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1.
Am J Hum Genet ; 107(4): 622-635, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32946763

RESUMO

Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this study we first estimated the heritability explained by known common low penetrance risk alleles for EOC. The narrow sense heritability (hg2) of EOC overall and high-grade serous ovarian cancer (HGSOCs) were estimated to be 5%-6%. Partitioned SNP heritability across broad functional categories indicated a significant contribution of regulatory elements to EOC heritability. We collated epigenomic profiling data for 77 cell and tissue types from Roadmap Epigenomics and ENCODE, and from H3K27Ac ChIP-seq data generated in 26 ovarian cancer and precursor-related cell and tissue types. We identified significant enrichment of risk single-nucleotide polymorphisms (SNPs) in active regulatory elements marked by H3K27Ac in HGSOCs. To further investigate how risk SNPs in active regulatory elements influence predisposition to ovarian cancer, we used motifbreakR to predict the disruption of transcription factor binding sites. We identified 469 candidate causal risk variants in H3K27Ac peaks that are predicted to significantly break transcription factor (TF) motifs. The most frequently broken motif was REST (p value = 0.0028), which has been reported as both a tumor suppressor and an oncogene. Overall, these systematic functional annotations with epigenomic data improve interpretation of EOC risk variants and shed light on likely cells of origin.


Assuntos
Carcinoma Epitelial do Ovário/genética , Proteínas Correpressoras/genética , Cistadenocarcinoma Seroso/genética , Elementos Facilitadores Genéticos , Histonas/genética , Proteínas do Tecido Nervoso/genética , Neoplasias Ovarianas/genética , Alelos , Sítios de Ligação , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/patologia , Mapeamento Cromossômico , Proteínas Correpressoras/metabolismo , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/patologia , Feminino , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Padrões de Herança , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Penetrância , Polimorfismo de Nucleotídeo Único , Risco
2.
BMC Genomics ; 20(1): 745, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619158

RESUMO

BACKGROUND: The development of next generation sequencing (NGS) methods led to a rapid rise in the generation of large genomic datasets, but the development of user-friendly tools to analyze and visualize these datasets has not developed at the same pace. This presents a two-fold challenge to biologists; the expertise to select an appropriate data analysis pipeline, and the need for bioinformatics or programming skills to apply this pipeline. The development of graphical user interface (GUI) applications hosted on web-based servers such as Shiny can make complex workflows accessible across operating systems and internet browsers to those without programming knowledge. RESULTS: We have developed GENAVi (Gene Expression Normalization Analysis and Visualization) to provide a user-friendly interface for normalization and differential expression analysis (DEA) of human or mouse feature count level RNA-Seq data. GENAVi is a GUI based tool that combines Bioconductor packages in a format for scientists without bioinformatics expertise. We provide a panel of 20 cell lines commonly used for the study of breast and ovarian cancer within GENAVi as a foundation for users to bring their own data to the application. Users can visualize expression across samples, cluster samples based on gene expression or correlation, calculate and plot the results of principal components analysis, perform DEA and gene set enrichment and produce plots for each of these analyses. To allow scalability for large datasets we have provided local install via three methods. We improve on available tools by offering a range of normalization methods and a simple to use interface that provides clear and complete session reporting and for reproducible analysis. CONCLUSION: The development of tools using a GUI makes them practical and accessible to scientists without bioinformatics expertise, or access to a data analyst with relevant skills. While several GUI based tools are currently available for RNA-Seq analysis we improve on these existing tools. This user-friendly application provides a convenient platform for the normalization, analysis and visualization of gene expression data for scientists without bioinformatics expertise.


Assuntos
Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA/métodos , Software , Interpretação Estatística de Dados , Visualização de Dados , Internet , Reprodutibilidade dos Testes , Interface Usuário-Computador
3.
Gynecol Oncol ; 153(2): 343-355, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30898391

RESUMO

OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7). CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.


