis, Genetic, Female, Head and Neck Neoplasms genetics, Humans, Inflammation complications, Male, Mouth Neoplasms genetics, Squamous Cell Carcinoma of Head and Neck, Chronic Periodontitis genetics, Enhancer Elements, Genetic genetics, Inflammation genetics, Precancerous Conditions genetics
- Abstract
Chronic periodontitis (CP) is a chronic inflammatory disease independently associated with higher incidence of oral cavity squamous cell carcinoma (OSCC). However, the molecular mechanism responsible for this increased incidence is unknown. Here we profiled the DNA methylome of CP patients and healthy controls and compared to a large set of OSCC samples from TCGA. We observed a significant overlap between the altered DNA methylation patterns in CP and in OSCC, suggesting an emergence of a pre-neoplastic epigenome in CP. Remarkably, the hypermethylated CpGs in CP were significantly enriched for enhancer elements. This aberrant enhancer methylation is functional and able to disrupt enhancer activity by preventing the binding of chromatin looping factors. This study provides new insights on the molecular mechanisms linking chronic inflammation and tumor predisposition, highlighting the role of epigenetic disruption of transcriptional enhancers.
- Published
- 2016
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29. Physical activity and genetic predisposition to obesity in a multiethnic longitudinal study.
- Author
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Reddon H, Gerstein HC, Engert JC, Mohan V, Bosch J, Desai D, Bailey SD, Diaz R, Yusuf S, Anand SS, and Meyre D
- Subjects
- Adult, Alleles, Body Mass Index, Ethnicity genetics, Female, Follow-Up Studies, Genetic Association Studies, Genotype, Humans, Longitudinal Studies, Male, Middle Aged, Patient Outcome Assessment, Polymorphism, Single Nucleotide, Risk, Genetic Predisposition to Disease, Motor Activity, Obesity epidemiology, Obesity genetics
- Abstract
Physical activity (PA) has been shown to reduce the impact of FTO variation and obesity genetic risk scores (GRS) on BMI. We examined this interaction using a quantitative measure of PA and two adiposity indexes in a longitudinal multi-ethnic study. We analyzed the impact of PA on the association between 14 obesity predisposing variants (analyzed independently and as a GRS) and baseline/follow-up obesity measures in the multi-ethnic prospective cohort EpiDREAM (17423 participants from six ethnic groups). PA was analyzed using basic (low-moderate-high) and quantitative measures (metabolic equivalents (METS)), while BMI and the body adiposity index (BAI) were used to measure obesity. Increased PA was associated with decreased BMI/BAI at baseline/follow-up. FTO rs1421085, CDKAL1 rs2206734, TNNl3K rs1514176, GIPR rs11671664 and the GRS were associated with obesity measures at baseline and/or follow-up. Risk alleles of three SNPs displayed nominal associations with increased (NTRK2 rs1211166, BDNF rs1401635) or decreased (NPC1 rs1805081) basic PA score independently of BMI/BAI. Both basic and quantitative PA measures attenuated the association between FTO rs1421085 risk allele and BMI/BAI at baseline and follow-up. Our results show that physical activity can blunt the genetic effect of FTO rs1421085 on adiposity by 36-75% in a longitudinal multi-ethnic cohort.
- Published
- 2016
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30. ABC: a tool to identify SNVs causing allele-specific transcription factor binding from ChIP-Seq experiments.
- Author
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Bailey SD, Virtanen C, Haibe-Kains B, and Lupien M
- Subjects
- Algorithms, Alleles, Chromatin genetics, Computational Biology methods, Female, Hepatocyte Nuclear Factor 3-alpha metabolism, Humans, Protein Binding, Breast Neoplasms genetics, Chromatin metabolism, Chromatin Immunoprecipitation methods, High-Throughput Nucleotide Sequencing methods, Mutation genetics, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic genetics, Transcription Factors metabolism
- Abstract
Motivation: Detection of allelic imbalances in ChIP-Seq reads is a powerful approach to identify functional non-coding single nucleotide variants (SNVs), either polymorphisms or mutations, which modulate the affinity of transcription factors for chromatin. We present ABC, a computational tool that identifies allele-specific binding of transcription factors from aligned ChIP-Seq reads at heterozygous SNVs. ABC controls for potential false positives resulting from biases introduced by the use of short sequencing reads in ChIP-Seq and can efficiently process a large number of heterozygous SNVs., Results: ABC successfully identifies previously characterized functional SNVs, such as the rs4784227 breast cancer risk associated SNP that modulates the affinity of FOXA1 for the chromatin., Availability and Implementation: The code is open-source under an Artistic-2.0 license and versioned on GitHub (https://github.com/mlupien/ABC/). ABC is written in PERL and can be run on any platform with both PERL (≥5.18.1) and R (≥3.1.1) installed. The script requires the PERL Statistics::R module., Contact: mlupien@uhnres.utoronto.ca, Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
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31. BioID identifies novel c-MYC interacting partners in cultured cells and xenograft tumors.
