Institute of Biomedical Technology/BioMediTech and Prostate Cancer Research Center, University of Tampere and Fimlab Laboratories, Biokatu 8, FI-33014 Tampere, Finland.
Eur J Cancer. 2013 Oct;49(15):3335-43. doi: 10.1016/j.ejca.2013.06.006. Epub 2013 Jul 2.
Chromosomal region 11q13-14 associates with prostate cancer (PrCa). Previously, we identified a rare intronic mutation on EMSY (11q13.5) that increases the risk of aggressive PrCa and associates with familial PrCa. Here, we further study the genetic structure and variants of the PrCa susceptibility region 11q13.5.
This study included 2716 unselected hospital-based PrCa cases, 1318 cases of a screening trial and 908 controls of Finnish origin. We imputed single nucleotide polymorphisms (SNPs) and structural variants from the 1000 Genomes Project and validated the associations of the variants in two PrCa patient sets by genotyping. Genetic structure was studied with haplotype analysis.
Two independent regions at 11q13.5 were associated with PrCa risk. The most significant association was at EMSY (rs10899221, odds ratio (OR) 1.29-1.40, P=3.5 × 10(-4)-0.002) near the previously identified mutation. Correlated intronic SNPs rs10899221 and rs72944758 formed with other EMSY variants common and rare haplotypes that were associated with increased risk (P=4.0 × 10(-4)) and decreased risk (P=0.01) of PrCa, respectively. The other associated region was intergenic. Among the six validated variants, rs12277366 was significant in both patient sets (OR 1.15-1.17, P=0.01). Haplotypes associated with an increased risk (P=0.02) and a decreased risk (P=0.02) were identified. In addition, the intergenic region was strongly associated with PrCa death, with the most significant association at rs12277366 (OR=0.72, P=4.8 × 10(-5)).
These findings indicate that 11q13.5 contributes to PrCa predisposition with complex genetic structure and is associated with PrCa death.
染色体区域 11q13-14 与前列腺癌（PrCa）相关。此前，我们在 EMSY（11q13.5）上发现了一个罕见的内含子突变，该突变增加了侵袭性 PrCa 的风险，并与家族性 PrCa 相关。在这里，我们进一步研究了 11q13.5 前列腺癌易感性区域的遗传结构和变异。
这项研究包括 2716 例未经选择的基于医院的前列腺癌病例、1318 例筛查试验病例和 908 例芬兰裔对照。我们从 1000 基因组计划中推断单核苷酸多态性（SNP）和结构变异，并通过基因分型在两个前列腺癌患者组中验证变异的关联。遗传结构通过单倍型分析进行研究。
11q13.5 上有两个独立的区域与 PrCa 风险相关。最显著的关联位于 EMSY（rs10899221，优势比（OR）1.29-1.40，P=3.5×10(-4)-0.002）附近，该区域先前已发现突变。相关内含子 SNP rs10899221 和 rs72944758 与 EMSY 变体共同形成常见和罕见单倍型，与增加风险（P=4.0×10(-4)）和降低风险（P=0.01）相关。另一个相关区域是基因间的。在验证的六个变体中，rs12277366 在两个患者组中均具有统计学意义（OR 1.15-1.17，P=0.01）。确定了与增加风险（P=0.02）和降低风险（P=0.02）相关的单倍型。此外，基因间区域与前列腺癌死亡强烈相关，最显著的关联位于 rs12277366（OR=0.72，P=4.8×10(-5)）。
这些发现表明 11q13.5 通过复杂的遗传结构对 PrCa 易感性有贡献，并与 PrCa 死亡相关。