Assuntos
Carcinoma Epitelial do Ovário/genética , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
4.
Bioinformatics ; 35(11): 1974-1977, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30364927

RESUMO

MOTIVATION: DNA methylation has been used to identify functional changes at transcriptional enhancers and other cis-regulatory modules (CRMs) in tumors and other disease tissues. Our R/Bioconductor package ELMER (Enhancer Linking by Methylation/Expression Relationships) provides a systematic approach that reconstructs altered gene regulatory networks (GRNs) by combining enhancer methylation and gene expression data derived from the same sample set. RESULTS: We present a completely revised version 2 of ELMER that provides numerous new features including an optional web-based interface and a new Supervised Analysis mode to use pre-defined sample groupings. We show that Supervised mode significantly increases statistical power and identifies additional GRNs and associated Master Regulators, such as SOX11 and KLF5 in Basal-like breast cancer. AVAILABILITY AND IMPLEMENTATION: ELMER v.2 is available as an R/Bioconductor package at http://bioconductor.org/packages/ELMER/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Redes Reguladoras de Genes , Transcriptoma , Metilação de DNA , Software
5.
Cancer Res ; 79(3): 467-481, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30487138

RESUMO

Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. SIGNIFICANCE: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene.See related commentary by Choi and Brown, p. 439.


Assuntos
Carcinoma Epitelial do Ovário/genética , Cromossomos Humanos Par 9 , Neoplasias Ovarianas/genética , Sequência de Bases , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Mapeamento Cromossômico , Cistadenocarcinoma Seroso/genética , DNA de Neoplasias/genética , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único
6.
Nat Med ; 24(12): 1887-1898, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30478421

RESUMO

Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Fator 3-alfa Nuclear de Hepatócito/genética , Proteínas de Homeodomínio/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/genética , Fatores de Transcrição/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Androgênios/genética , Androgênios/metabolismo , Animais , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/antagonistas & inibidores , Humanos , Masculino , Camundongos , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Immunity ; 47(5): 890-902.e4, 2017 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-29166589

RESUMO

Granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell progenitors (MDPs) produce monocytes during homeostasis and in response to increased demand during infection. Both progenitor populations are thought to derive from common myeloid progenitors (CMPs), and a hierarchical relationship (CMP-GMP-MDP-monocyte) is presumed to underlie monocyte differentiation. Here, however, we demonstrate that mouse MDPs arose from CMPs independently of GMPs, and that GMPs and MDPs produced monocytes via similar but distinct monocyte-committed progenitors. GMPs and MDPs yielded classical (Ly6Chi) monocytes with gene expression signatures that were defined by their origins and impacted their function. GMPs produced a subset of "neutrophil-like" monocytes, whereas MDPs gave rise to a subset of monocytes that yielded monocyte-derived dendritic cells. GMPs and MDPs were also independently mobilized to produce specific combinations of myeloid cell types following the injection of microbial components. Thus, the balance of GMP and MDP differentiation shapes the myeloid cell repertoire during homeostasis and following infection.


Assuntos
Células Dendríticas/fisiologia , Células Precursoras de Granulócitos/fisiologia , Monócitos/fisiologia , Células Progenitoras Mieloides/fisiologia , Animais , Antígenos Ly/análise , Diferenciação Celular , Leucossialina/análise , Camundongos , Análise de Sequência de RNA , Transcriptoma
8.
Oncotarget ; 8(70): 114540-114553, 2017 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-29383100

RESUMO

In a murine melanoma model, malignant transformation promoted by a sustained stress condition was causally related to increased levels of reactive oxygen species resulting in DNA damage and massive epigenetic alterations. Since the chromatin modifier Sirtuin-1 (SIRT1) is a protein attracted to double-stranded DNA break (DSB) sites and can recruit other components of the epigenetic machinery, we aimed to define the role of SIRT1 in melanomagenesis through our melanoma model. The DNA damage marker, γH2AX was found increased in melanocytes after 24 hours of deadhesion, accompanied by increased SIRT1 expression and decreased levels of its target, H4K16ac. Moreover, SIRT1 started to be associated to DNMT3B during the stress condition, and this complex was maintained along malignant progression. Mxd1 was identified by ChIP-seq among the DNA sequences differentially associated with SIRT1 during deadhesion and was shown to be a common target of both, SIRT1 and DNMT3B. In addition, Mxd1 was found downregulated from pre-malignant melanocytes to metastatic melanoma cells. Treatment with DNMT inhibitor 5AzaCdR reversed the Mxd1 expression. Sirt1 stable silencing increased Mxd1 mRNA expression and led to down-regulation of MYC targets, such as Cdkn1a, Bcl2 and Psen2, whose upregulation is associated with human melanoma aggressiveness and poor prognosis. We demonstrated a novel role of the stress responsive protein SIRT1 in malignant transformation of melanocytes associated with deadhesion. Mxd1 was identified as a new SIRT1 target gene. SIRT1 promoted Mxd1 silencing, which led to increased activity of MYC oncogene contributing to melanoma progression.

