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1.
Nat Commun ; 10(1): 3615, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399598

RESUMO

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL.


Assuntos
Epigênese Genética/genética , Epigênese Genética/fisiologia , Epigenômica , Predisposição Genética para Doença/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfócitos B/metabolismo , Sequência de Bases , Cromatina/metabolismo , Metilação de DNA , Regulação Leucêmica da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição
2.
Hum Genomics ; 13(1): 37, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429796

RESUMO

BACKGROUND: While genome-wide association studies (GWAS) of multiple myeloma (MM) have identified variants at 23 regions influencing risk, the genes underlying these associations are largely unknown. To identify candidate causal genes at these regions and search for novel risk regions, we performed a multi-tissue transcriptome-wide association study (TWAS). RESULTS: GWAS data on 7319 MM cases and 234,385 controls was integrated with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues (sample sizes, N = 80-491), including lymphocyte cell lines and whole blood, to predict gene expression. We identified 108 genes at 13 independent regions associated with MM risk, all of which were in 1 Mb of known MM GWAS risk variants. Of these, 94 genes, located in eight regions, had not previously been considered as a candidate gene for that locus. CONCLUSIONS: Our findings highlight the value of leveraging expression data from multiple tissues to identify candidate genes responsible for GWAS associations which provide insight into MM tumorigenesis. Among the genes identified, a number have plausible roles in MM biology, notably APOBEC3C, APOBEC3H, APOBEC3D, APOBEC3F, APOBEC3G, or have been previously implicated in other malignancies. The genes identified in this TWAS can be explored for follow-up and validation to further understand their role in MM biology.

3.
Nat Commun ; 10(1): 2154, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089142

RESUMO

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.


Assuntos
Neoplasias Colorretais/genética , Loci Gênicos , Predisposição Genética para Doença , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Conjuntos de Dados como Assunto , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
5.
Nat Commun ; 10(1): 213, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631080

RESUMO

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

6.
Blood Adv ; 3(1): 21-32, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30606723

RESUMO

The identification of driver mutations is fundamental to understanding oncogenesis. Although genes frequently mutated in B-cell lymphoma have been identified, the search for driver mutations has largely focused on the coding genome. Here we report an analysis of the noncoding genome using whole-genome sequencing data from 117 patients with B-cell lymphoma. Using promoter capture Hi-C data in naive B cells, we define cis-regulatory elements, which represent an enriched subset of the noncoding genome in which to search for driver mutations. Regulatory regions were identified whose mutation significantly alters gene expression, including copy number variation at cis-regulatory elements targeting CD69, IGLL5, and MMP14, and single nucleotide variants in a cis-regulatory element for TPRG1 We also show the commonality of pathways targeted by coding and noncoding mutations, exemplified by MMP14, which regulates Notch signaling, a pathway important in lymphomagenesis and whose expression is associated with patient survival. This study provides an enhanced understanding of lymphomagenesis and describes the advantages of using chromosome conformation capture to decipher noncoding mutations relevant to cancer biology.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Linfoma de Células B/genética , Mutação , RNA não Traduzido/genética , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Bases de Dados Genéticas , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética/métodos , Humanos , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Fases de Leitura Aberta , Regiões Promotoras Genéticas , Sequenciamento Completo do Genoma
7.
Blood ; 132(19): 2040-2052, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30194254

RESUMO

To further our understanding of inherited susceptibility to Hodgkin lymphoma (HL), we performed a meta-analysis of 7 genome-wide association studies totaling 5325 HL cases and 22 423 control patients. We identify 5 new HL risk loci at 6p21.31 (rs649775; P = 2.11 × 10-10), 6q23.3 (rs1002658; P = 2.97 × 10-8), 11q23.1 (rs7111520; P = 1.44 × 10-11), 16p11.2 (rs6565176; P = 4.00 × 10-8), and 20q13.12 (rs2425752; P = 2.01 × 10-8). Integration of gene expression, histone modification, and in situ promoter capture Hi-C data at the 5 new and 13 known risk loci implicates dysfunction of the germinal center reaction, disrupted T-cell differentiation and function, and constitutive NF-κB activation as mechanisms of predisposition. These data provide further insights into the genetic susceptibility and biology of HL.


Assuntos
Centro Germinativo/patologia , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Polimorfismo de Nucleotídeo Único , Linfócitos T/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Código das Histonas , Doença de Hodgkin/imunologia , Humanos , Imunidade , NF-kappa B/genética , NF-kappa B/imunologia , Regiões Promotoras Genéticas , Linfócitos T/imunologia , Linfócitos T/metabolismo
8.
Nat Genet ; 50(10): 1375-1380, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30224643

RESUMO

Efforts are being directed to systematically analyze the non-coding regions of the genome for cancer-driving mutations1-6. cis-regulatory elements (CREs) represent a highly enriched subset of the non-coding regions of the genome in which to search for such mutations. Here we use high-throughput chromosome conformation capture techniques (Hi-C) for 19,023 promoter fragments to catalog the regulatory landscape of colorectal cancer in cell lines, mapping CREs and integrating these with whole-genome sequence and expression data from The Cancer Genome Atlas7,8. We identify a recurrently mutated CRE interacting with the ETV1 promoter affecting gene expression. ETV1 expression influences cell viability and is associated with patient survival. We further refine our understanding of the regulatory effects of copy-number variations, showing that RASL11A is targeted by a previously identified enhancer amplification1. This study reveals new insights into the complex genetic alterations driving tumor development, providing a paradigm for employing chromosome conformation capture to decipher non-coding CREs relevant to cancer biology.


