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

Proc Natl Acad Sci U S A. 2009 May 12;106(19):7933-8. doi: 10.1073/pnas.0902104106.

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

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Affiliation

1 Laboratory of Experimental Immunology, Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.

PMID: 19383797 DOI: 10.1073/pnas.0902104106

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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