9.
Sci Rep ; 6: 30509, 2016 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-27461410

RESUMO

Recent genome-wide association studies (GWAS) of Parkinson's disease (PD) revealed at least 26 risk loci, with associated single nucleotide polymorphisms (SNPs) located in non-coding DNA having unknown functions in risk. In order to explore in which cell types these SNPs (and their correlated surrogates at r(2) ≥ 0.8) could alter cellular function, we assessed their location overlap with histone modification regions that indicate transcription regulation in 77 diverse cell types. We found statistically significant enrichment of risk SNPs at 12 loci in active enhancers or promoters. We investigated 4 risk loci in depth that were most significantly enriched (-logeP > 14) and contained 8 putative enhancers in the different cell types. These enriched loci, along with eQTL associations, were unexpectedly present in non-neuronal cell types. These included lymphocytes, mesendoderm, liver- and fat-cells, indicating that cell types outside the brain are involved in the genetic predisposition to PD. Annotating regulatory risk regions within specific cell types may unravel new putative risk mechanisms and molecular pathways that contribute to PD development.


Assuntos
Doença de Parkinson/etiologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Sequências Reguladoras de Ácido Nucleico , Cromossomos Humanos , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Doença de Parkinson/genética , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Bioinformatics ; 31(23): 3847-9, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26272984

RESUMO

UNLABELLED: Functional annotation represents a key step toward the understanding and interpretation of germline and somatic variation as revealed by genome-wide association studies (GWAS) and The Cancer Genome Atlas (TCGA), respectively. GWAS have revealed numerous genetic risk variants residing in non-coding DNA associated with complex diseases. For sequences that lie within enhancers or promoters of transcription, it is not straightforward to assess the effects of variants on likely transcription factor binding sites. Consequently we introduce motifbreakR, which allows the biologist to judge whether the sequence surrounding a polymorphism or mutation is a good match, and how much information is gained or lost in one allele of the polymorphism or mutation relative to the other. MotifbreakR is flexible, giving a choice of algorithms for interrogation of genomes with motifs from many public sources that users can choose from. MotifbreakR can predict effects for novel or previously described variants in public databases, making it suitable for tasks beyond the scope of its original design. Lastly, it can be used to interrogate any genome curated within bioconductor. AVAILABILITY AND IMPLEMENTATION: https://github.com/Simon-Coetzee/MotifBreakR, www.bioconductor.org. CONTACT: dennis.hazelett@cshs.org.


Assuntos
Mutação , Polimorfismo de Nucleotídeo Único , Elementos Reguladores de Transcrição , Sequências Reguladoras de Ácido Nucleico , Software , Fatores de Transcrição/metabolismo , Algoritmos , Animais , Sítios de Ligação , Genômica , Humanos , Camundongos , Análise de Sequência de DNA
11.
Hum Mol Genet ; 24(13): 3595-607, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25804953

RESUMO

Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10(-30)), OSECs (P = 2.4 × 10(-23)) and HMECs (P = 6.7 × 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.


Assuntos
Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Cromatina/genética , Cromatina/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Histonas/genética , Histonas/metabolismo , Humanos , Especificidade de Órgãos , Neoplasias Ovarianas/metabolismo , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico
12.
BMC Genomics ; 15: 331, 2014 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-24885402

RESUMO

BACKGROUND: The precise nature of how cell type specific chromatin structures at enhancer sites affect gene expression is largely unknown. Here we identified cell type specific enhancers coupled with gene expression in two different types of breast epithelial cells, HMEC (normal breast epithelial cells) and MDAMB231 (triple negative breast cancer cell line). RESULTS: Enhancers were defined by modified neighboring histones [using chromatin immunoprecipitation followed by sequencing (ChIP-seq)] and nucleosome depletion [using formaldehyde-assisted isolation of regulatory elements followed by sequencing (FAIRE-seq)]. Histone modifications at enhancers were related to the expression levels of nearby genes up to 750 kb away. These expression levels were correlated with enhancer status (poised or active), defined by surrounding histone marks. Furthermore, about fifty percent of poised and active enhancers contained nucleosome-depleted regions. We also identified response element motifs enriched at these enhancer sites that revealed key transcription factors (e.g. TP63) likely involved in regulating breast epithelial enhancer-mediated gene expression. By utilizing expression data, potential target genes of more than 600 active enhancers were identified. These genes were involved in proteolysis, epidermis development, cell adhesion, mitosis, cell cycle, and DNA replication. CONCLUSIONS: These findings facilitate the understanding of epigenetic regulation specifically, such as the relationships between regulatory elements and gene expression and generally, how breast epithelial cellular phenotypes are determined by cell type specific enhancers.


