TY - JOUR
T1 - Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility
AU - Lou, Hong
AU - Yeager, Meredith
AU - Li, Hongchuan
AU - Bosquet, Jesus Gonzalez
AU - Hayes, Richard B.
AU - Orr, Nick
AU - Yu, Kai
AU - Hutchinson, Amy
AU - Jacobs, Kevin B.
AU - Kraft, Peter
AU - Wacholder, Sholom
AU - Chatterjee, Nilanjan
AU - Feigelson, Heather Spencer
AU - Thun, Michael J.
AU - Diver, W. Ryan
AU - Albanes, Demetrius
AU - Virtamo, Jarmo
AU - Weinstein, Stephanie
AU - Ma, Jing
AU - Gaziano, J. Michael
AU - Stampfer, Meir
AU - Schumacher, Fredrick R.
AU - Giovannucci, Edward
AU - Cancel-Tassin, Geraldine
AU - Cussenot, Olivier
AU - Valeri, Antoine
AU - Andriole, Gerald L.
AU - Crawford, E. David
AU - Anderson, Stephen K.
AU - Tucker, Margaret
AU - Hoover, Robert N.
AU - Fraumeni, Joseph F.
AU - Thomas, Gilles
AU - Hunter, David J.
AU - Dean, Michael
AU - Chanock, Stephen J.
PY - 2009/5/12
Y1 - 2009/5/12
N2 - 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.
AB - 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.
KW - CREB transcription factor
KW - Genome-wide association studies
KW - Prostate cancer genetics
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U2 - 10.1073/pnas.0902104106
DO - 10.1073/pnas.0902104106
M3 - Article
C2 - 19383797
AN - SCOPUS:66049160161
SN - 0027-8424
VL - 106
SP - 7933
EP - 7938
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 19
ER -