Assuntos
Transformação Celular Neoplásica/genética , Cromossomos Humanos/química , Códon sem Sentido , Neoplasias Colorretais/genética , Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Células CACO-2 , Neoplasias Colorretais/epidemiologia , DNA de Neoplasias/química , Bases de Dados Genéticas , Frequência do Gene , Células HT29 , Células HeLa , Células Hep G2 , Humanos , Células K562 , Células MCF-7 , Conformação de Ácido Nucleico , Regiões Promotoras Genéticas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Células Tumorais Cultivadas
9.
Nat Commun ; 9(1): 3707, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30213928

RESUMO

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.


Assuntos
Predisposição Genética para Doença , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único , Teorema de Bayes , Cromatina/química , Imunoprecipitação da Cromatina , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Regiões Promotoras Genéticas , Controle de Qualidade , Locos de Características Quantitativas , Risco
10.
Curr Protoc Hum Genet ; : e63, 2018 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-29979818

RESUMO

Chromosome conformation capture (3C), coupled with next-generation sequencing (Hi-C), provides a means for deciphering not only the principles underlying genome folding and architecture, but more broadly, the role 3D chromatin structure plays in gene regulation and the replication and repair of DNA. The recently implemented modification, in situ Hi-C, maintains nuclear integrity during digestion and ligation steps, reducing random ligation of Hi-C fragments. Although Hi-C allows for genome-wide characterization of chromatin contacts, it requires high-depth sequencing to discover significant contacts. To address this, Capture Hi-C (CHi-C) enriches standard Hi-C libraries for regions of biological interest, for example by specifically targeting gene promoters, aiding identification of biologically significant chromatin interactions compared to conventional Hi-C, for an equivalent number of sequence reads. Illustrating the application of CHi-C applied to genome-wide analysis of chromatin interactions with promoters, we detail the protocols for in situ Hi-C and CHi-C library generation for sequencing, as well as the bioinformatics tools for data analysis. © 2018 by John Wiley & Sons, Inc.

11.
Int J Cancer ; 142(3): 540-546, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28960316

RESUMO

Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10-9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.


Assuntos
Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Estudos de Casos e Controles , Estudos de Coortes , Estônia/epidemiologia , Finlândia/epidemiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Sistema de Registros
12.
Blood Cancer J ; 9(1): 1, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30602759

RESUMO

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/genética , Mieloma Múltiplo/genética , Alelos , Estudos de Casos e Controles , Bases de Dados Genéticas , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Especificidade de Órgãos/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
13.
Nat Commun ; 8(1): 1892, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29196614

RESUMO

Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10-8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10-17), 6q23.3 (rs6928977, P = 4.62 × 10-11), 10p14 (rs3781093, P = 9.49 × 10-13), 13q34 (rs112998813, P = 4.58 × 10-8) and 16p13.13 (rs34972832, P = 2.12 × 10-8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.


Assuntos
Predisposição Genética para Doença , Doença de Hodgkin/genética , Alelos , Estudo de Associação Genômica Ampla , Cadeias beta de HLA-DP/genética , Cadeias HLA-DRB1/genética , Humanos , Polimorfismo de Nucleotídeo Único
14.
Cell Rep ; 20(11): 2556-2564, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-28903037

RESUMO

Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.


Assuntos
Cromossomos Humanos Par 5/genética , Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Elongação da Transcrição/genética , Alelos , Diploide , Epigênese Genética , Epigenômica , Loci Gênicos , Humanos , Proteínas Nucleares/metabolismo , Mapeamento Físico do Cromossomo , Prognóstico , Ligação Proteica , Fatores de Risco , Elongação da Transcrição Genética , Resposta a Proteínas não Dobradas/genética
15.
Nat Genet ; 49(7): 1133-1140, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28604728

RESUMO

Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.


Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/genética , Adulto , Cromatina/genética , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Polimorfismo de Nucleotídeo Único , Risco , Neoplasias Testiculares/epidemiologia , Adulto Jovem
16.
Sci Rep ; 7: 41071, 2017 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-28112199

RESUMO

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10-9) with opposing effects between CLL (P = 1.97 × 10-8) and HL (P = 3.31 × 10-3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10-12) was associated with increased CLL and HL risk (P = 4.68 × 10-12), and reduced MM risk (P = 1.12 × 10-2), and Gly70 in HLA-DQB1 (P = 3.15 × 10-10) showed opposing effects between CLL (P = 3.52 × 10-3) and HL (P = 3.41 × 10-9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.


