Department of Clinical Laboratory, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Carcinogenesis. 2021 Jun 21;42(6):826-830. doi: 10.1093/carcin/bgab031.
Insulin and insulin-like growth factors play important roles in carcinogenesis. Circulating insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) have been linked to cancer susceptibility. The associations of circulating IGF-1 and IGFBP-3 with the risk of renal cell carcinoma (RCC) are inconsistent. Recent large genome-wide association studies have identified 413 single nucleotide polymorphisms (SNPs) associated with IGF-1 and 4 SNPs associated with IGFBP-3. In this large case-control study consisting of 2069 RCC patients and 2052 healthy controls of European ancestry, we used a two-sample Mendelian randomization (MR) approach to investigate the associations of genetically predicted circulating IGF-1 and IGFBP-3 with RCC risk. We used an individual level data-based genetic risk score (GRS) and a summary statistics-based inverse-variance weighting (IVW) method in MR analyses. We found that genetically predicted IGF-1 was significantly associated with RCC risk in both the GRS analysis [odds ratio (OR) = 0.43 per SD increase, 95% confidence interval (CI), 0.34-0.53] and the IVW analysis (OR = 0.46 per SD increase, 95% CI, 0.37-0.57). Dichotomized at the median GRS value of IGF-1 in controls, individuals with high GRS had a 45% reduced RCC risk (OR = 0.55, 95% CI, 0.48-0.62) compared with those with low GRS. Genetically predicted circulating IGFBP-3 was not associated with RCC risk. This is the largest RCC study of circulating IGF-1 and IGFBP-3 to date and our data suggest a strong inverse relationship between circulating IGF-1 level and RCC risk.
胰岛素和胰岛素样生长因子在癌症发生中起着重要作用。循环胰岛素样生长因子-1（IGF-1）和胰岛素样生长因子结合蛋白-3（IGFBP-3）与癌症易感性有关。循环 IGF-1 和 IGFBP-3 与肾细胞癌（RCC）风险的关联不一致。最近的大型全基因组关联研究已经确定了 413 个与 IGF-1 相关的单核苷酸多态性（SNP）和 4 个与 IGFBP-3 相关的 SNP。在这项由 2069 名 RCC 患者和 2052 名欧洲血统健康对照组成的大型病例对照研究中，我们使用两样本孟德尔随机化（MR）方法来研究遗传预测的循环 IGF-1 和 IGFBP-3 与 RCC 风险的关联。我们在 MR 分析中使用了个体水平数据遗传风险评分（GRS）和基于汇总统计信息的逆方差加权（IVW）方法。我们发现，遗传预测的 IGF-1 与 RCC 风险显著相关，无论是在 GRS 分析中（每增加一个标准差的比值比[OR]为 0.43，95%置信区间[CI]为 0.34-0.53）还是在 IVW 分析中（每增加一个标准差的 OR 为 0.46，95%CI 为 0.37-0.57）。以对照中 IGF-1 的中位数 GRS 值为界对其进行二分，与低 GRS 个体相比，高 GRS 个体的 RCC 风险降低了 45%（OR = 0.55，95%CI，0.48-0.62）。遗传预测的循环 IGFBP-3 与 RCC 风险无关。这是迄今为止关于循环 IGF-1 和 IGFBP-3 的最大 RCC 研究，我们的数据表明循环 IGF-1 水平与 RCC 风险之间存在很强的反比关系。
