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. 2009 May 12;106(19):7933-8.
doi: 10.1073/pnas.0902104106. Epub 2009 Apr 21.

Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility

Hong Lou  1 , Meredith Yeager, Hongchuan Li, Jesus Gonzalez Bosquet, Richard B Hayes, Nick Orr, Kai Yu, Amy Hutchinson, Kevin B Jacobs, Peter Kraft, Sholom Wacholder, Nilanjan Chatterjee, Heather Spencer Feigelson, Michael J Thun, W Ryan Diver, Demetrius Albanes, Jarmo Virtamo, Stephanie Weinstein, Jing Ma, J Michael Gaziano, Meir Stampfer, Fredrick R Schumacher, Edward Giovannucci, Geraldine Cancel-Tassin, Olivier Cussenot, Antoine Valeri, Gerald L Andriole, E David Crawford, Stephen K Anderson, Margaret Tucker, Robert N Hoover, Joseph F Fraumeni Jr, Gilles Thomas, David J Hunter, Michael Dean, Stephen J Chanock
Affiliations

Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility

Hong Lou et al. Proc Natl Acad Sci U S A. .

Abstract

Two recent genome-wide association studies have independently identified a prostate cancer susceptibility locus on chromosome 10q11.2. The most significant single-nucleotide polymorphism (SNP) marker reported, rs10993994, is 57 bp centromeric of the first exon of the MSMB gene, which encodes beta-microseminoprotein (prostatic secretory protein 94). In this study, a fine-mapping analysis using HapMap SNPs was conducted across a approximately 65-kb region (chr10: 51168330-51234020) flanking rs10993994 with 13 tag SNPs in 6,118 prostate cancer cases and 6,105 controls of European origin from the Cancer Genetic Markers of Susceptibility (CGEMS) project. rs10993994 remained the most strongly associated marker with prostate cancer risk [P = 8.8 x 10(-18); heterozygous odds ratio (OR) = 1.20, 95% confidence interval (CI): 1.11-1.30; homozygous OR = 1.64, 95% CI: 1.47-1.86 for the adjusted genotype test with 2 df]. In follow-up functional analyses, the T variant of rs10993994 significantly affected expression of in vitro luciferase reporter constructs. In electrophoretic mobility shift assays, the C allele of rs10993994 preferentially binds to the CREB transcription factor. Analysis of tumor cell lines with a CC or CT genotype revealed a high level of MSMB gene expression compared with cell lines with a TT genotype. These findings were specific to the alleles of rs10993994 and were not observed for other SNPs determined by sequence analysis of the proximal promoter. Together, our mapping study and functional analyses implicate regulation of expression of MSMB as a plausible mechanism accounting for the association identified at this locus. Further investigation is warranted to determine whether rs10993994 alone or in combination with additional variants contributes to prostate cancer susceptibility.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
A schematic of the MSMB gene. Four exons are indicated by the numbered white rectangles. Nucleotide sequence of 336-bp MSMB gene, including 5′-region and Exon 1, is shown with the putative transcription factor binding sites in bold. Numbering is relative to the transcriptional start site at exon 1. Transcription orientations are indicated by arrows.
Fig. 2.
Fig. 2.
The SNP rs10993994 contributes to MSMB promoter activity. Effect of MSMB promoter polymorphisms on promoter activity in 293T, PC3, and MCF7 cells is shown. Values represent fold increase of luciferase activity relative to empty pGL3 vector. The mean and SD of at least 3 independent experiments are shown.
Fig. 3.
Fig. 3.
Binding of CREB transcription factor to the promoter of the MSMB gene. Electrophoretic mobility shift assay (EMSA) analysis of the CREB binding site corresponding to the SNP rs10993994 observed in MSMB promoter region. (A) Oligonucleotides used for EMSA analysis. The sense strand of oligonucleotide probes corresponding to the predicted CREB binding site of the MSMB promoter is shown. (B) EMSA analysis performed on MCF7 nuclear extracts with probes indicated in A. The right panels show supershift analysis of the MSMB-C probe from MCF7 extracts in the presence of specific Abs.
Fig. 4.
Fig. 4.
Quantitative analysis of MSMB mRNA expression by Taqman real-time RT-PCR. (A) List of cell lines with detectable MSMB mRNA expression. The relative mRNA expression level of MSMB gene was normalized by the following formula: (copy number of target gene)/(copy number of 18S rRNA) × 107. (B) Distribution of MSMB mRNA expression relative to with or without C at SNP rs10993994.
Fig. 5.
Fig. 5.
Location of and LD (D') among 13 SNPs genotyped for association with prostate cancer. Data shown are from 6,105 prostate cancer control individuals. The region shown is chr10:51168330-51234020.
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