- Author
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Dingar D, Kalkat M, Chan PK, Srikumar T, Bailey SD, Tu WB, Coyaud E, Ponzielli R, Kolyar M, Jurisica I, Huang A, Lupien M, Penn LZ, and Raught B
- Subjects
- Animals, Cell Line, Tumor, Chromosomal Proteins, Non-Histone genetics, DNA-Binding Proteins genetics, Heterografts, Histone Acetyltransferases genetics, Humans, Lysine Acetyltransferase 5, Male, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Transplantation, Neoplasms, Experimental genetics, Proto-Oncogene Proteins c-myc genetics, Transcription Factors genetics, Chromosomal Proteins, Non-Histone metabolism, DNA-Binding Proteins metabolism, Histone Acetyltransferases metabolism, Neoplasms, Experimental metabolism, Proto-Oncogene Proteins c-myc metabolism, Transcription Factors metabolism
- Abstract
The BioID proximity-based biotin labeling technique was recently developed for the characterization of protein-protein interaction networks [1]. To date, this method has been applied to a number of different polypeptides expressed in cultured cells. Here we report the adaptation of BioID to the identification of protein-protein interactions surrounding the c-MYC oncoprotein in human cells grown both under standard culture conditions and in mice as tumor xenografts. Notably, in vivo BioID yielded >100 high confidence MYC interacting proteins, including >30 known binding partners. Putative novel MYC interactors include components of the STAGA/KAT5 and SWI/SNF chromatin remodeling complexes, DNA repair and replication factors, general transcription and elongation factors, and transcriptional co-regulators such as the DNA helicase protein chromodomain 8 (CHD8). Providing additional confidence in these findings, ENCODE ChIP-seq datasets highlight significant coincident binding throughout the genome for the MYC interactors identified here, and we validate the previously unreported MYC-CHD8 interaction using both a yeast two hybrid analysis and the proximity-based ligation assay. In sum, we demonstrate that BioID can be utilized to identify bona fide interacting partners for a chromatin-associated protein in vivo. This technique will allow for a much improved understanding of protein-protein interactions in a previously inaccessible biological setting., Biological Significance: The c-MYC (MYC) oncogene is a transcription factor that plays important roles in cancer initiation and progression. MYC expression is deregulated in more than 50% of human cancers, but the role of this protein in normal cell biology and tumor progression is still not well understood, in part because identifying MYC-interacting proteins has been technically challenging: MYC-containing chromatin-associated complexes are difficult to isolate using traditional affinity purification methods, and the MYC protein is exceptionally labile, with a half-life of only ~30 min. Developing a new strategy to gain insight into MYC-containing protein complexes would thus mark a key advance in cancer research. The recently described BioID proximity-based labeling technique represents a promising new complementary approach for the characterization of protein-protein interactions (PPIs) in cultured cells. Here we report that BioID can also be used to characterize protein-protein interactions for a chromatin-associated protein in tumor xenografts, and present a comprehensive, high confidence in vivo MYC interactome. This article is part of a Special Issue entitled: Protein dynamics in health and disease. Guest Editors: Pierre Thibault and Anne-Claude Gingras., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2015
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32. ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters.
- Author
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Bailey SD, Zhang X, Desai K, Aid M, Corradin O, Cowper-Sal Lari R, Akhtar-Zaidi B, Scacheri PC, Haibe-Kains B, and Lupien M
- Subjects
- Binding Sites, Chromatin genetics, Humans, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Trans-Activators genetics, Chromatin metabolism, Promoter Regions, Genetic, Trans-Activators metabolism
- Abstract
Chromatin interactions connect distal regulatory elements to target gene promoters guiding stimulus- and lineage-specific transcription. Few factors securing chromatin interactions have so far been identified. Here, by integrating chromatin interaction maps with the large collection of transcription factor-binding profiles provided by the ENCODE project, we demonstrate that the zinc-finger protein ZNF143 preferentially occupies anchors of chromatin interactions connecting promoters with distal regulatory elements. It binds directly to promoters and associates with lineage-specific chromatin interactions and gene expression. Silencing ZNF143 or modulating its DNA-binding affinity using single-nucleotide polymorphisms (SNPs) as a surrogate of site-directed mutagenesis reveals the sequence dependency of chromatin interactions at gene promoters. We also find that chromatin interactions alone do not regulate gene expression. Together, our results identify ZNF143 as a novel chromatin-looping factor that contributes to the architectural foundation of the genome by providing sequence specificity at promoters connected with distal regulatory elements.
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- 2015
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33. Enhancer alterations in cancer: a source for a cell identity crisis.
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Kron KJ, Bailey SD, and Lupien M
- Abstract
Enhancers are selectively utilized to orchestrate gene expression programs that first govern pluripotency and then proceed to highly specialized programs required for the process of cellular differentiation. Whereas gene-proximal promoters are typically active across numerous cell types, distal enhancer activation is cell-type-specific and central to cell fate determination, thereby accounting for cell identity. Recent studies have highlighted the diversity of enhancer usage, cataloguing millions of such elements in the human genome. The disruption of enhancer activity, through genetic or epigenetic alterations, can impact cell-type-specific functions, resulting in a wide range of pathologies. In cancer, these alterations can promote a 'cell identity crisis', in which enhancers associated with oncogenes and multipotentiality are activated, while those promoting cell fate commitment are inactivated. Overall, these alterations favor an undifferentiated cellular phenotype. Here, we review the current knowledge regarding the role of enhancers in normal cell function, and discuss how genetic and epigenetic changes in enhancer elements potentiate oncogenesis. In addition, we discuss how understanding the mechanisms regulating enhancer activity can inform therapeutic opportunities in cancer cells and highlight key challenges that remain in understanding enhancer biology as it relates to oncology.
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- 2014
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34. Human somatic cell mutagenesis creates genetically tractable sarcomas.
