Fine mapping association study and functional analysis implicate a SNP in MSMB at 10q11 as a causal variant for prostate cancer risk.
A single nucleotide polymorphism (SNP) at 10q11 (rs10993994) in the 5' region of the MSMB gene was recently implicated in prostate cancer risk in two genome-wide association studies. To identify possible causal variants in the region, we genotyped 16 tagging SNPs and imputed 29 additional SNPs in approximately 65 kb genomic region at 10q11 in a Swedish population-based case-control study (CAncer of the Prostate in Sweden), including 2899 cases and 1722 controls. We found evidence for two independent loci, separated by a recombination hotspot, associated with prostate cancer risk. Among multiple significant SNPs at locus 1, the initial SNP rs10993994 was most significant. Importantly, using an MSMB promoter reporter assay, we showed that the risk allele of this SNP had only 13% of the promoter activity of the wild-type allele in a prostate cancer model, LNCaP cells. Curiously, the second, novel locus (locus 2) was within NCOA4 (also known as ARA70), which is known to enhance androgen receptor transcriptional activity in prostate cancer cells. However, its association was only weakly confirmed in one of the three additional study populations. The observations that rs10993994 is the strongest associated variant in the region and its risk allele has a major effect on the transcriptional activity of MSMB, a gene with previously described prostate cancer suppressor function, together suggest the T allele of rs10993994 as a potential causal variant at 10q11 that confers increased risk of prostate cancer.
Chang
Bao-Li
BL
Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Cramer
Scott D
SD
Wiklund
Fredrik
F
Isaacs
Sarah D
SD
Stevens
Victoria L
VL
Sun
Jielin
J
Smith
Shelly
S
Pruett
Kristen
K
Romero
Lina M
LM
Wiley
Kathleen E
KE
Kim
Seong-Tae
ST
Zhu
Yi
Y
Zhang
Zheng
Z
Hsu
Fang-Chi
FC
Turner
Aubrey R
AR
Adolfsson
Jan
J
Liu
Wennuan
W
Kim
Jin Woo
JW
Duggan
David
D
Carpten
John
J
Zheng
S Lilly
SL
Rodriguez
Carmen
C
Isaacs
William B
WB
Grönberg
Henrik
H
Xu
Jianfeng
J
D000728:Androgens / Q000494:pharmacology; D001483:Base Sequence; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics*; D029584:Prostatic Secretory Proteins / Q000235:genetics*; D013548:Sweden
D000728:Androgens; D029584:Prostatic Secretory Proteins; C043076:beta-microseminoprotein