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

Hong Lou, 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 GazianoMeir 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, Gilles Thomas, David J. Hunter, Michael Dean, Stephen J. Chanock

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)7933-7938
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number19
DOIs
StatePublished - May 12 2009
Externally publishedYes

Fingerprint

Single Nucleotide Polymorphism
Prostatic Neoplasms
Chromosomes
Genotype
Prostatic Secretory Proteins
Alleles
Odds Ratio
Confidence Intervals
HapMap Project
Genome-Wide Association Study
Electrophoretic Mobility Shift Assay
Genetic Predisposition to Disease
Tumor Cell Line
Luciferases
Genetic Markers
Sequence Analysis
Exons
Transcription Factors
Gene Expression
Cell Line

Keywords

  • CREB transcription factor
  • Genome-wide association studies
  • Prostate cancer genetics

ASJC Scopus subject areas

  • General

Cite this

Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility. / Lou, Hong; Yeager, Meredith; Li, Hongchuan; Bosquet, Jesus Gonzalez; Hayes, Richard B.; Orr, Nick; Yu, Kai; Hutchinson, Amy; Jacobs, Kevin B.; Kraft, Peter; Wacholder, Sholom; Chatterjee, Nilanjan; Feigelson, Heather Spencer; Thun, Michael J.; Diver, W. Ryan; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Ma, Jing; Gaziano, J. Michael; Stampfer, Meir; Schumacher, Fredrick R.; Giovannucci, Edward; Cancel-Tassin, Geraldine; Cussenot, Olivier; Valeri, Antoine; Andriole, Gerald L.; Crawford, E. David; Anderson, Stephen K.; Tucker, Margaret; Hoover, Robert N.; Fraumeni, Joseph F.; Thomas, Gilles; Hunter, David J.; Dean, Michael; Chanock, Stephen J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 19, 12.05.2009, p. 7933-7938.

Research output: Contribution to journalArticle

Lou, H, Yeager, M, Li, H, Bosquet, JG, Hayes, RB, Orr, N, Yu, K, Hutchinson, A, Jacobs, KB, Kraft, P, Wacholder, S, Chatterjee, N, Feigelson, HS, Thun, MJ, Diver, WR, Albanes, D, Virtamo, J, Weinstein, S, Ma, J, Gaziano, JM, Stampfer, M, Schumacher, FR, Giovannucci, E, Cancel-Tassin, G, Cussenot, O, Valeri, A, Andriole, GL, Crawford, ED, Anderson, SK, Tucker, M, Hoover, RN, Fraumeni, JF, Thomas, G, Hunter, DJ, Dean, M & Chanock, SJ 2009, 'Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 19, pp. 7933-7938. https://doi.org/10.1073/pnas.0902104106
Lou, Hong ; Yeager, Meredith ; Li, Hongchuan ; Bosquet, Jesus Gonzalez ; Hayes, Richard B. ; Orr, Nick ; Yu, Kai ; Hutchinson, Amy ; Jacobs, Kevin B. ; Kraft, Peter ; Wacholder, Sholom ; Chatterjee, Nilanjan ; Feigelson, Heather Spencer ; Thun, Michael J. ; Diver, W. Ryan ; Albanes, Demetrius ; Virtamo, Jarmo ; Weinstein, Stephanie ; Ma, Jing ; Gaziano, J. Michael ; Stampfer, Meir ; Schumacher, Fredrick R. ; Giovannucci, Edward ; Cancel-Tassin, Geraldine ; Cussenot, Olivier ; Valeri, Antoine ; Andriole, Gerald L. ; Crawford, E. David ; Anderson, Stephen K. ; Tucker, Margaret ; Hoover, Robert N. ; Fraumeni, Joseph F. ; Thomas, Gilles ; Hunter, David J. ; Dean, Michael ; Chanock, Stephen J. / Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 19. pp. 7933-7938.
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title = "Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility",
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 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.",
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author = "Hong Lou and Meredith Yeager and Hongchuan Li and Bosquet, {Jesus Gonzalez} and Hayes, {Richard B.} and Nick Orr and Kai Yu and Amy Hutchinson and Jacobs, {Kevin B.} and Peter Kraft and Sholom Wacholder and Nilanjan Chatterjee and Feigelson, {Heather Spencer} and Thun, {Michael J.} and Diver, {W. Ryan} and Demetrius Albanes and Jarmo Virtamo and Stephanie Weinstein and Jing Ma and Gaziano, {J. Michael} and Meir Stampfer and Schumacher, {Fredrick R.} and Edward Giovannucci and Geraldine Cancel-Tassin and Olivier Cussenot and Antoine Valeri and Andriole, {Gerald L.} and Crawford, {E. David} and Anderson, {Stephen K.} and Margaret Tucker and Hoover, {Robert N.} and Fraumeni, {Joseph F.} and Gilles Thomas and Hunter, {David J.} and Michael Dean and Chanock, {Stephen J.}",
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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

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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.

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KW - Genome-wide association studies

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