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Molyneux SD, Waterhouse PD, Shelton D, Shao YW, Watling CM, Tang QL, Harris IS, Dickson BC, Tharmapalan P, Sandve GK, Zhang X, Bailey SD, Berman H, Wunder JS, Izsvák Z, Lupien M, Mak TW, and Khokha R
- Subjects
- Cell Line, DNA Transposable Elements, Genetic Vectors genetics, Genome, Human, HEK293 Cells, Humans, RNA-Binding Proteins genetics, Retroviridae genetics, Mutagenesis, Insertional, Sarcoma genetics
- Abstract
Creating spontaneous yet genetically tractable human tumors from normal cells presents a fundamental challenge. Here we combined retroviral and transposon insertional mutagenesis to enable cancer gene discovery starting with human primary cells. We used lentiviruses to seed gain- and loss-of-function gene disruption elements, which were further deployed by Sleeping Beauty transposons throughout the genome of human bone explant mesenchymal cells. De novo tumors generated rapidly in this context were high-grade myxofibrosarcomas. Tumor insertion sites were enriched in recurrent somatic copy-number aberration regions from multiple cancer types and could be used to pinpoint new driver genes that sustain somatic alterations in patients. We identified HDLBP, which encodes the RNA-binding protein vigilin, as a candidate tumor suppressor deleted at 2q37.3 in greater than one out of ten tumors across multiple tissues of origin. Hybrid viral-transposon systems may accelerate the functional annotation of cancer genomes by enabling insertional mutagenesis screens in higher eukaryotes that are not amenable to germline transgenesis.
- Published
- 2014
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- View/download PDF
35. Laying a solid foundation for Manhattan--'setting the functional basis for the post-GWAS era'.
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Zhang X, Bailey SD, and Lupien M
- Subjects
- DNA, Intergenic genetics, Genetic Predisposition to Disease, Genetic Variation, Genome genetics, Humans, Open Reading Frames genetics, Genome-Wide Association Study
- Abstract
Genome-wide association studies (GWAS) have identified more than 8900 genetic variants, mainly single-nucleotide polymorphisms (SNPs), associated with hundreds of human traits and diseases, which define risk-associated loci. Variants that map to coding regions can affect protein sequence, translation rate, and alternative splicing, all of which influence protein function. However, the vast majority of sequence variants map to non-coding intergenic and intronic regions, and it has been much more challenging to assess the functional nature of these variants. Recent work annotating the non-coding regions of the genome has contributed to post-GWAS studies by facilitating the identification of the functional targets of risk-associated loci. Many non-coding genetic variants within risk-associated loci alter gene expression by modulating the activity of cis-regulatory elements. We review here these recent findings, discuss their implication for the post-GWAS era, and relate their importance to the interpretation of disease-associated mutations identified through whole-genome sequencing., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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36. Variation at the DPP4 locus influences apolipoprotein B levels in South Asians and exhibits heterogeneity in Europeans related to BMI.
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Bailey SD, Xie C, Paré G, Montpetit A, Mohan V, Yusuf S, Gerstein H, Engert JC, and Anand SS
- Subjects
- Adult, Asian People, Case-Control Studies, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 genetics, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, White People, Apolipoproteins B blood, Body Mass Index, Dipeptidyl Peptidase 4 genetics
- Abstract
Aims/hypothesis: Dyslipidaemia, a common feature of type 2 diabetes, is characterised by an increase in atherogenic particles, quantifiable through apolipoprotein B (ApoB) levels. Genetic studies of lipid levels have focused on Europeans; a study in South Asians could identify novel genes., Methods: We tested 31,739 single nucleotide polymorphisms (SNPs) from ∼ 2,000 genes in 2,573 South Asians from the epidemiological arm of the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study (EpiDREAM) for association with ApoB and we tested two novel associations for replication in 1,181 South Asians from the INTERHEART case-control study., Results: The SNP, rs4664443, within DPP4 was associated with ApoB (p = 7.98 × 10(-5)) in EpiDREAM. The observed association was replicated in the INTERHEART South Asians (one-sided p = 9.65 × 10(-3); combined two-sided p = 4.68 × 10(-6)). The rs4664443 SNP was not associated with ApoB among five other EpiDREAM ethnicities. However, because South Asians had a significantly lower mean BMI compared with other EpiDREAM ethnicities, we tested for and found an interaction between rs4664443 and BMI for ApoB among the Europeans, the largest subgroup in EpiDREAM (p = 4.14 × 10(-3) for interaction), observing an association with ApoB in Europeans with a BMI <25 kg/m(2) (p = 2.35 × 10(-3)), but not with a BMI ≥ 25 kg/m(2) (p = 0.21). The association between rs4664443 and ApoB among all EpiDREAM individuals with BMI <25 kg/m(2) was significant (n = 2,972; p = 1.44 × 10(-5)) compared with those with a BMI ≥ 25 kg/m(2) (n = 11,559; p = 0.81), and there was evidence of association among all genotyped individuals with a BMI <25 kg/m(2), including the INTERHEART South Asians (n = 3,601; p = 9.52 × 10(-7))., Conclusion/interpretation: Variation at the DPP4 locus is associated with ApoB in South Asians and displays heterogeneity related to BMI in other ethnicities.
- Published
- 2014
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37. Information on infantile colic on the World Wide Web.
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Bailey SD, D'Auria JP, and Haushalter JP
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- Checklist, Colic therapy, Counseling, Crying psychology, Decision Making, Female, Humans, Infant, Infant, Newborn, Male, Practice Guidelines as Topic, Pregnancy, Quality Control, United States epidemiology, Colic etiology, Information Services standards, Internet standards, Parents psychology
- Abstract
Introduction: The purpose of this study was to explore and describe the type and quality of information on infantile colic that a parent might access on the World Wide Web., Methods: Two checklists were used to evaluate the quality indicators of 24 Web sites and the colic-specific content., Results: Fifteen health information Web sites met more of the quality parameters than the nine commercial sites. Eight Web sites included information about colic and infant abuse, with six being health information sites., Discussion: The colic-specific content on 24 Web sites reflected current issues and controversies; however, the completeness of the information in light of current evidence varied among the Web sites. Strategies to avoid complications of parental stress or infant abuse were not commonly found on the Web sites. Pediatric professionals must guide parents to reliable colic resources that also include emotional support and understanding of infant crying. A best evidence guideline for the United States would eliminate confusion and uncertainty about which colic therapies are safe and effective for parents and professionals., (Copyright © 2013 National Association of Pediatric Nurse Practitioners. Published by Mosby, Inc. All rights reserved.)
