Mutation analysis of the MSMB gene in familial prostate cancer.
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ABSTRACT: Background
MSMB, a gene coding for beta-microseminoprotein, has been identified as a candidate susceptibility gene for prostate cancer (PrCa) in two genome-wide association studies (GWAS). SNP rs10993994 is 2 bp upstream of the transcription initiation site of MSMB and was identified as an associated PrCa risk variant. The MSMB protein is underexpressed in PrCa and it was previously proposed to be an independent marker for the recurrence of cancer after radical prostatectomy.Methods
In this study, the coding region of this gene and 1500 bp upstream of the 5'UTR has been sequenced in germline DNA in 192 PrCa patients with family history. To evaluate the possible effects of these variants we used in silico analysis.Results
No deleterious mutations were identified, however, nine new sequence variants were found, most of these in the promoter and 5'UTR region. In silico analysis suggests that four of these SNPs are likely to have some effect on gene expression either by affecting ubiquitous or prostate-specific transcription factor (TF)-binding sites or modifying splicing efficiency.Interpretation
We conclude that MSMB is unlikely to be a familial PrCa gene and propose that the high-risk alleles of the SNPs in the 5'UTR effect PrCa risk by modifying MSMB gene expression in response to hormones in a tissue-specific manner.
SUBMITTER: Kote-Jarai Z
PROVIDER: S-EPMC2816656 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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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Project description:Genome-wide association studies (GWASs) identified microseminoprotein-? (MSMB) gene rs10993994 polymorphism was significantly associated with prostate cancer (PC) risk. However, the association between MSMB gene rs10993994 polymorphism and PC risk remains controversial. Therefore, we performed a systematic review and meta-analysis by searching in the databases of PubMed, and Embase. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by using fixed-effect or random-effect models. A total of 11 publications containing 13 case-control studies for rs10993994 polymorphism were included in our analysis. Our data indicated that MSMB gene rs10993994 polymorphism was associated with an increased risk of PC. Stratification analyses of ethnicity suggested rs10993994 polymorphism increased the risk of PC among Caucasians, but not among Asians. In conclusion, this meta-analysis indicates that MSMB gene rs10993994 polymorphism increases the risk of PC.
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Project description:Recently, a genetic variant (rs10993994) in the MSMB gene associated with prostate cancer (PCa) risk was shown to correlate with reduced prostate secretory protein of 94 amino acids (PSP94) levels. Although the biological activity of PSP94 is unclear, one of its hypothesized functions is to protect prostatic cells from pathogens. Number of sexual partners and a history of sexually transmitted infections (STIs) have been positively associated with PCa risk, and these associations may be related to pathogen-induced chronic prostatic inflammation. Based on these observations, we investigated whether MSMB genotype modifies the PCa-sexual history association.We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the association between number of sexual partners and PCa by fitting logistic regression models, stratified by MSMB genotype, and adjusted for age, family history of PCa, and PCa screening history among 1,239 incident cases and 1,232 controls.Compared with 1-4 female sexual partners, men with ? 15 such partners who carried the variant T allele of rs10993994 were at increased risk for PCa (OR = 1.32; 95% CI, 1.03-1.71); no association was observed in men with the CC genotype (OR = 1.03; 95% CI, 0.73-1.46; P = 0.05 for interaction). Similar estimates were observed for total sexual partners (any T allele OR = 1.37; 95% CI, 1.07-1.77; CC genotype OR = 1.11; 95% CI, 0.79-1.55; P = 0.06 for interaction).The rs10993994 genotype in the MSMB gene modifies the association between number of sexual partners and PCa risk. These findings support a hypothesized biological mechanism whereby prostatic infection/inflammation may enhance risk of PCa.
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Project description:Genome-wide association studies of prostate cancer have identified single nucleotide polymorphism (SNP) markers in a region of chromosome 10q11.2, harboring the microseminoprotein-? (MSMB) gene. Both the gene product of MSMB, the prostate secretory protein 94 (PSP94) and its binding protein (PSPBP), have been previously investigated as serum biomarkers for prostate cancer progression. Recent functional work has shown that different alleles of the significantly associated SNP in the promoter of MSMB found to be associated with prostate cancer risk, rs10993994, can influence its expression in tumors and in vitro studies. Since it is plausible that additional variants in this region contribute to the risk of prostate cancer, we have used next-generation sequencing technology to resequence a ~97-kb region that includes the area surrounding MSMB (chr10: 51,168,025-51,265,101) in 36 prostate cancer cases, 26 controls of European origin, and 8 unrelated CEPH individuals in order to identify additional variants to investigate in functional studies. We identified 241 novel polymorphisms within this region, including 142 in the 51-kb block of linkage disequilibrium (LD) that contains rs10993994 and the proximal promoter of MSMB. No sites were observed to be polymorphic within the exons of MSMB.
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Project description:Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states.
