title: Investigation of the relationship between prostate cancer and MSMB and NCOA4 genetic variants and protein expression.
abstract: Two genome-wide association studies (GWAS) identified the β-microseminoprotein (MSMB) promoter SNP, rs10993994:C>T, as significantly associated with prostate cancer (PC) risk. Follow-up studies demonstrate that the variant allele directly affects expression of the MSMB-encoded protein, PSP94, and also suggest that it affects mRNA expression levels of an adjacent gene, NCOA4, which is involved in androgen receptor transactivation. In a population-based study of 1,323 cases and 1,268 age-matched controls, we found the NCOA4 SNP, rs7350420:T>C, was associated with a 15% reduction in PC risk, but the association was not significant after adjustment for the rs10993994:C>T genotype. Tumor tissue microarrays of 519 radical prostatectomy patients were used to measure PSP94 and NCOA4 protein expression. Taken together, these data confirm that the rs10993994:C>T variant allele is associated with decreased PSP94 expression, and the association is stronger in tumor compared to normal prostate tissue. No association was observed between rs10993994:C>T and NCOA4 expression, and only moderate associations were seen between two NCOA4 SNPs, rs10761618:T>C and rs7085433:G>A, and NCOA4 protein expression. These data indicate that the increase in PC risk associated with rs10993994:C>T is likely mediated by the variant's effect on PSP94 expression; however, this effect does not extend to NCOA4 in the data presented here.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Liesel M
authors.initials: LM
authors.lastname: FitzGerald
authors.forename: Xiaotun
authors.initials: X
authors.lastname: Zhang
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kolb
authors.forename: Erika M
authors.initials: EM
authors.lastname: Kwon
authors.forename: Ying Ching
authors.initials: YC
authors.lastname: Liew
authors.forename: Antonio
authors.initials: A
authors.lastname: Hurtado-Coll
authors.forename: Beatrice S
authors.initials: BS
authors.lastname: Knudsen
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stanford
mesh_terms: D000328:Adult; D000368:Aged; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D056918:Nuclear Receptor Coactivators / Q000235:genetics* / Q000378:metabolism; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D029584:Prostatic Secretory Proteins / Q000235:genetics* / Q000378:metabolism; D012042:Registries / Q000706:statistics & numerical data; D018570:Risk Assessment / Q000706:statistics & numerical data; D012307:Risk Factors; D046888:Tissue Array Analysis
chemical_list: C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D029584:Prostatic Secretory Proteins; C043076:beta-microseminoprotein