- Published
- 2013
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38. Genetic information and the prediction of incident type 2 diabetes in a high-risk multiethnic population: the EpiDREAM genetic study.
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Anand SS, Meyre D, Pare G, Bailey SD, Xie C, Zhang X, Montpetit A, Desai D, Bosch J, Mohan V, Diaz R, McQueen MJ, Cordell HJ, Keavney B, Yusuf S, Gaudet D, Gerstein H, and Engert JC
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Genotype, Humans, Middle Aged, Multivariate Analysis, White People genetics, Young Adult, Diabetes Mellitus, Type 2 genetics, Polymorphism, Single Nucleotide genetics
- Abstract
Objective: To determine if 16 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2DM) in Europeans are also associated with T2DM in South Asians and Latinos and if they can add to the prediction of incident T2DM in a high-risk population., Research Design and Methods: In the EpiDREAM prospective cohort study, physical measures, questionnaires, and blood samples were collected from 25,063 individuals at risk for dysglycemia. Sixteen SNPs that have been robustly associated with T2DM in Europeans were genotyped. Among 15,466 European, South Asian, and Latino subjects, we examined the association of these 16 SNPs alone and combined in a gene score with incident cases of T2DM (n = 1,016) that developed during 3.3 years of follow-up., Results: Nine of the 16 SNPs were significantly associated with T2DM, and their direction of effect was consistent across the three ethnic groups. The gene score was significantly higher among subjects who developed incident T2DM (cases vs. noncases: 16.47 [2.50] vs. 15.99 [2.56]; P = 0.00001). The gene score remained an independent predictor of incident T2DM, with an odds ratio of 1.08 (95% CI 1.05-1.11) per additional risk allele after adjustment for T2DM risk factors. The gene score in those with no family history of T2DM was 16.02, whereas it was 16.19 in those with one parent with T2DM and it was 16.32 in those with two parents with T2DM (P trend = 0.0004). The C statistic of T2DM risk factors was 0.708 (0.691-0.725) and increased only marginally to 0.714 (0.698-0.731) with the addition of the gene score (P for C statistic change = 0.0052)., Conclusions: T2DM genetic associations are generally consistent across ethnic groups, and a gene score only adds marginal information to clinical factors for T2DM prediction.
- Published
- 2013
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39. Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression.
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Cowper-Sal lari R, Zhang X, Wright JB, Bailey SD, Cole MD, Eeckhoute J, Moore JH, and Lupien M
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- Alleles, Apoptosis Regulatory Proteins, Estrogen Receptor alpha genetics, Female, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome-Wide Association Study, High Mobility Group Proteins, Histone-Lysine N-Methyltransferase, Humans, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Risk Factors, Trans-Activators, Breast Neoplasms genetics, Chromatin genetics, Hepatocyte Nuclear Factor 3-alpha genetics, Receptors, Progesterone genetics
- Abstract
Genome-wide association studies (GWAS) have identified thousands of SNPs that are associated with human traits and diseases. But, because the vast majority of these SNPs are located in non-coding regions of the genome, the mechanisms by which they promote disease risk have remained elusive. Employing a new methodology that combines cistromics, epigenomics and genotype imputation, we annotate the non-coding regions of the genome in breast cancer cells and systematically identify the functional nature of SNPs associated with breast cancer risk. Our results show that breast cancer risk-associated SNPs are enriched in the cistromes of FOXA1 and ESR1 and the epigenome of histone H3 lysine 4 monomethylation (H3K4me1) in a cancer- and cell type-specific manner. Furthermore, the majority of the risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, thereby resulting in allele-specific gene expression, which is exemplified by the effect of the rs4784227 SNP on the TOX3 gene within the 16q12.1 risk locus.
- Published
- 2012
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40. Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus.
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Zhang X, Cowper-Sal lari R, Bailey SD, Moore JH, and Lupien M
- Subjects
- Alleles, Chromatin genetics, Chromatin metabolism, Chromosome Mapping methods, Chromosomes, Human, Pair 17 metabolism, Epigenomics methods, Gene Expression Regulation, Neoplastic, Genetic Loci, Genome-Wide Association Study, Hepatocyte Nuclear Factor 3-alpha genetics, Hepatocyte Nuclear Factor 3-alpha metabolism, Humans, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms metabolism, Receptors, Androgen genetics, Receptors, Androgen metabolism, Risk Factors, SOX9 Transcription Factor metabolism, Transcription Factor AP-1 genetics, Transcription Factor AP-1 metabolism, Chromosomes, Human, Pair 17 genetics, Enhancer Elements, Genetic, Genome, Human, Prostatic Neoplasms genetics, SOX9 Transcription Factor genetics
- Abstract
Genome-wide association studies (GWAS) are identifying genetic predisposition to various diseases. The 17q24.3 locus harbors the single nucleotide polymorphism (SNP) rs1859962 that is statistically associated with prostate cancer (PCa). It defines a 130-kb linkage disequilibrium (LD) block that lies in an ∼2-Mb gene desert area. The functional biology driving the risk associated with this LD block is unknown. Here, we integrate genome-wide chromatin landscape data sets, namely, epigenomes and chromatin openness from diverse cell types. This identifies a PCa-specific enhancer within the rs1859962 risk LD block that establishes a 1-Mb chromatin loop with the SOX9 gene. The rs8072254 and rs1859961 SNPs mapping to this enhancer impose allele-specific gene expression. The variant allele of rs8072254 facilitates androgen receptor (AR) binding driving increased enhancer activity. The variant allele of rs1859961 decreases FOXA1 binding while increasing AP-1 binding. The latter is key to imposing allele-specific gene expression. The rs8072254 variant in strong LD with the rs1859962 risk SNP can account for the risk associated with this locus, while rs1859961 is a rare variant less likely to contribute to the risk associated with this LD block. Together, our results demonstrate that multiple genetic variants mapping to a unique enhancer looping to the SOX9 oncogene can account for the risk associated with the PCa 17q24.3 locus. Allele-specific recruitment of the transcription factors androgen receptor (AR) and activating protein-1 (AP-1) account for the increased enhancer activity ascribed to this PCa-risk LD block. This further supports the notion that an integrative genomics approach can identify the functional biology disrupted by genetic risk variants.
