Promoter variants in the MSMB gene associated with prostate cancer regulate MSMB/NCOA4 fusion transcripts

Human Genetics Section, Basic Research Program, SAIC-Frederick Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Human Genetics (Impact Factor: 4.82). 06/2012; 131(9):1453-66. DOI: 10.1007/s00439-012-1182-2
Source: PubMed


Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prostate epithelial cells and secreted into seminal plasma. Variants in the promoter of the MSMB gene have been associated with the risk of prostate cancer (PCa) in several independent genome-wide association studies. Both MSMB and an adjacent gene, NCOA4, are subjected to transcriptional control via androgen response elements. The gene product of NCOA4 interacts directly with the androgen receptor as a co-activator to enhance AR transcriptional activity. Here, we provide evidence for the expression of full-length MSMB-NCOA4 fusion transcripts regulated by the MSMB promoter. The predominant MSMB-NCOA4 transcript arises by fusion of the 5'UTR and exons 1-2 of the MSMB pre-mRNA, with exons 2-10 of the NCOA4 pre-mRNA, producing a stable fusion protein, comprising the essential domains of NCOA4. Analysis of the splice sites of this transcript shows an unusually strong splice acceptor at NCOA4 exon 2 and the presence of Alu repeats flanking the exons potentially involved in the splicing event. Transfection experiments using deletion clones of the promoter coupled with luciferase reporter assays define a core MSMB promoter element located between -27 and -236 of the gene, and a negative regulatory element immediately upstream of the start codon. Computational network analysis reveals that the MSMB gene is functionally connected to NCOA4 and the androgen receptor signaling pathway. The data provide an example of how GWAS-associated variants may have multiple genetic and epigenetic effects.

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    • "This is the first study to investigate the association between two promoter SNPs (rs12770171, -184C/T and rs10993994, -2C/T) and BPH development. Some previous studies have focused on the correlation between polymorphisms of the MSMB gene and prostate cancer [18,19,20]. Although BPH is not directly linked to prostate cancer, epidemiological studies suggest that patients with BPH have an increased risk of prostate cancer [21]. "
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    ABSTRACT: Purpose Benign prostatic hyperplasia (BPH) is the most common prostate disease in aging men. Microseminoprotein-beta (MSMB) is abundant in semen. In this study, we investigated association between single nucleotide polymorphisms (SNPs) at the promoter of the MSMB gene and the risk for developing BPH in a Korean population. Methods We genotyped two promoter polymorphisms (rs12770171, -184C/T and rs10993994, -2C/T) of the MSMB gene by direct sequencing. Ninety-five BPH patients and 78 control subjects were recruited for this study. SNPStats and Haploview version 4.2 were used for genetic analyses. Multiple logistic regression models (codominant, dominant, recessive, and log-additive models) were applied to determine the odds ratio (OR), 95% confidence interval (CI), and P-value. Results Genotype frequency of the rs12770171 SNP showed significant difference between BPH patients and controls (OR, 2.14; 95% CI, 1.07-4.27; P=0.032 in the codominant 1 model; OR, 2.31; 95% CI, 1.19-4.47; P=0.011 in the dominant model; and OR, 2.05; 95% CI, 1.17-3.61; P=0.009 in the log-additive model). Moreover, the SNP also showed association between the two groups (OR, 2.05; 95% CI, 1.19-3.52; P=0.009). The rs10993994 SNP was not associated with BPH. In haplotype analysis, CC and TT haplotypes were associated with BPH (P<0.05). Conclusions This result indicates that a promoter polymorphism (rs12770170, -184C/T) in the MSMB gene may be associated with BPH development in a Korean population.
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    ABSTRACT: Prostate cancer (PCa) is one of the most common malignancies in the world with over 890 000 cases and over 258 000 deaths worldwide each year. Nearly all mortalities from PCa are due to metastatic disease, typically through tumors that evolve to be hormone-refractory or castrate-resistant. Despite intensive epidemiological study, there are few known environmental risk factors, and age and family history are the major determinants. However, there is extreme heterogeneity in PCa incidence worldwide, suggesting that major determining factors have not been described. Genome-wide association studies have been performed and a considerable number of significant, but low-risk loci have been identified. In addition, several groups have analyzed PCa by determination of genomic copy number, fusion gene generation and targeted resequencing of candidate genes, as well as exome and whole genome sequencing. These initial studies have examined both primary and metastatic tumors as well as murine xenografts and identified somatic alterations in TP53 and other potential driver genes, and the disturbance of androgen response and cell cycle pathways. It is hoped that continued characterization of risk factors as well as gene mutation and misregulation in tumors will aid in understanding, diagnosing and better treating PCa.Asian Journal of Andrology advance online publication, 8 April 2013; doi:10.1038/aja.2013.29.
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    ABSTRACT: Prostate cancer (PCa) is the second most frequently diagnosed malignancy in men. Genome-wide association studies (GWAS) has been highly successful in discovering susceptibility loci for prostate cancer. Currently, more than twenty GWAS have identified more than fifty common variants associated with susceptibility with PCa. Yet with the increase in loci, voices from the scientific society are calling for more. In this review, we summarize current findings, discuss the common problems troubling current studies and shed light upon possible breakthroughs in the future. GWAS is the beginning of something wonderful. Although we are quite near the end of the beginning, post-GWAS studies are just taking off and future studies are needed extensively. It is believed that in the future GWAS information will be helpful to build a comprehensive system intergraded with PCa prevention, diagnosis, molecular classification, personalized therapy.
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