Investigation of the Relationship Between Prostate Cancer and<i>MSMB</i>and<i>NCOA4</i>Genetic Variants and Protein Expression

FitzGerald, Liesel M.; Zhang, Xiaotun; Kolb, Suzanne; Kwon, Erika M.; Liew, Ying Ching; Hurtado-Coll, Antonio; Knudsen, Beatrice S.; Ostrander, Elaine A.; Stanford, Janet L.

doi:10.1002/humu.22176

Cited by 26 publications

(21 citation statements)

References 25 publications

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“…Following the theory proposed by Laurence [12], the present study provides initial epidemiological support for the hypothesis that the PSP94 protein may inhibit the adverse effects of a sexually transmitted pathogen on prostatic tissue, since men who carry the T allele of rs10993994 have been shown to have lower PSP94 expression in prostate tissue and lower PSP94 concentrations in urine, and are also at increased risk for PCa [6][7][8][9][10][11]. The biological mechanism by which PSP94 may inhibit an STI is unknown.…”

Section: Discussionsupporting

confidence: 71%

“…The PSP94 protein is encoded by the b-microseminoprotein (MSMB) gene. Several studies, including our own [6], have observed that the variant T allele of SNP rs10993994, which is in the proximal promoter region of the MSMB gene, is associated with increased PCa risk and with lower PSP94 protein expression in tissue and urine [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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MSMB gene variant alters the association between prostate cancer and number of sexual partners

2013

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Background 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. Methods We estimated odds ratios (OR) and 95% confidence intervals (CI) 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. Results 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). Conclusions 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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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

MSMB gene variant alters the association between prostate cancer and number of sexual partners

2013

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“…Intra-patient concordance was evaluated on each of the two core samples from the same 2% sample. As previously described, 19 immunostaining was assessed using a score created by multiplying staining intensity (0 for no staining, 1 for light staining, and 2 for strong staining) by the corresponding percentage of cells staining positive at each intensity. The mean score was used for cases with data from duplicate cores.…”

Section: Methodsmentioning

confidence: 99%

Prostate Cancer Expression Profiles of Cytoplasmic ERβ1 and Nuclear ERβ2 are Associated with Poor Outcomes following Radical Prostatectomy

et al. 2016

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Purpose Existing data regarding the expression of estrogen receptors (ER) and prostate cancer outcomes have been limited. We evaluated the relationship of expression profiles of ERβ subtypes and the estrogen receptor GPR30 with patient factors at diagnosis and outcomes following radical prostatectomy. Materials and Methods Tissue microarrays constructed from 566 men with long-term clinical follow-up were analyzed with immunohistochemistry targeting ERβ1, ERβ2, ERβ5 and GPR30. An experienced pathologist scored receptor distributions and staining intensities. Tumor staining characteristics were evaluated for associations with patient characteristics, recurrence free survival, and prostate cancer-specific mortality (PCSM) following radical prostatectomy. Results: Prostate cancer cells had unique receptor subtype staining patterns with ERβ1 demonstrating predominantly nuclear localization, while ERβ2, ERβ5 and GPR30 were predominantly cytoplasmic. After controlling for patient factors, intense cytoplasmic ERβ1 staining was independently associated with time to recurrence (HR 1.7, 95% CI 1.1-2.6, p=0.01) and PCSM (HR 6.6, 95% CI 1.8-24.9, p=0.01). Similarly, intense nuclear ERβ2 staining was independently associated with PCSM (HR 3.9, 95% CI 1.1-13.4, p=0.03). Patients with cytoplasmic ERβ1 and nuclear ERβ2 co-staining had significantly worse 15-year PCSM vs. patients expressing only cytoplasmic ERβ1, only nuclear ERβ2, or neither (16.4% vs. 4.3% vs. 0.0% vs 2.0 %, respectively p=0.001). Conclusions Increased cytoplasmic ERβ1 and nuclear ERβ2 expression are associated with worse cancer-specific outcomes following radical prostatectomy. These findings suggest that tumor ERβ1 and ERβ2 staining patterns provide prognostic information for radical prostatectomy patients.

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“…Fitzgerald et al 38 could find no association between SNPs in this region and overall NCOA4 expression and Rinckleb et al 39 presented data that there is an association of rs10993994 risk homozygosity and DNA repair capacity. Therefore, this PCa GWAS locus is very complex and the association signal may be a combination of very subtle effects on more than one gene/pathway.…”

Section: Genetics and Genomics Of Prostate Cancer M Dean And H Lou 310mentioning

confidence: 99%

Genetics and genomics of prostate cancer

Dean¹,

Li²

2013

Asian J Androl

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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.

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Investigation of the Relationship Between Prostate Cancer andMSMBandNCOA4Genetic Variants and Protein Expression

Cited by 26 publications

References 25 publications

MSMB gene variant alters the association between prostate cancer and number of sexual partners

MSMB gene variant alters the association between prostate cancer and number of sexual partners

Prostate Cancer Expression Profiles of Cytoplasmic ERβ1 and Nuclear ERβ2 are Associated with Poor Outcomes following Radical Prostatectomy

Genetics and genomics of prostate cancer

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