- Published
- 2012
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41. The HDL proteome in acute coronary syndromes shifts to an inflammatory profile.
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Alwaili K, Bailey D, Awan Z, Bailey SD, Ruel I, Hafiane A, Krimbou L, Laboissiere S, and Genest J
- Subjects
- Adult, Aged, Case-Control Studies, Cell Line, Cholesterol blood, Cholesterol metabolism, Coronary Artery Disease blood, Humans, Male, Middle Aged, Acute Coronary Syndrome blood, Blood Proteins metabolism, Inflammation blood, Lipoproteins, HDL blood, Proteome metabolism
- Abstract
Inflammation is a major factor underlying acute coronary syndromes (ACS). HDL particles may be remodeled, becoming functionally defective, under the inflammatory conditions seen in ACS. Shotgun proteomics was used to monitor changes in the HDL proteome between male age-matched control, stable CAD, and ACS subjects (n=10/group). HDL was isolated by ultracentrifugation and separated by 1D-gel followed by LC-MS/MS. We identified 67 HDL-associated proteins, 20 of which validated recently identified proteins including vitronectin and complement C4B, and 5 of which were novel. Using gene ontology analysis, we found that the HDL-proteome consisted of proteins involved in cholesterol homeostasis (~50%), with significant contributions by proteins involved in lipid binding, antioxidant, acute-phase response, immune response, and endopeptidase/protease inhibition. Importantly, levels of apoA-IV were significantly reduced in ACS patients, whereas levels of serum amyloid A (SAA) and complement C3 (C3) were significantly increased (spectral counting; t-test p≤0.05), as confirmed by immunoblot or ELISA. Despite differences in protein composition, ABCA1, ABCG1, and SR-BI mediated cholesterol efflux assays did not indicate that HDL from ACS patients is functionally deficient as compared to controls, when corrected for apoA-I mass. Our results support that the HDL proteome differs between control, CAD and ACS patients. Increased abundance of SAA, C3, and other inflammatory proteins in HDL from ACS patients suggests that HDL reflects a shift to an inflammatory profile which, in turn, might alter the protective effects of HDL on the atherosclerotic plaque. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010)., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2012
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42. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.
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Lanktree MB, Guo Y, Murtaza M, Glessner JT, Bailey SD, Onland-Moret NC, Lettre G, Ongen H, Rajagopalan R, Johnson T, Shen H, Nelson CP, Klopp N, Baumert J, Padmanabhan S, Pankratz N, Pankow JS, Shah S, Taylor K, Barnard J, Peters BJ, Maloney CM, Lobmeyer MT, Stanton A, Zafarmand MH, Romaine SP, Mehta A, van Iperen EP, Gong Y, Price TS, Smith EN, Kim CE, Li YR, Asselbergs FW, Atwood LD, Bailey KM, Bhatt D, Bauer F, Behr ER, Bhangale T, Boer JM, Boehm BO, Bradfield JP, Brown M, Braund PS, Burton PR, Carty C, Chandrupatla HR, Chen W, Connell J, Dalgeorgou C, Boer Ad, Drenos F, Elbers CC, Fang JC, Fox CS, Frackelton EC, Fuchs B, Furlong CE, Gibson Q, Gieger C, Goel A, Grobbee DE, Hastie C, Howard PJ, Huang GH, Johnson WC, Li Q, Kleber ME, Klein BE, Klein R, Kooperberg C, Ky B, Lacroix A, Lanken P, Lathrop M, Li M, Marshall V, Melander O, Mentch FD, Meyer NJ, Monda KL, Montpetit A, Murugesan G, Nakayama K, Nondahl D, Onipinla A, Rafelt S, Newhouse SJ, Otieno FG, Patel SR, Putt ME, Rodriguez S, Safa RN, Sawyer DB, Schreiner PJ, Simpson C, Sivapalaratnam S, Srinivasan SR, Suver C, Swergold G, Sweitzer NK, Thomas KA, Thorand B, Timpson NJ, Tischfield S, Tobin M, Tomaszewski M, Verschuren WM, Wallace C, Winkelmann B, Zhang H, Zheng D, Zhang L, Zmuda JM, Clarke R, Balmforth AJ, Danesh J, Day IN, Schork NJ, de Bakker PI, Delles C, Duggan D, Hingorani AD, Hirschhorn JN, Hofker MH, Humphries SE, Kivimaki M, Lawlor DA, Kottke-Marchant K, Mega JL, Mitchell BD, Morrow DA, Palmen J, Redline S, Shields DC, Shuldiner AR, Sleiman PM, Smith GD, Farrall M, Jamshidi Y, Christiani DC, Casas JP, Hall AS, Doevendans PA, Christie JD, Berenson GS, Murray SS, Illig T, Dorn GW 2nd, Cappola TP, Boerwinkle E, Sever P, Rader DJ, Reilly MP, Caulfield M, Talmud PJ, Topol E, Engert JC, Wang K, Dominiczak A, Hamsten A, Curtis SP, Silverstein RL, Lange LA, Sabatine MS, Trip M, Saleheen D, Peden JF, Cruickshanks KJ, März W, O'Connell JR, Klungel OH, Wijmenga C, Maitland-van der Zee AH, Schadt EE, Johnson JA, Jarvik GP, Papanicolaou GJ, Grant SF, Munroe PB, North KE, Samani NJ, Koenig W, Gaunt TR, Anand SS, van der Schouw YT, Soranzo N, Fitzgerald GA, Reiner A, Hegele RA, Hakonarson H, and Keating BJ
- Subjects
- Adult, Black or African American genetics, Asian People genetics, Female, Gene Frequency, Genome-Wide Association Study, Hispanic or Latino genetics, Humans, Interleukin-11 genetics, Male, Smad3 Protein genetics, White People genetics, Body Height genetics, Cardiovascular System, Genetic Heterogeneity, Genetic Loci, Polymorphism, Single Nucleotide
- Abstract
Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
- Published
- 2011
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43. Fine mapping of the insulin-induced gene 2 identifies a variant associated with LDL cholesterol and total apolipoprotein B levels.
