title: Fine mapping association study and functional analysis implicate a SNP in MSMB at 10q11 as a causal variant for prostate cancer risk.
abstract: 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.
authors.affiliation: Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Bao-Li
authors.initials: BL
authors.lastname: Chang
authors.forename: Scott D
authors.initials: SD
authors.lastname: Cramer
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wiklund
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Isaacs
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Stevens
authors.forename: Jielin
authors.initials: J
authors.lastname: Sun
authors.forename: Shelly
authors.initials: S
authors.lastname: Smith
authors.forename: Kristen
authors.initials: K
authors.lastname: Pruett
authors.forename: Lina M
authors.initials: LM
authors.lastname: Romero
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Wiley
authors.forename: Seong-Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Fang-Chi
authors.initials: FC
authors.lastname: Hsu
authors.forename: Aubrey R
authors.initials: AR
authors.lastname: Turner
authors.forename: Jan
authors.initials: J
authors.lastname: Adolfsson
authors.forename: Wennuan
authors.initials: W
authors.lastname: Liu
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.forename: John
authors.initials: J
authors.lastname: Carpten
authors.forename: S Lilly
authors.initials: SL
authors.lastname: Zheng
authors.forename: Carmen
authors.initials: C
authors.lastname: Rodriguez
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.forename: Henrik
authors.initials: H
authors.lastname: Grönberg
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
mesh_terms: 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
chemical_list: D000728:Androgens; D029584:Prostatic Secretory Proteins; C043076:beta-microseminoprotein