Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility

摘要: 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 MSMB gene, which encodes β-microseminoprotein (prostatic secretory protein 94). In this study, fine-mapping analysis using HapMap SNPs was conducted across ≈65-kb region (chr10: 51168330–51234020) flanking rs10993994 with 13 tag in 6,118 cases and 6,105 controls European origin from Cancer Genetic Markers Susceptibility (CGEMS) project. remained strongly associated risk [P = 8.8 × 10−18; heterozygous odds ratio (OR) 1.20, 95% confidence interval (CI): 1.11–1.30; homozygous OR 1.64, CI: 1.47–1.86 for adjusted genotype test 2 df]. follow-up functional analyses, T variant significantly affected expression vitro luciferase reporter constructs. electrophoretic mobility shift assays, C allele preferentially binds to CREB transcription factor. Analysis tumor cell lines CC or CT revealed high level gene compared TT genotype. These findings were specific alleles not observed other determined by sequence proximal promoter. Together, our mapping study analyses implicate regulation as plausible mechanism accounting at locus. Further investigation warranted determine whether alone combination additional variants contributes susceptibility.