- Author
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Do R, Bailey SD, Paré G, Montpetit A, Desbiens K, Hudson TJ, Yusuf S, Bouchard C, Gaudet D, Pérusse L, Anand S, Vohl MC, Pastinen T, and Engert JC
- Subjects
- Adult, Animals, Genome-Wide Association Study, Genotype, Humans, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins metabolism, Microfilament Proteins genetics, Microfilament Proteins metabolism, Middle Aged, Obesity physiopathology, Apolipoproteins B blood, Cholesterol, LDL blood, Chromosome Mapping methods, Intracellular Signaling Peptides and Proteins genetics, Membrane Proteins genetics, Polymorphism, Single Nucleotide
- Abstract
Background: In a whole-genome scan, a single nucleotide polymorphism (SNP) (rs7566605) upstream of the insulin-induced gene 2 (INSIG2) was shown to influence body mass index and obesity in the Framingham Heart Study, with replication of these results in an additional 4 of 5 studies. However, other studies could not replicate the association. Because INSIG2 plays an important role in cholesterol biosynthesis, we hypothesized that human INSIG2 variants might play a role in the regulation of plasma lipid and lipoprotein levels., Methods and Results: We selected tagging SNPs spanning >100 kb of INSIG2 locus and sequenced 18 434 base pairs to discover novel SNPs. Thirty-two SNPs were genotyped in 645 individuals from the Quebec Family Study. Two SNPs (rs10490626 and rs12464355) were associated with plasma low-density lipoprotein cholesterol (LDL-C) (P<0.0015) and total apolipoprotein B (apoB) levels (P<0.014), whereas no association was found between any SNP and body mass index. We replicated the finding of rs10490626 for both LDL-C and total apoB in additional study samples, including 758 individuals from Saguenay-Lac St. Jean, Quebec (P=0.040 for LDL-C, P=0.044 for apoB), 3247 Europeans (P=0.028 for LDL-C, P=0.030 for apoB), and 1695 South Asians (P=0.0036 for LDL-C, P=0.034 for apoB) from the INTERHEART study (for LDL-C, the combined 2-sided P=6.2×10⁻⁵ and for total apoB, P=0.0011). Furthermore, we identified a variant in the human sorbin and SH(3)-domain-containing-1 gene that was associated with INSIG2 mRNA levels, and this SNP was shown to act in combination with rs10490626 to affect LDL-C (P=0.022) in the Quebec Family Study and in INTERHEART South Asians (P=0.019) and Europeans (P=0.052)., Conclusion: These results suggest that INSIG2 genetic variants may have a more direct role in lipid and lipoprotein metabolism than in obesity.
- Published
- 2010
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44. Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.
- Author
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Bailey SD, Xie C, Do R, Montpetit A, Diaz R, Mohan V, Keavney B, Yusuf S, Gerstein HC, Engert JC, and Anand S
- Subjects
- Female, Humans, Hypoglycemic Agents pharmacology, Male, Polymorphism, Single Nucleotide drug effects, Ramipril pharmacology, Rosiglitazone, Thiazolidinediones adverse effects, Thiazolidinediones pharmacology, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 etiology, Edema chemically induced, Edema genetics, Hypoglycemic Agents therapeutic use, NFATC Transcription Factors genetics, Ramipril therapeutic use, Thiazolidinediones therapeutic use
- Abstract
Objective: Thiazolidinediones are used to treat type 2 diabetes. Their use has been associated with peripheral edema and congestive heart failure-outcomes that may have a genetic etiology., Research Design and Methods: We genotyped 4,197 participants of the multiethnic DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) trial with a 50k single nucleotide polymorphisms (SNP) array, which captures ∼2000 cardiovascular, inflammatory, and metabolic genes. We tested 32,088 SNPs for an association with edema among Europeans who received rosiglitazone (n = 965)., Results: One SNP, rs6123045, in NFATC2 was significantly associated with edema (odds ratio 1.89 [95% CI 1.47-2.42]; P = 5.32 × 10(-7), corrected P = 0.017). Homozygous individuals had the highest edema rate (hazard ratio 2.89, P = 4.22 × 10(-4)) when compared with individuals homozygous for the protective allele, with heterozygous individuals having an intermediate risk. The interaction between the SNP and rosiglitazone for edema was significant (P = 7.68 × 10(-3)). Six SNPs in NFATC2 were significant in both Europeans and Latin Americans (P < 0.05)., Conclusions: Genetic variation at the NFATC2 locus contributes to edema among individuals who receive rosiglitazone.
