Refining the prostate cancer genetic association within the JAZF1 gene on chromosome 7p15.2.
Prokunina-Olsson L., Fu YP., Tang W., Jacobs KB., Hayes RB., Kraft P., Berndt SI., Wacholder S., Yu K., Hutchinson A., Spencer Feigelson H., Thun MJ., Diver WR., Albanes D., Virtamo J., Weinstein S., Schumacher FR., Cancel-Tassin G., Cussenot O., Valeri A., Andriole GL., Crawford ED., Haiman CA., Henderson BE., Kolonel L., Le Marchand L., Siddiq A., Riboli E., Travis R., Kaaks R., Isaacs WB., Isaacs SD., Grönberg H., Wiklund F., Xu J., Vatten LJ., Hveem K., Kumle M., Tucker M., Hoover RN., Fraumeni JF., Hunter DJ., Thomas G., Chatterjee N., Chanock SJ., Yeager M.
BACKGROUND: 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)). METHODS: 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. RESULTS: 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). CONCLUSION: rs10486567 remains the most significant marker for PrCa risk within JAZF1 in individuals of European ancestry. IMPACT: Future studies should identify all variants in high linkage disequilibrium with rs10486567 and evaluate their functional significance for PrCa.