Assuntos
Pleiotropia Genética/genética , Estudo de Associação Genômica Ampla , Doença de Hodgkin/genética , Leucemia Linfocítica Crônica de Células B/genética , Mieloma Múltiplo/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Doença de Hodgkin/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Proteínas Oncogênicas/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
17.
Nat Commun ; 7: 13656, 2016 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-27882933

RESUMO

Genome-wide association studies have identified several risk loci for multiple myeloma (MM); however, the mechanisms by which they influence MM are unknown. Here by using genetic association data and functional characterization, we demonstrate that rs4487645 G>T, the most highly associated variant (P = 5.30 × 10-25), resides in an enhancer element 47 kb upstream of the transcription start site of c-Myc-interacting CDCA7L. The G-risk allele, associated with increased CDCA7L expression (P=1.95 × 10-36), increases IRF4 binding and the enhancer interacts with the CDCA7L promoter. We show that suppression of CDCA7L limits MM proliferation through apoptosis, and increased CDCA7L expression is associated with adverse patient survival. These findings implicate IRF4-mediated CDCA7L expression in MM biology and indicate how germline variation might confer susceptibility to MM.


Assuntos
Apoptose/genética , Elementos Facilitadores Genéticos/genética , Regulação Neoplásica da Expressão Gênica , Fatores Reguladores de Interferon/metabolismo , Mieloma Múltiplo/genética , Proteínas Repressoras/genética , Alelos , Linhagem Celular Tumoral , Predisposição Genética para Doença , Humanos , Mieloma Múltiplo/metabolismo , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Ligação Proteica/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Locos de Características Quantitativas , Proteínas Repressoras/metabolismo
18.
Hum Mol Genet ; 25(11): 2349-2359, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27005424

RESUMO

To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10-8, odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2 = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Neoplasias Colorretais/genética , Doenças Inflamatórias Intestinais/genética , Proteínas de Membrana/genética , Proteínas Musculares/genética , Grupo com Ancestrais do Continente Asiático , Neoplasias Colorretais/patologia , Grupo com Ancestrais do Continente Europeu , Feminino , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Doenças Inflamatórias Intestinais/patologia , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco
19.
Cancer Cell ; 28(5): 557-568, 2015 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-26602815

RESUMO

Histone H3K36 trimethylation (H3K36me3) is frequently lost in multiple cancer types, identifying it as an important therapeutic target. Here we identify a synthetic lethal interaction in which H3K36me3-deficient cancers are acutely sensitive to WEE1 inhibition. We show that RRM2, a ribonucleotide reductase subunit, is the target of this synthetic lethal interaction. RRM2 is regulated by two pathways here: first, H3K36me3 facilitates RRM2 expression through transcription initiation factor recruitment; second, WEE1 inhibition degrades RRM2 through untimely CDK activation. Therefore, WEE1 inhibition in H3K36me3-deficient cells results in RRM2 reduction, critical dNTP depletion, S-phase arrest, and apoptosis. Accordingly, this synthetic lethality is suppressed by increasing RRM2 expression or inhibiting RRM2 degradation. Finally, we demonstrate that WEE1 inhibitor AZD1775 regresses H3K36me3-deficient tumor xenografts.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Histonas/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Nucleotídeos/metabolismo , Proteínas Tirosina Quinases/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Western Blotting , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Humanos , Lisina/genética , Lisina/metabolismo , Metilação/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Dados de Sequência Molecular , Neoplasias/genética , Neoplasias/prevenção & controle , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Nucleotídeos/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Pirazóis/farmacologia , Pirimidinas/farmacologia , Pirimidinonas , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonucleosídeo Difosfato Redutase/genética , Ribonucleosídeo Difosfato Redutase/metabolismo , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido Nucleico , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Nucleic Acids Res ; 42(4): 2320-9, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24293653

RESUMO

The ARF tumour suppressor protein, the gene of which is frequently mutated in many human cancers, plays an important role in the cellular stress response by orchestrating up-regulation of p53 protein and consequently promoting cell-cycle delay. Although p53 protein function has been clearly linked to the cellular DNA damage response, the role of ARF protein in this process is unclear. Here, we report that arf gene transcription is induced by DNA strand breaks (SBs) and that ARF protein accumulates in response to persistent DNA damage. We discovered that poly(ADP-ribose) synthesis catalysed by PARP1 at the sites of unrepaired SBs activates ARF transcription through a protein signalling cascade, including the NAD(+)-dependent deacetylase SIRT1 and the transcription factor E2F1. Our data suggest that poly(ADP-ribose) synthesis at the sites of SBs initiates DNA damage signal transduction by reducing the cellular concentration of NAD(+), thus down-regulating SIRT1 activity and consequently activating E2F1-dependent ARF transcription. Our findings suggest a vital role for ARF in DNA damage signalling, and furthermore explain the critical requirement for ARF inactivation in cancer cells, which are frequently deficient in DNA repair and accumulate DNA damage.


Assuntos
Quebras de DNA , Poli(ADP-Ribose) Polimerases/fisiologia , Proteína Supressora de Tumor p14ARF/biossíntese , Fator de Transcrição E2F1/fisiologia , Células HeLa , Humanos , Poli(ADP-Ribose) Polimerase-1 , Transdução de Sinais , Sirtuína 1/fisiologia , Proteína Supressora de Tumor p14ARF/genética
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