Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital and Department of Epidemiology and Health Statistics School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Carcinogenesis. 2019 Oct 16;40(10):1191-1197. doi: 10.1093/carcin/bgz074.
Obesity is one of modifiable risk factors for clear cell renal cell cancer (ccRCC). We aim to identify the association between obesity-driven biomarkers and ccRCC risk. This is a retrospective, two-phase, case-control study involving 682 cases and 733 controls. Obesity-driven biomarkers [gastric inhibitory polypeptide (GIP), C-peptide, insulin, resistin, adipsin, peptide YY, pancreatic polypeptide, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor-1, monocyte chemoattractant protein 1, lipocalin2, leptin, adiponectin] were measured using the Milliplex method. Multivariate logistic regression was used to assess the associations between biomarkers and ccRCC risk. Results revealed that GIP, C-peptide, IL-6 and TNF-α levels were consistently distinct between cases and controls. These markers were significantly associated with ccRCC risk in both phases (except C-peptide). In the combined population, compared with individuals with low levels of the biomarkers, individuals with high level of GIP [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.40-0.67] had lower risk, whereas individuals with high levels of C-peptide (OR = 1.46, 95% CI: 1.15-1.87), IL-6 (OR = 2.20, 95% CI: 1.50-3.22), TNF-α (OR = 1.90, 95% CI: 1.49-2.43) had significantly higher risk. Stratified analysis showed consistent associations with ccRCC risk in most subgroups (P < 0.05). The risk score based on the IL-6, TNF-α and GIP was positively associated with ccRCC risk in a dose-response manner (P for trend = 2.18E-13). Data from The Cancer Genome Atlas indicate that insulin signaling, IL-6 signaling and TNF-α signaling were enhanced in tumors. Collectively, our study demonstrates the integrative effect of insulin resistance and inflammation in ccRCC development, which may elucidate the basis of association between obesity and carcinogenesis. Further confirmation in prospective cohort studies are warranted for clinical applications in prevention and precision medicine of ccRCC.
肥胖是透明细胞肾细胞癌 (ccRCC) 的可改变风险因素之一。我们旨在确定肥胖驱动的生物标志物与 ccRCC 风险之间的关联。这是一项回顾性、两阶段、病例对照研究，涉及 682 例病例和 733 例对照。使用 Milliplex 方法测量肥胖驱动的生物标志物[胃抑制多肽 (GIP)、C 肽、胰岛素、抵抗素、 adiposin、肽 YY、胰多肽、白细胞介素 6 (IL-6)、肿瘤坏死因子-α (TNF-α)、纤溶酶原激活物抑制剂-1、单核细胞趋化蛋白 1、脂联素 2、瘦素、脂联素]。多变量逻辑回归用于评估生物标志物与 ccRCC 风险之间的关联。结果表明，GIP、C 肽、IL-6 和 TNF-α 水平在病例和对照之间始终存在明显差异。这些标志物在两个阶段均与 ccRCC 风险显著相关（除 C 肽外）。在合并人群中，与低水平生物标志物的个体相比，高水平 GIP 的个体[比值比 (OR) = 0.52，95%置信区间 (CI)：0.40-0.67]风险较低，而高水平 C 肽的个体 (OR = 1.46，95% CI：1.15-1.87)、IL-6 (OR = 2.20，95% CI：1.50-3.22)、TNF-α (OR = 1.90，95% CI：1.49-2.43) 风险显著较高。分层分析显示，在大多数亚组中与 ccRCC 风险的关联一致（P < 0.05）。基于 IL-6、TNF-α 和 GIP 的风险评分与 ccRCC 风险呈剂量反应关系呈正相关（P 趋势=2.18E-13）。癌症基因组图谱的数据表明，胰岛素信号、IL-6 信号和 TNF-α 信号在肿瘤中增强。总之，我们的研究表明胰岛素抵抗和炎症在 ccRCC 发展中的综合作用，这可能阐明肥胖与致癌作用之间关联的基础。需要在前瞻性队列研究中进一步证实，以将其应用于 ccRCC 的预防和精准医学。