- Published
- 2010
- Full Text
- View/download PDF
45. Social comparisons, appearance related comments, contingent self-esteem and their relationships with body dissatisfaction and eating disturbance among women.
- Author
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Bailey SD and Ricciardelli LA
- Subjects
- Adolescent, Adult, Beauty, Body Mass Index, Female, Humans, Interpersonal Relations, Surveys and Questionnaires, Body Image, Feeding Behavior psychology, Feeding and Eating Disorders psychology, Self Concept, Social Environment
- Abstract
This study examined social comparisons, appearance related comments and contingent self-esteem, and their relationships with body dissatisfaction and eating disturbance in young adult women. Importantly, the role of both positive and negative appearance related comments, and upward and downward comparisons, were investigated. A self-report questionnaire assessing each of these variables was completed by one hundred and ninety-six women aged 18-35. A higher frequency of negative comments and contingent self-esteem were associated with higher upward comparisons, and more positive comments were associated with higher downward comparisons. Overall, social comparisons were shown to be more important than verbal commentary and contingent self-esteem. More upward comparisons and less downward comparisons uniquely predicted higher body dissatisfaction and eating disturbance. In addition, negative appearance comments were found to be more salient than positive comments. Negative comments and contingent self-esteem uniquely predicted more eating disturbance but positive comments were not a predictor of body dissatisfaction or eating disturbance. Longitudinal studies are now required to establish the direction of these relationships and to more fully examine the interplay among the factors. In addition, given that our study only assessed self-reported social comparisons, our findings need to be validated against experimental methods., (Copyright 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
46. Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects.
- Author
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Dastani Z, Pajukanta P, Marcil M, Rudzicz N, Ruel I, Bailey SD, Lee JC, Lemire M, Faith J, Platko J, Rioux J, Hudson TJ, Gaudet D, Engert JC, and Genest J
- Subjects
- Canada, France, Gene Expression Regulation, Genome, Human, Humans, Lod Score, RNA, Messenger genetics, RNA, Messenger metabolism, Sequence Analysis, DNA, Cholesterol, HDL genetics, Chromosomes, Human, Pair 16 genetics, Genetic Linkage, Genetic Predisposition to Disease, Physical Chromosome Mapping
- Abstract
Low levels of high-density lipoprotein cholesterol (HDL-C) are an independent risk factor for cardiovascular disease. To identify novel genetic variants that contribute to HDL-C, we performed genome-wide scans and quantitative association studies in two study samples: a Quebec-wide study consisting of 11 multigenerational families and a study of 61 families from the Saguenay-Lac St-Jean (SLSJ) region of Quebec. The heritability of HDL-C in these study samples was 0.73 and 0.49, respectively. Variance components linkage methods identified a LOD score of 2.61 at 98 cM near the marker D16S515 in Quebec-wide families and an LOD score of 2.96 at 86 cM near the marker D16S2624 in SLSJ families. In the Quebec-wide sample, four families showed segregation over a 25.5-cM (18 Mb) region, which was further reduced to 6.6 Mb with additional markers. The coding regions of all genes within this region were sequenced. A missense variant in CHST6 segregated in four families and, with additional families, we observed a P value of 0.015 for this variant. However, an association study of this single-nucleotide polymorphism (SNP) in unrelated Quebec-wide samples was not significant. We also identified an SNP (rs11646677) in the same region, which was significantly associated with a low HDL-C (P=0.016) in the SLSJ study sample. In addition, RT-PCR results from cultured cells showed a significant difference in the expression of CHST6 and KIAA1576, another gene in the region. Our data constitute additional evidence for a locus on chromosome 16q23-24 that affects HDL-C levels in two independent French-Canadian studies.
- Published
- 2010
- Full Text
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47. Male-to-female sexual aggression among Iraq, Afghanistan, and Vietnam veterans: co-occurring substance abuse and intimate partner aggression.
- Author
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Teten AL, Schumacher JA, Bailey SD, and Kent TA
- Subjects
- Female, Humans, Male, Surveys and Questionnaires, United States epidemiology, Afghan Campaign 2001-, Iraq War, 2003-2011, Sex Offenses statistics & numerical data, Sexual Partners, Substance-Related Disorders epidemiology, Vietnam Conflict
- Abstract
The current study examined the frequency and correlates of coercive sexual behaviors by male Iraq, Afghanistan, and/or Vietnam veterans recruited from a Veterans Affairs trauma recovery clinic (n = 92) toward their female partners. Men who reported sexual aggression in the past year (n = 37) compared to men who did not report sexual aggression in the past year (n = 55) more frequently reported impulsive aggression, dominating/isolating, and physically assaulting their partner, and were more likely to have a substance abuse diagnosis. Sexually aggressive men were significantly less likely than nonsexually aggressive men to have a diagnosis of depression. Posttraumatic stress disorder, an established risk factor for nonsexual partner aggression among veterans, was not associated with sexual aggression.
- Published
- 2009
- Full Text
- View/download PDF
48. When anxiety symptoms masquerade as medical symptoms: what medical specialists know about panic disorder and available psychological treatments.
