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

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 β-microseminoprotein (prostatic secretory protein 94). In this study, a fine-mapping analysis using HapMap SNPs was conducted across a ≈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 × 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.

[1]  J. Carpten,et al.  Fine mapping association study and functional analysis implicate a SNP in MSMB at 10q11 as a causal variant for prostate cancer risk. , 2009, Human molecular genetics.

[2]  M. Stampfer,et al.  Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. , 2008, The Lancet. Oncology.

[3]  Karin M. Fredrikson,et al.  Comprehensive resequence analysis of a 136 kb region of human chromosome 8q24 associated with prostate and colon cancers , 2008, Human Genetics.

[4]  Francis S Collins,et al.  A HapMap harvest of insights into the genetics of common disease. , 2008, The Journal of clinical investigation.

[5]  W. Willett,et al.  Multiple loci identified in a genome-wide association study of prostate cancer , 2008, Nature Genetics.

[6]  Ali Amin Al Olama,et al.  Multiple newly identified loci associated with prostate cancer susceptibility , 2008, Nature Genetics.

[7]  D. Gudbjartsson,et al.  Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes , 2007, Nature Genetics.

[8]  David Reich,et al.  A common genetic risk factor for colorectal and prostate cancer , 2007, Nature Genetics.

[9]  W. Gerald,et al.  Association of Cysteine-Rich Secretory Protein 3 and β-Microseminoprotein with Outcome after Radical Prostatectomy , 2007, Clinical Cancer Research.

[10]  M. Bollen,et al.  The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2 , 2007, Oncogene.

[11]  P. Donnelly,et al.  Replicating genotype–phenotype associations , 2007, Nature.

[12]  D. Gudbjartsson,et al.  Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24 , 2007, Nature Genetics.

[13]  P. Fearnhead,et al.  Genome-wide association study of prostate cancer identifies a second risk locus at 8q24 , 2007, Nature Genetics.

[14]  A. Whittemore,et al.  Multiple regions within 8q24 independently affect risk for prostate cancer , 2007, Nature Genetics.

[15]  J. R. Reeves,et al.  Prognostic Value of Prostate Secretory Protein of 94 Amino Acids and its Binding Protein after Radical Prostatectomy , 2006, Clinical Cancer Research.

[16]  A. Whittemore,et al.  Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men , 2006, Proceedings of the National Academy of Sciences.

[17]  A. Gylfason,et al.  A common variant associated with prostate cancer in European and African populations , 2006, Nature Genetics.

[18]  T. Golub,et al.  Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. , 2006, Cancer research.

[19]  Hugues Sicotte,et al.  SNP500Cancer: a public resource for sequence validation, assay development, and frequency analysis for genetic variation in candidate genes , 2005, Nucleic Acids Res..

[20]  Michael C O'Donovan,et al.  Strong bias in the location of functional promoter polymorphisms , 2005, Human mutation.

[21]  Daniel J Schaid,et al.  The complex genetic epidemiology of prostate cancer. , 2004, Human molecular genetics.

[22]  J. Cheville,et al.  Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression. , 2003, Cancer research.

[23]  R. Houlston,et al.  A systematic review and meta‐analysis of familial prostate cancer risk , 2003, BJU international.

[24]  E. Latulippe,et al.  Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. , 2002, Cancer research.

[25]  N. Seidah,et al.  Molecular cloning and sequence of the cDNA for a 94-amino-acid seminal plasma protein secreted by the human prostate. , 1987, DNA.

[26]  C. Carlson,et al.  Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. , 2004, American journal of human genetics.