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Project description:BACKGROUND: Genome wide association studies (GWAS) have identified several genetic variants that are associated with prostate cancer. Most of these variants, like other GWAS association signals, are located in non-coding regions of potential candidate genes, and thus could act at the level of the mRNA transcript. METHODS: We measured the expression and isoform usage of seven prostate cancer candidate genes in benign and malignant prostate by real-time PCR, and correlated these factors with cancer status and genotype at the GWAS risk variants. RESULTS: We determined that levels of LMTK2 transcripts in prostate adenocarcinomas were only 32% of those in benign tissues (p = 3.2 x 10(-7)), and that an independent effect of genotype at variant rs6465657 on LMTK2 expression in benign (n = 39) and malignant tissues (n = 21) was also evident (P = 0.002). We also identified that whilst HNF1B(C) and MSMB2 comprised the predominant isoforms in benign tissues (90% and 98% of total HNF1B or MSMB expression), HNF1B(B) and MSMB1 were predominant in malignant tissue (95% and 96% of total HNF1B or MSMB expression; P = 1.7 x 10(-7) and 4 x 10(-4) respectively), indicating major shifts in isoform usage. CONCLUSIONS: Our results indicate that the amount or nature of mRNA transcripts expressed from the LMTK2, HNF1B and MSMB candidate genes is altered in prostate cancer, and provides further evidence for a role for these genes in this disorder. The alterations in isoform usage we detect highlights the potential importance of alternative mRNA processing and moderation of mRNA stability as potentially important disease mechanisms.
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Project description:Sexually transmitted infections and its contribution to prostate cancer (PC) development have been relevant in different populations. MSMB gene polymorphism (rs10993994) has exhibited an association both with PC as well as the susceptibility to sexually transmitted infections. Hitherto, these conditions have been not studied in Mexico yet, neither if sexually transmitted infections could modify the MSMB and PC association. Herein, socio-demographic features, sexually transmitted infections records, the reproductive backgrounds, and the genetic characterisation were analysed in 322 incident PC cases and 628 population healthy controls from Mexico City. Whole PC, early-onset PC (PC at < 60 years old), late-onset PC (? 60 years old), and PC aggressiveness were used to evaluate the genetic variants contribution to PC risk using unconditional logistic regression models. Overall, none associations between the allelic variants of rs10993994 polymorphisms with whole and PC aggressiveness were found. Howbeit, the TT genotype carriers presented the highest susceptibility to develop early-onset PC (OR = 2.66; 95% CI = 1.41, 5.04; p = 0.03) than CC+CT carriers, both with codominant and recessive models. Although none association between whole PC and MSMB gene polymorphism was found, our results were reinforced by prior studies in European descendent populations, suggesting a contribution between rs10993994 and early-onset PC development.
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Project description:A recent study of familial and early onset prostate cancer reported a recurrent rare germline mutation of HOXB13 among men of European descent. The gene resides within the 17q21 hereditary prostate cancer linkage interval.We evaluated the G84E germline mutation (rs138213197) of HOXB13 in a case-control study of familial prostate cancer at Vanderbilt University (Nashville, TN) to independently evaluate the association of the mutation with familial prostate cancer. We genotyped 928 familial prostate cancer probands and 930 control probands without a personal or family history of prostate cancer.Our study confirmed the association between the G84E mutation of HOXB13 and risk of prostate cancer among subjects of European descent. We observed the mutation in 16 familial cases and in two controls, each as heterozygotes. The odds ratio (OR) for prostate cancer was 7.9 [95% confidence interval, (CI) 1.8-34.5, P = 0.0062] among carriers of the mutation. The carrier rate was 1.9% among all familial case probands and 2.7% among probands of pedigrees with ?3 affected. In a separate case series of 268 probands of European descent with no additional family history of prostate cancer, the carrier rate was 1.5%.The germline mutation G84E of HOXB13 is a rare but recurrent mutation associated with elevated risk of prostate cancer in men of European descent, with an effect size that is greater than observed for previously validated risk variants of genome wide association studies.This study independently confirms the association of a germline HOXB13 mutation with familial prostate cancer.
| S-EPMC3415588 | biostudies-literature
Project description:BACKGROUND. With recent advances in high-throughput sequencing technologies, many prostate cancer risk loci have been identified, including rs10993994, a single nucleotide polymorphism (SNP) located near the MSMB gene. Variant allele (T) carriers of this SNP produce less prostate secretory protein 94 (PSP94), the protein product of MSMB, and have an increased risk of prostate cancer (approximately 25% per T allele), suggesting that PSP94 plays a protective role in prostate carcinogenesis, although the mechanisms for such protection are unclear. METHODS. We reviewed the literature on possible mechanisms for PSP94 protection for prostate cancer. RESULTS. One possible mechanism is tumor suppression, as PSP94 has been observed to inhibit cell or tumor growth in in vitro and in vivo models. Another novel mechanism, which we propose in this review article, is that PSP94 may protect against prostate cancer by preventing or limiting an intracellular fungal infection in the prostate. This mechanism is based on the recent discovery of PSP94's fungicidal activity in low-calcium environments (such as the cytosol of epithelial cells), and accumulating evidence suggesting a role for inflammation in prostate carcinogenesis. We provide further details of our proposed mechanism in this review article. CONCLUSIONS. To explore this mechanism, future studies should consider screening prostate specimens for fungi using the rapidly expanding number of molecular techniques capable of identifying infectious agents from the entire tree of life.
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