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 beta-microseminoprotein (prostatic secretory protein 94). In this study, a fine-mapping analysis using HapMap SNPs was conducted across a approximately 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.
Lou
Hong
H
Laboratory of Experimental Immunology, Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.
Yeager
Meredith
M
Li
Hongchuan
H
Bosquet
Jesus Gonzalez
JG
Hayes
Richard B
RB
Orr
Nick
N
Yu
Kai
K
Hutchinson
Amy
A
Jacobs
Kevin B
KB
Kraft
Peter
P
Wacholder
Sholom
S
Chatterjee
Nilanjan
N
Feigelson
Heather Spencer
HS
Thun
Michael J
MJ
Diver
W Ryan
WR
Albanes
Demetrius
D
Virtamo
Jarmo
J
Weinstein
Stephanie
S
Ma
Jing
J
Gaziano
J Michael
JM
Stampfer
Meir
M
Schumacher
Fredrick R
FR
Giovannucci
Edward
E
Cancel-Tassin
Geraldine
G
Cussenot
Olivier
O
Valeri
Antoine
A
Andriole
Gerald L
GL
Crawford
E David
ED
Anderson
Stephen K
SK
Tucker
Margaret
M
Hoover
Robert N
RN
Fraumeni
Joseph F
JF
Thomas
Gilles
G
Hunter
David J
DJ
Dean
Michael
M
Chanock
Stephen J
SJ
D000483:Alleles; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D016678:Genome; D006579:Heterozygote; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D029584:Prostatic Secretory Proteins / Q000235:genetics* / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D029584:Prostatic Secretory Proteins; C043076:beta-microseminoprotein