Two Independent Prostate Cancer Risk–Associated Loci at 11q13

Abstract

Single nucleotide polymorphisms (SNP) at 11q13 were recently implicated in prostate cancer risk by two genome-wide association studies and were consistently replicated in multiple study populations. To explore prostate cancer association in the regions flanking these SNPs, we genotyped 31 tagging SNPs in a f110 kb region at 11q13 in a Swedish case-control study (Cancer of the Prostate in Sweden), including 2,899 cases and 1,722 controls. We found evidence of prostate cancer association for the previously implicated SNPs including rs10896449, which we termed locus 1. In addition, multiple SNPs on the centromeric side of the region, including rs12418451, were also significantly associated with prostate cancer risk (termed locus 2). The two groups of SNPs were separated by a recombination hotspot. We then evaluated these two representative SNPs in an additional f4,000 cases and f3,000 controls from three study populations and confirmed both loci at 11q13. In the combined allelic test of all four populations, P = 4.0 Â 10 À11 for rs10896449 at locus 1 and P = 1.2 Â 10 À6 for rs12418451 at locus 2, and both remained significant after adjusting for the other locus and study population. The prostate cancer association at these two 11q13 loci was unlikely confounded by prostate-specific antigen (PSA) detection bias because neither SNP was associated with PSA levels in controls. Unlike locus 1, in which no known gene is located, several putative mRNAs are in close proximity to locus 2. Additional confirmation studies at locus 2 and functional studies for both loci are needed to advance our knowledge on the etiology of prostate cancer. (Cancer Epidemiol

Inherited genetic variant predisposes to aggressive but not indolent prostate cancer

“…Our finding differs from the two dozen PCa risk-associated SNPs discovered to date from GWAS (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Although the associations for some SNPs, such as those at 8q24, were stronger among patients with aggressive PCa in some studies when each type of case is compared versus unaffected controls (35,36), these SNPs were not associated with PCa aggressiveness in any of the studies when patients with more or less aggressive PCa were directly compared.…”

“…Recent breakthroughs in genome-wide association studies (GWAS) have led to the discovery of more than two dozen reported SNPs that are associated with PCa risk by comparing men with or without PCa using case-control study designs (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Unfortunately, none of these PCa risk-associated SNPs consistently distinguish risk for more or less aggressive cancer (26)(27)(28), nor are they associated with prostate cancer-specific mortality (29).…”

A Systematic Review of Replication Studies of Prostate Cancer Susceptibility Genetic Variants in High-Risk Men Originally Identified from Genome-Wide Association Studies

“…Both rs7931342 and rs10896449 at 11q13 are located in a gene-poor region. rs10896449 has been found to be significantly associated with prostate cancer risk in a GWAS and confirmed in a study of 4 primarily Caucasian populations (12,48). rs10993994 is located near MSMB (beta-microseminoprotein), which encodes a product (PSP94) that at lower levels is associated with more aggressive prostate cancer (49).…”

Current status of genome-wide association studies in cancer

“…Hence, some have advocated regional resequencing to augment the public databases (Parikh et al 2010;Yeager et al 2008Yeager et al , 2009b for pursuit of common variants. In some cases, upon closer inspection, more than one common variant, each with small effect sizes, contributes to the specific cancer susceptibility as has been demonstrated for 8q24, 11q13 and the HNF1B locus on chromosome 17 (Amundadottir et al 2006;Eeles et al 2009;Gudmundsson et al 2007;Haiman et al 2007;Yeager et al 2007Yeager et al , 2009aChung et al 2011;Zheng et al 2009a;Sun et al 2008). It is still too early in the post-GWAS era to assess whether many of the GWAS signals will be explained by common variants or perhaps, by less common or rare variants residing on the background of common haplotypes, as suggested by some but questioned by others (Dickson et al 2010;Wray et al 2011).…”

“…3). Initially, one locus was reported for prostate cancer, but in two fine mapping studies, as many as three independent loci have been established, two separated from the centromeric loci by a recombination hot spot (Chung et al 2011;Zheng et al 2009a). The prostate signals map to an intergenic region flanked by TPCN2 at its centromeric end and by MYEOV at its telomeric end; the former encodes two-pore segment channel 2, which was recently found to contain two coding SNPs, associated with blond versus brown hair color , whereas MYEOV is frequently over-expressed in multiple myeloma, breast cancer and oral and esophageal squamous cell carcinomas (Janssen et al 2000(Janssen et al , 2002.…”