Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci.
Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci.
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DOI：
10.1158/1055-9965.epi-14-0317
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发表时间：
2015-07
期刊：
影响因子：
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通讯作者：
PRACTICAL Consortium
中科院分区：
文献类型：
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作者：
Amin Al Olama A;Benlloch S;Antoniou AC;Giles GG;Severi G;Neal DE;Hamdy FC;Donovan JL;Muir K;Schleutker J;Henderson BE;Haiman CA;Schumacher FR;Pashayan N;Pharoah PD;Ostrander EA;Stanford JL;Batra J;Clements JA;Chambers SK;Weischer M;Nordestgaard BG;Ingles SA;Sorensen KD;Orntoft TF;Park JY;Cybulski C;Maier C;Doerk T;Dickinson JL;Cannon-Albright L;Brenner H;Rebbeck TR;Zeigler-Johnson C;Habuchi T;Thibodeau SN;Cooney KA;Chappuis PO;Hutter P;Kaneva RP;Foulkes WD;Zeegers MP;Lu YJ;Zhang HW;Stephenson R;Cox A;Southey MC;Spurdle AB;FitzGerald L;Leongamornlert D;Saunders E;Tymrakiewicz M;Guy M;Dadaev T;Little SJ;Govindasami K;Sawyer E;Wilkinson R;Herkommer K;Hopper JL;Lophatonanon A;Rinckleb AE;Kote-Jarai Z;Eeles RA;Easton DF;UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology;UK ProtecT Study Collaborators;PRACTICAL Consortium
全基因组关联研究已经确定了与前列腺癌（PrCa）风险相关的多种遗传变异，这些变异解释了相当大比例的家族相对风险。这些变体可用于根据PrCa风险对个体进行分层。我们对40，414名个体的25个PrCa易感基因位点进行了基因分型，并得出了多基因风险评分（PRS）。我们估计了与PRS定义的不同风险分层相关的PrCa经验比值比，并通过PRS分层和家族史推导出发生PrCa的年龄特异性绝对风险。PRS分布最高1%男性的PrCa风险是最低1%男性的30.6倍（95% CI 16.4-57.3），是中位风险的4.2倍（95% CI 3.2-5.5）。对于PRS分布中前1%有家族史的男性，到85岁时PrCa的绝对风险为65.8%，而最低1%的男性为3.7%。PRS与血清PSA水平呈弱相关（相关系数=0.09）。风险分析可以识别出PrCa风险大幅增加或降低的男性。以每单位PRS的OR测量的效应量在年轻男性和有PrCa家族史的男性中较高。将额外的新发现的基因位点纳入PRS应能提高风险特征的预测价值。我们证明，基于SNPs的风险分析可以识别出风险大幅增加或降低的男性，这可能对有针对性的预防和筛查计划产生有益的影响。
Genome-wide association studies have identified multiple genetic variants associated with prostate cancer (PrCa) risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of PrCa. We genotyped 25 PrCa susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical Odds Ratios for PrCa associated with different risk strata defined by PRS and derived age-specific absolute risks of developing PrCa by PRS stratum and family history. The PrCa risk for men in the top 1% of the PRS distribution was 30.6 (95% CI 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI 3.2–5.5) fold compared with the median risk. The absolute risk of PrCa by age 85 was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation=0.09). Risk profiling can identify men at substantially increased or reduced risk of PrCa. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of PrCa. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.