Assuntos
Histonas/metabolismo , Glândulas Mamárias Humanas/metabolismo , Nucleossomos , Sequências Reguladoras de Ácido Nucleico , Linhagem Celular Tumoral , Feminino , Humanos , Glândulas Mamárias Humanas/patologia , Fatores de Transcrição/metabolismo
13.
PLoS Genet ; 10(1): e1004102, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24497837

RESUMO

Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations--we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at r(2) ≥ 0.88%. 88% of the 727 SNPs fall within putative enhancers, and many alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancers, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium (r(2) = 0.91) with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process.


Assuntos
Elementos Facilitadores Genéticos , Anotação de Sequência Molecular/classificação , Neoplasias da Próstata/genética , Elementos de Resposta/genética , Alelos , Cromatina/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Fatores de Risco , Fatores de Transcrição/genética
14.
Hum Mol Genet ; 23(8): 2198-209, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24256810

RESUMO

Genome-wide association studies of colorectal cancer (CRC) have identified a number of common variants associated with modest risk, including rs3802842 at chromosome 11q23.1. Several genes map to this region but rs3802842 does not map to any known transcribed or regulatory sequences. We reasoned, therefore, that rs3802842 is not the functional single-nucleotide polymorphism (SNP), but is in linkage disequilibrium (LD) with a functional SNP(s). We performed ChIP-seq for histone modifications in SW480 and HCT-116 CRC cells, and incorporated ChIP-seq and DNase I hypersensitivity data available through ENCODE within a 137-kb genomic region containing rs3802842 on 11q23.1. We identified SNP rs10891246 in LD with rs3802842 that mapped within a bidirectional promoter region of genes C11orf92 and C11orf93. Following mutagenesis to the risk allele, the promoter demonstrated lower levels of reporter gene expression. A second SNP rs7130173 was identified in LD with rs3802842 that mapped to a candidate enhancer region, which showed strong unidirectional activity in both HCT-116 and SW480 CRC cells. The risk allele of rs7130173 demonstrated reduced enhancer activity compared with the common allele, and reduced nuclear protein binding affinity in electromobility shift assays compared with the common allele suggesting differential transcription factor (TF) binding. SNPs rs10891246 and rs7130173 are on the same haplotype, and expression quantitative trait loci (eQTL) analyses of neighboring genes implicate C11orf53, C11orf92 and C11orf93 as candidate target genes. These data imply that rs10891246 and rs7130173 are functional SNPs mapping to 11q23.1 and that C11orf53, C11orf92 and C11orf93 represent novel candidate target genes involved in CRC etiology.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 11/genética , Neoplasias Colorretais/genética , Elementos Facilitadores Genéticos/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Imunoprecipitação da Cromatina , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Luciferases/metabolismo , Repetições de Microssatélites/genética , Locos de Características Quantitativas , Fatores de Risco , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas
15.
PLoS One ; 8(5): e63925, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23717510

RESUMO

Breast Cancer (BCa) genome-wide association studies revealed allelic frequency differences between cases and controls at index single nucleotide polymorphisms (SNPs). To date, 71 loci have thus been identified and replicated. More than 320,000 SNPs at these loci define BCa risk due to linkage disequilibrium (LD). We propose that BCa risk resides in a subgroup of SNPs that functionally affects breast biology. Such a shortlist will aid in framing hypotheses to prioritize a manageable number of likely disease-causing SNPs. We extracted all the SNPs, residing in 1 Mb windows around breast cancer risk index SNP from the 1000 genomes project to find correlated SNPs. We used FunciSNP, an R/Bioconductor package developed in-house, to identify potentially functional SNPs at 71 risk loci by coinciding them with chromatin biofeatures. We identified 1,005 SNPs in LD with the index SNPs (r(2)≥0.5) in three categories; 21 in exons of 18 genes, 76 in transcription start site (TSS) regions of 25 genes, and 921 in enhancers. Thirteen SNPs were found in more than one category. We found two correlated and predicted non-benign coding variants (rs8100241 in exon 2 and rs8108174 in exon 3) of the gene, ANKLE1. Most putative functional LD SNPs, however, were found in either epigenetically defined enhancers or in gene TSS regions. Fifty-five percent of these non-coding SNPs are likely functional, since they affect response element (RE) sequences of transcription factors. Functionality of these SNPs was assessed by expression quantitative trait loci (eQTL) analysis and allele-specific enhancer assays. Unbiased analyses of SNPs at BCa risk loci revealed new and overlooked mechanisms that may affect risk of the disease, thereby providing a valuable resource for follow-up studies.


