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

被引：79

作者：

Lou, Hong ^{[2
,3
]}

Yeager, Meredith ^{[1
,3
]}

Li, Hongchuan ^{[2
]}

Bosquet, Jesus Gonzalez ^{[1
]}

Hayes, Richard B. ^{[1
]}

Orr, Nick ^{[1
]}

Yu, Kai ^{[1
]}

Hutchinson, Amy ^{[1
,3
]}

Jacobs, Kevin B. ^{[4
]}

Kraft, Peter ^{[5
]}

Wacholder, Sholom ^{[1
]}

Chatterjee, Nilanjan ^{[1
]}

Feigelson, Heather Spencer ^{[6
]}

Thun, Michael J. ^{[6
]}

Diver, W. Ryan ^{[6
]}

Albanes, Demetrius ^{[1
]}

Virtamo, Jarmo ^{[8
]}

Weinstein, Stephanie ^{[1
]}

Ma, Jing ^{[7
]}

Gaziano, J. Michael ^{[9
]}

Stampfer, Meir ^{[7
]}

Schumacher, Fredrick R. ^{[5
,7
]}

Giovannucci, Edward ^{[10
]}

Cancel-Tassin, Geraldine ^{[11
]}

Cussenot, Olivier ^{[11
]}

Valeri, Antoine ^{[11
]}

Andriole, Gerald L. ^{[12
]}

Crawford, E. David ^{[13
]}

Anderson, Stephen K. ^{[2
]}

Tucker, Margaret ^{[1
]}

Hoover, Robert N. ^{[1
]}

Fraumeni, Joseph F., Jr. ^{[1
]}

Thomas, Gilles ^{[4
]}

Hunter, David J. ^{[5
]}

Dean, Michael ^{[2
]}

Chanock, Stephen J. ^{[1
]}

机构：

[1] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[2] NCI, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21702 USA

[3] NCI, Core Genotyping Facil, Adv Technol Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA

[4] Bioinformed Consulting Serv, Gaithersburg, MD 20877 USA

[5] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA

[6] Amer Canc Soc, Dept Epidemiol & Surveillance Res, Atlanta, GA 30303 USA

[7] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[8] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FIN-00300 Helsinki, Finland

[9] Harvard Univ, Sch Med, Channing Lab, Brigham & Womens Hosp, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Div Aging, Brigham & Womens Hosp, Boston, MA 02115 USA

[11] Hop Tenon, AP HP, Ctr Rech Pathol Prostat, F-75970 Paris, France

[12] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63108 USA

[13] Univ Colorado Denver & Hlth Sci Ctr, Dept Surg, Denver, CO 80204 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 19期

关键词：

genome-wide association studies; prostate cancer genetics; CREB transcription factor; GENOME-WIDE ASSOCIATION; RADICAL PROSTATECTOMY; RISK LOCUS; PROTEIN; EXPRESSION; 8Q24; POLYMORPHISMS; EPIDEMIOLOGY; SEQUENCE; DISEASE;

D O I：

10.1073/pnas.0902104106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 approximate to 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.

引用

页码：7933 / 7938

页数：6

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