循环胰岛素样生长因子与总体、侵袭性和早发性前列腺癌风险的关系：20 项前瞻性研究的协作分析和孟德尔随机化分析。
Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: a collaborative analysis of 20 prospective studies and Mendelian randomization analysis.
机构信息
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
出版信息
Int J Epidemiol. 2023 Feb 8;52(1):71-86. doi: 10.1093/ije/dyac124.
BACKGROUND
Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer.
METHODS
Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium.
RESULTS
In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I.
CONCLUSIONS
These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.
背景
先前的研究在评估循环胰岛素样生长因子（IGFs）和 IGF 结合蛋白（IGFBPs）与临床相关前列腺癌作为主要终点方面的作用时，效力有限，并且遗传预测的 IGF-I 与侵袭性前列腺癌的关系尚不清楚。我们旨在研究 IGF-I、IGF-II、IGFBP-1、IGFBP-2 和 IGFBP-3 浓度与总体、侵袭性和早期发病前列腺癌的关系。
方法
使用内源性激素、营养生物标志物和前列腺癌协作组数据集（多达 20 项研究，17009 例前列腺癌病例，包括 2332 例侵袭性病例）进行生物标志物的前瞻性分析。使用条件逻辑回归估计前列腺癌的比值比（OR）和 95%置信区间（CI）。对于 IGF-I，使用通过英国生物库（158444 名男性）确定的工具和 PRACTICAL 中的结果数据（多达 85554 例病例，包括 15167 例侵袭性病例）进行两样本孟德尔随机分析（MR）。此外，我们使用共定位排除连锁不平衡引起的混杂。
结果
在观察性分析中，IGF-I 与总体（每增加 1 个 SD 的 OR=1.09：95%CI 1.07，1.11）、侵袭性（1.09：1.03，1.16）和可能的早发性疾病（1.11：1.00，1.24）风险呈正相关；MR 分析中的相关性相似（每增加 1 个 SD 的 OR=1.07：1.00，1.15；1.10：1.01，1.20；1.13：0.98，1.30）。共定位也表明 IGF-I 和前列腺癌之间存在共同信号（PP4：99%）。IGF-II（1.06：1.02，1.11）和 IGFBP-3（1.08：1.04，1.11）较高的男性总体前列腺癌风险较高，而 IGFBP-1 较高与较低的风险相关（0.95：0.91，0.99）；这些关联在调整 IGF-I 后减弱。
结论
这些发现支持 IGF-I 在前列腺癌发展中的作用，包括侵袭性疾病。
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