Multiple loci identified in a genome-wide association study of prostate cancer

Abstract

We followed our initial genome-wide association study (GWAS) of 527,869 SNPs on 1,172 individuals with prostate cancer and 1,157 controls of European origin-nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial prospective study-by testing 26,958 SNPs in four independent studies (total of 3,941 cases and 3,964 controls). In the combined joint analysis, we confirmed three previously reported loci (two independent SNPs at 8q24 and one in HNF1B (formerly known as TCF2 on 17q); P < 10(-10)). In addition, loci on chromosomes 7, 10 (two loci) and 11 were highly significant (between P < 7.31 x 10(-13) and P < 2.14 x 10(-6)). Loci on chromosome 10 include MSMB, which encodes beta-microseminoprotein, a primary constituent of semen and a proposed prostate cancer biomarker, and CTBP2, a gene with antiapoptotic activity; the locus on chromosome 7 is at JAZF1, a transcriptional repressor that is fused by chromosome translocation to SUZ12 in endometrial cancer. Of the nine loci that showed highly suggestive associations (P < 2.5 x 10(-5)), four best fit a recessive model and included candidate susceptibility genes: CPNE3, IL16 and CDH13. Our findings point to multiple loci with moderate effects associated with susceptibility to prostate cancer that, taken together, in the future may predict high risk in select individuals.

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

“…Single nucleotide polymorphisms (SNPs) in several genetic loci like 8q24, 22q13 and 17q12 were reported to be linked to PCa susceptibility, early onset of the disease and tumor agressiveness (Al Olama, et al, 2014; Berndt, et al, 2015; Chang, et al, 2009; Cheng, et al, 2009; Eeles, et al, 2009; Eeles, et al, 2013; Gudmundsson, et al, 2009; Helfand, et al, 2015; Levin, et al, 2008; Salinas, et al, 2008; Schumacher, et al, 2011; Takata, et al, 2010; Thomas, et al, 2008; Witte, 2007). Although little is known about the functional aspect of risk SNPs, some studies showed cancer SNPs predominately present in multiple putative regulatory elements (2011; Sille, et al, 2012).…”

Growth inhibition properties of the putative prostate cancer biomarkers PSP94 and CRISP-3

“…9 The MSMB gene is (epi)genetically silenced in PCa. [10][11][12][13] Recently, genome-wide association studies identified a C/T single nucleotide polymorphism rs10993994 in the promoter region of the MSMB gene that correlated with a significantly increased risk of developing PCa. 10,11 The 'TT' genotype, comprising two risk alleles, was associated with a lower expression of the MSMB gene and a severely decreased binding of the transcription factor CREB (cyclic AMP response element-binding protein), which was explained by changes of the CREB-binding site.…”

“…[10][11][12][13] Recently, genome-wide association studies identified a C/T single nucleotide polymorphism rs10993994 in the promoter region of the MSMB gene that correlated with a significantly increased risk of developing PCa. 10,11 The 'TT' genotype, comprising two risk alleles, was associated with a lower expression of the MSMB gene and a severely decreased binding of the transcription factor CREB (cyclic AMP response element-binding protein), which was explained by changes of the CREB-binding site. 12 In addition, the expression of MSMB is downregulated in PCa by methylation of CpG islands as well as by Polycomb-regulated histone modifications, which are both known to silence genes by making them less accessible to transcription factors.…”

Genetics and genomics of prostate cancer

“…12,[19][20][21][22][23][24] Over 33 loci have been identified that qualify as being genome-wide significant and replicated in more than one study, or internally in multiple validation sets (Supplementary Table 2). The majority of these loci are in intergenic regions, many near known genes, and a few have known biological relevance to PCa.…”

“…26,27 One of the strongest SNP associations is to the rs10993994 SNP on chromosome 10, in front of the MSMB gene. 21,23,28,29 MSMB encodes beta-microseminoprotein, an immunoglobulin binding factor family protein produced by the epithelial cells of the prostate gland and secreted into the seminal plasma. The MSMB protein has inhibin-like activity and may play a role as an autocrine paracrine factor in uterine, breast and other female reproductive tissues.…”