- Author
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Teng EJ, Chaison AD, Bailey SD, Hamilton JD, and Dunn NJ
- Subjects
- Adult, Analysis of Variance, Anxiety psychology, Clinical Competence statistics & numerical data, Cognitive Behavioral Therapy statistics & numerical data, Female, Humans, Male, Middle Aged, Physicians, Family statistics & numerical data, Somatoform Disorders psychology, Surveys and Questionnaires, Texas, Anxiety therapy, Health Knowledge, Attitudes, Practice, Practice Patterns, Physicians' statistics & numerical data, Referral and Consultation statistics & numerical data, Somatoform Disorders therapy
- Abstract
Under-recognition of somatic symptoms associated with panic in primary care settings results in unnecessary and costly diagnostic procedures and inappropriate referrals to cardiologists, gastroenterologists, and neurologists. In the current study specialists' knowledge regarding the nature and treatment of panic were examined. One-hundred and fourteen specialists completed a questionnaire assessing their knowledge about panic attacks, including their perceptions of psychologists' role in treating panic. Respondents answered 51% of knowledge items correctly. Although most knew the definition of a panic attack, they knew less about clinical features of panic and its treatment. Specifically, whereas 97.4% believed medication effectively relieves panic symptoms, only 32.5% knew that cognitive-behavioral therapy (CBT) is a first-line treatment. Only 6% reported knowing how to implement CBT, and only 56.1% recognized that psychologists could effectively treat panic. These findings demonstrate significant gaps in specialists' knowledge about panic and the need to enhance physician knowledge about panic attacks and their treatment.
- Published
- 2008
- Full Text
- View/download PDF
49. Treating comorbid panic disorder in veterans with posttraumatic stress disorder.
- Author
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Teng EJ, Bailey SD, Chaison AD, Petersen NJ, Hamilton JD, and Dunn NJ
- Subjects
- Adult, Agoraphobia diagnosis, Agoraphobia psychology, Chronic Disease, Combat Disorders diagnosis, Combat Disorders psychology, Comorbidity, Female, Follow-Up Studies, Humans, Male, Middle Aged, Panic Disorder diagnosis, Panic Disorder psychology, Personality Inventory, Agoraphobia therapy, Cognitive Behavioral Therapy methods, Combat Disorders therapy, Panic Disorder therapy, Veterans psychology
- Abstract
This study compares the effectiveness of panic control treatment (PCT) with that of a psychoeducational supportive treatment (PE-SUP) in treating panic disorder among a veteran sample with a primary diagnosis of chronic posttraumatic stress disorder (PTSD). Thirty-five patients randomized to receive 10 individual sessions of either PCT or PE-SUP underwent assessments at pretreatment, at 1-week posttreatment, and at a 3-month follow-up. Intent-to-treat analyses of covariance showed that PCT participants significantly improved on panic severity at posttreatment and panic fear at the 3-month follow-up. The PCT group also showed significant reductions in anxiety sensitivity at posttreatment and follow-up compared with that of the PE-SUP group. A significantly higher proportion of persons (63%) in the PCT group was panic free by the follow-up period compared with that of the PE-SUP group (19%). Patient self-report and clinician ratings showed no changes in general anxiety, depression, and PTSD symptoms in either group. These findings indicated that PCT was superior to an active control therapy in reducing the frequency, severity, and distress associated with panic disorder and suggested that brief cognitive-behavioral therapy for panic is effective for persons with chronic PTSD., (Copyright 2008 APA, all rights reserved.)
- Published
- 2008
- Full Text
- View/download PDF
50. Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study.
- Author
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Do R, Bailey SD, Desbiens K, Belisle A, Montpetit A, Bouchard C, Pérusse L, Vohl MC, and Engert JC
- Subjects
- Adult, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Body Mass Index, Bone Density, Family, Female, Humans, Male, Middle Aged, Quebec, Diabetes Mellitus, Type 2 genetics, Genetic Variation, Leptin blood, Obesity genetics, Polymorphism, Single Nucleotide, Proteins genetics
- Abstract
Objective: A genome-wide association study conducted by the Wellcome Trust Case Control Consortium recently associated single nucleotide polymorphisms (SNPs) in the FTO (fatso/fat mass and obesity associated) gene with type 2 diabetes. These associations were shown to be mediated by obesity. Other research groups found similar results in Europeans and Hispanics but not African Americans. The mechanism by which FTO influences obesity and type 2 diabetes is currently unknown. The present study investigated the role of two FTO SNPs (rs17817449 and rs1421085) in adiposity, insulin sensitivity, and body weight regulation, including energy intake and expenditure., Research Design and Methods: We genotyped 908 individuals from the Quebec City metropolitan area that participated in the Quebec Family Study, a long-term study of extensively phenotyped individuals designed to investigate factors involved in adiposity., Results: We found significant associations for both SNPs with several obesity-related phenotypes. In particular, rs17817449 was associated with BMI (P = 0.0014), weight (P = 0.0059), and waist circumference (P = 0.0021) under an additive model. In addition, this FTO SNP influenced fasting insulin (P = 0.011), homeostasis model assessment of insulin resistance (P = 0.038), and an insulin sensitivity index derived from an oral glucose tolerance test (P = 0.0091). Associations were also found with resting metabolic rate (RMR) (P = 0.042) and plasma leptin levels (P = 0.036). Adjustment for BMI abolished the associations with insulin sensitivity, RMR, and plasma leptin levels., Conclusions: These results confirm that genetic variation at the FTO locus contributes to the etiology of obesity, insulin resistance, and increased plasma leptin levels.
- Published
- 2008
- Full Text
- View/download PDF
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