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An Integrative Genomics Approach for Associating Genome-Wide Association Studies Information With Localized and Metastatic Prostate Cancer Phenotypes

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ABSTRACT

High-throughput genotyping has enabled discovery of genetic variants associated with an increased risk of developing prostate cancer using genome-wide association studies (GWAS). The goal of this study was to associate GWAS information of patients with primary organ–confined and metastatic prostate cancer using gene expression data and to identify molecular networks and biological pathways enriched for genetic susceptibility variants involved in the 2 disease states. The analysis revealed gene signatures for the 2 disease states and a gene signature distinguishing the 2 patient groups. In addition, the analysis revealed molecular networks and biological pathways enriched for genetic susceptibility variants. The discovered pathways include the androgen, apoptosis, and insulinlike growth factor signaling pathways. This analysis established putative functional bridges between GWAS discoveries and the biological pathways involved in primary organ–confined and metastatic prostate cancer.

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Gene interaction networks based on the set of genes containing genetic variants associated with an increased risk of developing prostate cancer and non–genome-wide association studies (GWAS) genes found to be highly significantly differentially expressed between patients with primary organ–confined prostate cancer and controls or normal samples. Genes containing single-nucleotide polymorphisms (SNPs) with strong associations are marked in red fonts. Blue fonts indicate genes containing SNPs with weak-to-moderate association. Genes in black font are non-GWAS genes. Nodes indicate the genes and the edges indicate interactions based on functional relationships. Information on functional relationships of the genes and biological processes in which the genes are involved is provided in Supplementary Table S4.
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f4-10.1177_1177271917695810: Gene interaction networks based on the set of genes containing genetic variants associated with an increased risk of developing prostate cancer and non–genome-wide association studies (GWAS) genes found to be highly significantly differentially expressed between patients with primary organ–confined prostate cancer and controls or normal samples. Genes containing single-nucleotide polymorphisms (SNPs) with strong associations are marked in red fonts. Blue fonts indicate genes containing SNPs with weak-to-moderate association. Genes in black font are non-GWAS genes. Nodes indicate the genes and the edges indicate interactions based on functional relationships. Information on functional relationships of the genes and biological processes in which the genes are involved is provided in Supplementary Table S4.

Mentions: To gain insights about the broader biological context in which the genetic susceptibility variants operate, we performed network and pathway analysis. We sought to identify molecular networks and biological pathways enriched for genetic susceptibility variants in each disease state. The results showing the molecular networks enriched for genetic susceptibility variants in primary organ–confined prostate cancer are presented in Figure 4. Network analysis revealed that the genes containing genetic susceptibility variants with strong associations—MSMB, KLK3, FGF10, AR, NKX3-1, TERT, POU5F1, RFX6, FOXP4, ITGA6, CTBP2, FSMR, NCOA4, and SQRDL (in red font)—are functionally related and interact with one another (Figure 4). The analysis also revealed that genes containing genetic variants with moderate-to-weak associations—PRPH, MYC, GLI2, RUVBL1, HOXB13, IGF2, ERG, KLK2, PRKCI, POLR2E, and KRT8 (in blue font)—are functionally related and interact with genes containing genetic variants with strong association (Figure 4). In addition, genes containing genetic susceptibility variants were found to interact with genes RELA, RIPK3, UBC, EWSR1, and ANKRD7 not reported in GWAS (Figure 4).


An Integrative Genomics Approach for Associating Genome-Wide Association Studies Information With Localized and Metastatic Prostate Cancer Phenotypes
Gene interaction networks based on the set of genes containing genetic variants associated with an increased risk of developing prostate cancer and non–genome-wide association studies (GWAS) genes found to be highly significantly differentially expressed between patients with primary organ–confined prostate cancer and controls or normal samples. Genes containing single-nucleotide polymorphisms (SNPs) with strong associations are marked in red fonts. Blue fonts indicate genes containing SNPs with weak-to-moderate association. Genes in black font are non-GWAS genes. Nodes indicate the genes and the edges indicate interactions based on functional relationships. Information on functional relationships of the genes and biological processes in which the genes are involved is provided in Supplementary Table S4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5391982&req=5

f4-10.1177_1177271917695810: Gene interaction networks based on the set of genes containing genetic variants associated with an increased risk of developing prostate cancer and non–genome-wide association studies (GWAS) genes found to be highly significantly differentially expressed between patients with primary organ–confined prostate cancer and controls or normal samples. Genes containing single-nucleotide polymorphisms (SNPs) with strong associations are marked in red fonts. Blue fonts indicate genes containing SNPs with weak-to-moderate association. Genes in black font are non-GWAS genes. Nodes indicate the genes and the edges indicate interactions based on functional relationships. Information on functional relationships of the genes and biological processes in which the genes are involved is provided in Supplementary Table S4.
Mentions: To gain insights about the broader biological context in which the genetic susceptibility variants operate, we performed network and pathway analysis. We sought to identify molecular networks and biological pathways enriched for genetic susceptibility variants in each disease state. The results showing the molecular networks enriched for genetic susceptibility variants in primary organ–confined prostate cancer are presented in Figure 4. Network analysis revealed that the genes containing genetic susceptibility variants with strong associations—MSMB, KLK3, FGF10, AR, NKX3-1, TERT, POU5F1, RFX6, FOXP4, ITGA6, CTBP2, FSMR, NCOA4, and SQRDL (in red font)—are functionally related and interact with one another (Figure 4). The analysis also revealed that genes containing genetic variants with moderate-to-weak associations—PRPH, MYC, GLI2, RUVBL1, HOXB13, IGF2, ERG, KLK2, PRKCI, POLR2E, and KRT8 (in blue font)—are functionally related and interact with genes containing genetic variants with strong association (Figure 4). In addition, genes containing genetic susceptibility variants were found to interact with genes RELA, RIPK3, UBC, EWSR1, and ANKRD7 not reported in GWAS (Figure 4).

View Article: PubMed Central - PubMed

ABSTRACT

High-throughput genotyping has enabled discovery of genetic variants associated with an increased risk of developing prostate cancer using genome-wide association studies (GWAS). The goal of this study was to associate GWAS information of patients with primary organ–confined and metastatic prostate cancer using gene expression data and to identify molecular networks and biological pathways enriched for genetic susceptibility variants involved in the 2 disease states. The analysis revealed gene signatures for the 2 disease states and a gene signature distinguishing the 2 patient groups. In addition, the analysis revealed molecular networks and biological pathways enriched for genetic susceptibility variants. The discovered pathways include the androgen, apoptosis, and insulinlike growth factor signaling pathways. This analysis established putative functional bridges between GWAS discoveries and the biological pathways involved in primary organ–confined and metastatic prostate cancer.

No MeSH data available.


Related in: MedlinePlus