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-phases, case-control study involving 682 cases and 733 controls. Obesity-driven biomarkers (GIP, C-peptide, Insulin, Resistin, Adipsin, PYY, PPY, IL-6, TNF-α, PAI1, MCP1, 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 GIP, C-peptide, IL6, 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 to individuals with low levels of the biomarkers, individuals with high level of GIP (OR=0.52, 95% 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 TCGA indicates 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.
Carcinogenesis. 2019 Apr 17 [Epub ahead of print]
Qinchuan Wang, Huakang Tu, Meiling Zhu, Dong Liang, Yuanqing Ye, David W Chang, Yin Long, Xifeng Wu
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., Department of Pharmaceutical Sciences, Texas Southern University, Houston, TX, USA.