Assuntos
Neoplasias da Mama/genética , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Alelos , Células Cultivadas , Cromatina/genética , Endonucleases/genética , Epigênese Genética/genética , Éxons/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Desequilíbrio de Ligação/genética , Elementos de Resposta/genética , Risco , Fatores de Risco , Fatores de Transcrição/genética , Sítio de Iniciação de Transcrição
16.
Gastroenterology ; 144(4): 799-807.e24, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23266556

RESUMO

BACKGROUND & AIMS: Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS: We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS: Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)). CONCLUSIONS: In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to ß-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.


Assuntos
Neoplasias Colorretais/genética , Ciclina D2/genética , Loci Gênicos/genética , Predisposição Genética para Doença/epidemiologia , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/epidemiologia , Proteínas de Ligação a DNA/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Laminina/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Medição de Risco , Distribuição por Sexo , Proteínas com Domínio T/genética
18.
Nucleic Acids Res ; 40(18): e139, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22684628

RESUMO

UNLABELLED: Single nucleotide polymorphisms (SNPs) are increasingly used to tag genetic loci associated with phenotypes such as risk of complex diseases. Technically, this is done genome-wide without prior restriction or knowledge of biological feasibility in scans referred to as genome-wide association studies (GWAS). Depending on the linkage disequilibrium (LD) structure at a particular locus, such tagSNPs may be surrogates for many thousands of other SNPs, and it is difficult to distinguish those that may play a functional role in the phenotype from those simply genetically linked. Because a large proportion of tagSNPs have been identified within non-coding regions of the genome, distinguishing functional from non-functional SNPs has been an even greater challenge. A strategy was recently proposed that prioritizes surrogate SNPs based on non-coding chromatin and epigenomic mapping techniques that have become feasible with the advent of massively parallel sequencing. Here, we introduce an R/Bioconductor software package that enables the identification of candidate functional SNPs by integrating information from tagSNP locations, lists of linked SNPs from the 1000 genomes project and locations of chromatin features which may have functional significance. AVAILABILITY: FunciSNP is available from Bioconductor (bioconductor.org).


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Software , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Genoma Humano , Glioma/genética , Humanos , Desequilíbrio de Ligação , Anotação de Sequência Molecular
19.
Cancer Epidemiol Biomarkers Prev ; 15(11): 2285-91, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17119059

RESUMO

Interleukin-6 (IL-6) promotes normal plasma cell development and proliferation of myeloma cells in culture. We evaluated IL-6 genotypes and body mass index (BMI) in a case-control study of multiple myeloma and plasmacytoma. DNA samples and questionnaires were obtained from incident cases of multiple myeloma (n = 134) and plasmacytoma (n = 16; plasma cell neoplasms) ascertained from the Los Angeles County population-based cancer registry and from siblings or cousins of cases (family controls, n = 112) and population controls (n = 126). Genotypes evaluated included IL-6 promoter gene single nucleotide polymorphisms (SNP) at positions -174, -572, and -597; one variable number of tandem repeats (-373 A(n)T(n)); and one SNP in the IL-6 receptor (IL-6ralpha) gene at position -358. The variant allele of the IL-6 promoter SNP -572 was associated with a roughly 2-fold increased risk of plasma cell neoplasms when cases were compared with family [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 0.7-4.7] or population controls (OR, 2.4; 95% CI, 1.2-4.7). The -373 9A/9A genotype was associated with a decreased risk compared with the most common genotype (OR for cases versus family controls, 0.4; 95% CI, 0.1-1.7; OR for cases versus population controls, 0.3; 95% CI, 0.1-0.9). No other SNPs were associated with risk. Obesity (BMI >or= 30 kg/m(2)) increased risk nonsignificantly by 40% and 80% when cases were compared with family controls or population controls, respectively, relative to persons with a BMI of <25 kg/m(2). These results suggest that IL-6 promoter genotypes may be associated with increased risk of plasma cell neoplasms.


Assuntos
Interleucina-6/biossíntese , Interleucina-6/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Plasmocitoma/genética , Plasmocitoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
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