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Human Molecular Genetics Advance Access originally published online on January 19, 2009
Human Molecular Genetics 2009 18(7):1368-1375; doi:10.1093/hmg/ddp035
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Fine mapping association study and functional analysis implicate a SNP in MSMB at 10q11 as a causal variant for prostate cancer risk

Bao-Li Chang1,2, Scott D. Cramer3, Fredrik Wiklund5, Sarah D. Isaacs7, Victoria L. Stevens8, Jielin Sun1,2, Shelly Smith1,2, Kristen Pruett1,2, Lina M. Romero3, Kathleen E. Wiley7, Seong-Tae Kim1,2, Yi Zhu1,2, Zheng Zhang1,2, Fang-Chi Hsu1,2,4, Aubrey R. Turner1,2, Jan Adolfsson6, Wennuan Liu1,2, Jin Woo Kim1,2, David Duggan9, John Carpten9, S. Lilly Zheng1,2, Carmen Rodriguez8, William B. Isaacs7, Henrik Grönberg5 and Jianfeng Xu1,2,3,*

1 Center for Cancer Genomics 2 Center for Human Genomics 3 Department of Cancer Biology 4 Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA 5 Department of Medical Epidemiology and Biostatistics 6 Oncological Center, CLINTEC, Karolinska Institutet, Stockholm, Sweden 7 Johns Hopkins Medical Institutions, Baltimore, MD, USA 8 Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA, USA 9 Translational Genomics Research Institute (TGen), Phoenix, AZ, USA

* To whom correspondence should be addressed at: Center for Cancer Genomics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. Tel: +1 336 7137500; Fax: +1 336 713 7566; Email: jxu{at}wfubmc.edu

Received October 23, 2008; Revised January 8, 2009; Accepted January 15, 2009

A single nucleotide polymorphism (SNP) at 10q11 (rs10993994) in the 5' region of the MSMB gene was recently implicated in prostate cancer risk in two genome-wide association studies. To identify possible causal variants in the region, we genotyped 16 tagging SNPs and imputed 29 additional SNPs in ~65 kb genomic region at 10q11 in a Swedish population-based case–control study (CAncer of the Prostate in Sweden), including 2899 cases and 1722 controls. We found evidence for two independent loci, separated by a recombination hotspot, associated with prostate cancer risk. Among multiple significant SNPs at locus 1, the initial SNP rs10993994 was most significant. Importantly, using an MSMB promoter reporter assay, we showed that the risk allele of this SNP had only 13% of the promoter activity of the wild-type allele in a prostate cancer model, LNCaP cells. Curiously, the second, novel locus (locus 2) was within NCOA4 (also known as ARA70), which is known to enhance androgen receptor transcriptional activity in prostate cancer cells. However, its association was only weakly confirmed in one of the three additional study populations. The observations that rs10993994 is the strongest associated variant in the region and its risk allele has a major effect on the transcriptional activity of MSMB, a gene with previously described prostate cancer suppressor function, together suggest the T allele of rs10993994 as a potential causal variant at 10q11 that confers increased risk of prostate cancer.


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