Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 8717 Grovemont Circle, Bethesda, MD 20892-4605, USA.
Cancer Epidemiol Biomarkers Prev. 2010 May;19(5):1349-55. doi: 10.1158/1055-9965.EPI-09-1181. Epub 2010 Apr 20.
Genome-wide association studies have identified multiple genetic variants associated with susceptibility to prostate cancer (PrCa). In the two-stage Cancer Genetic Markers of Susceptibility prostate cancer scan, a single-nucleotide polymorphism (SNP), rs10486567, located within intron 2 of JAZF1 gene on chromosome 7p15.2, showed a promising association with PrCa overall (P=2.14x10(-6)), with a suggestion of stronger association with aggressive disease (P=1.2x10(-7)).
In the third stage of genome-wide association studies, we genotyped 106 JAZF1 SNPs in 10,286 PrCa cases and 9,135 controls of European ancestry.
The strongest association was observed with the initial marker rs10486567, which now achieves genome-wide significance [P=7.79x10(-11); ORHET, 1.19 (95% confidence interval, 1.12-1.27); ORHOM, 1.37 (95% confidence interval, 1.20-1.56)]. We did not confirm a previous suggestion of a stronger association of rs10486567 with aggressive disease (P=1.60x10(-4) for aggressive cancer, n=4,597; P=3.25x10(-8) for nonaggressive cancer, n=4,514). Based on a multilocus model with adjustment for rs10486567, no additional independent signals were observed at chromosome 7p15.2. There was no association between PrCa risk and SNPs in JAZF1 previously associated with height (rs849140; P=0.587), body stature (rs849141, tagged by rs849136; P=0.171), and risk of type 2 diabetes and systemic lupus erythematosus (rs864745, tagged by rs849142; P=0.657).
rs10486567 remains the most significant marker for PrCa risk within JAZF1 in individuals of European ancestry.
Future studies should identify all variants in high linkage disequilibrium with rs10486567 and evaluate their functional significance for PrCa.
全基因组关联研究已经确定了多个与前列腺癌（PrCa）易感性相关的遗传变异。在两阶段癌症遗传易感性前列腺癌扫描中，位于 7p15.2 染色体 JAZF1 基因内含子 2 中的单核苷酸多态性（SNP）rs10486567 与整体前列腺癌呈显著相关（P=2.14x10(-6)），与侵袭性疾病的相关性更强（P=1.2x10(-7)）。
在全基因组关联研究的第三阶段，我们对 10286 例前列腺癌病例和 9135 例欧洲血统对照中的 106 个 JAZF1 SNP 进行了基因分型。
最初的标记物 rs10486567 观察到最强的相关性，现在达到了全基因组显著性水平[P=7.79x10(-11)；ORHET，1.19（95%置信区间，1.12-1.27）；ORHOM，1.37（95%置信区间，1.20-1.56）]。我们没有证实之前关于 rs10486567 与侵袭性疾病相关性更强的建议（P=1.60x10(-4)，侵袭性癌症，n=4597；P=3.25x10(-8)，非侵袭性癌症，n=4514）。基于调整 rs10486567 的多基因模型，在 7p15.2 染色体上没有观察到其他独立的信号。在欧洲血统人群中，JAZF1 中与身高（rs849140；P=0.587）、身高（rs849141，由 rs849136 标记；P=0.171）和 2 型糖尿病和系统性红斑狼疮风险相关的 SNP（rs864745，由 rs849142 标记；P=0.657）与前列腺癌风险之间没有关联。
在欧洲血统个体中，rs10486567 仍然是 JAZF1 中与前列腺癌风险最显著的标记物。
未来的研究应该确定与 rs10486567 高度连锁不平衡的所有变体，并评估它们对前列腺癌的功能意义。
