Systematic enrichment analysis of potentially functional regions for 103 prostate cancer risk-associated loci.
Prostate
; 75(12): 1264-76, 2015 Sep.
Article
em En
| MEDLINE
| ID: mdl-26015065
BACKGROUND: More than 100 prostate cancer (PCa) risk-associated single nucleotide polymorphisms (SNPs) have been identified by genome wide association studies (GWAS). However, the molecular mechanisms are unclear for most of these SNPs. METHODS: All reported PCa risk-associated SNPs reaching the genome-wide significance level of P < 1 × 10(-7) (index SNPs), as well as SNPs in linkage disequilibrium (LD, r(2) ≥ 0.5) with them were cataloged. Genomic regions with potentially functional impact were also identified, including UCSC annotated coding regions (exon and snoRNA/miRNA) and regulatory regions, as well as binding regions for transcription factors (TFs), histone modifications (HMs), DNase I hypersensitivity (DHSs), and RNA Polymerase IIA (POLR2A) defined by ChIP-Seq in prostate cell lines and tissues. Enrichment analysis was performed to test whether PCa risk-associated SNPs are located in these functional regions more than expected. RESULTS: A total of 103 PCa risk-associated index SNPs and 7,244 SNPs in LD with these index SNPs were cataloged. Genomic regions with potentially functional impact, grouped in 30 different categories of functionalities, were identified. Enrichment analysis indicated that genomic regions in the following 15 categories were enriched for the PCa risk-associated SNPs: exons, CpG regions, 6 TFs (AR, ERG, FOXA1, HOXB13, CTCF, and NR3C1), 5 HMs (H3K4me1, H3K4me2, H3K4me3, H3K27AC, and H3T11P), DHSs and POLR2A. In contrast, significantly fewer PCa risk SNPs were mapped to binding regions for H3K27me3, a repressive chromatin marker. CONCLUSIONS: The PCa risk-associated SNPs discovered to date may affect PCa risk through multiple different mechanisms, especially by affecting binding regions of TFs/HMs.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Fatores de Transcrição
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Desequilíbrio de Ligação
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Predisposição Genética para Doença
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Polimorfismo de Nucleotídeo Único
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Loci Gênicos
Tipo de estudo:
Etiology_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Humans
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Male
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article