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Ovarian Cancer Risk Variants Are Enriched in Histotype-Specific Enhancers and Disrupt Transcription Factor Binding Sites.
Jones, Michelle R; Peng, Pei-Chen; Coetzee, Simon G; Tyrer, Jonathan; Reyes, Alberto Luiz P; Corona, Rosario I; Davis, Brian; Chen, Stephanie; Dezem, Felipe; Seo, Ji-Heui; Kar, Siddartha; Dareng, Eileen; Berman, Benjamin P; Freedman, Matthew L; Plummer, Jasmine T; Lawrenson, Kate; Pharoah, Paul; Hazelett, Dennis J; Gayther, Simon A.
Afiliação
  • Jones MR; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Peng PC; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Coetzee SG; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Tyrer J; CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
  • Reyes ALP; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Corona RI; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Davis B; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Chen S; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Dezem F; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Seo JH; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Kar S; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK.
  • Dareng E; CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
  • Berman BP; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 9
  • Freedman ML; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Plummer JT; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Lawrenson K; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Pharoah P; CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
  • Hazelett DJ; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Gayther SA; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: simon.gayther@cshs.org.
Am J Hum Genet ; 107(4): 622-635, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32946763
ABSTRACT
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
Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Neoplasias Ovarianas / Histonas / Elementos Facilitadores Genéticos / Cistadenocarcinoma Seroso / Proteínas Correpressoras / Carcinoma Epitelial do Ovário / Proteínas do Tecido Nervoso Tipo de estudo: Estudo diagnóstico / Estudo de etiologia / Estudo prognóstico / Fatores de risco Limite: Feminino / Humanos Idioma: Inglês Revista: Am J Hum Genet Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Estados Unidos

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Neoplasias Ovarianas / Histonas / Elementos Facilitadores Genéticos / Cistadenocarcinoma Seroso / Proteínas Correpressoras / Carcinoma Epitelial do Ovário / Proteínas do Tecido Nervoso Tipo de estudo: Estudo diagnóstico / Estudo de etiologia / Estudo prognóstico / Fatores de risco Limite: Feminino / Humanos Idioma: Inglês Revista: Am J Hum Genet Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Estados Unidos
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