The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study

Abstract

BackgroundSeveral obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.Methods and findingsGenetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.ConclusionsThis study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

Estimating the magnitude of cancer overdiagnosis in Australia

“…For breast, prostate, renal, and thyroid cancers, we estimated the expected impact of obesity by including estimates of changes in relative risk with increasing body mass index (BMI), based on Australian mean BMI data …”

“…For renal cancer, the relative risk has been reported to increase by 56% per standard deviation rise in BMI, but this finding may have been influenced by investigation rates. 25 Based on changes in mean BMI in Australia from 1989 to 2012, 27 this yields relative risks of 1.56 × 1.8/7.5 or 1.13 for women and 1.56 × 1.8/5.2 or 1.19 for men. Were these estimates used for the expected increase in lifetime probability, overdiagnosis rates would be modestly smaller than the 58% (women) and 42% (men) we report.…”

The Role of Metabolic Factors in Renal Cancers

“…However, in their study, high serum IGF-1 levels at the time of diagnosis correlated with favourable prognosis; therefore, it seems that serum IGF-1 level may be an independent prognostic factor of renal cell carcinoma. In contrast, Johansson et al [ 61 ] demonstrated significant association between the variables related to fasting insulin and RCC risk. In their Mendelian randomization study, one standard deviation (SD) increment in fasting insulin increased the risk of RCC by 82%.…”

“…Zhang et al [ 60 ] suggested that the stabilization of hypoxia-inducible factors and inhibition of insulin-like growth factor receptor 1 signalling resulting from von Hippel-Lindau syndrome is the essential mechanism in RCC biology. According to Johansson et al [ 61 ], insulin resistance may lead to compensatory hyperinsulinemia resulting from enhanced insulin secretion by pancreatic β-cells to maintain normal blood glucose. It has been hypothesized that hyperinsulinemia may augment cancer cell growth and proliferation through insulin action via its receptor and the activation of IGF pathway [ 62 ].…”

Estimating the magnitude of cancer overdiagnosis in Australia

“…For breast, 23 prostate, 24 renal, 25 and thyroid cancers, 26 we estimated the expected impact of obesity by including estimates of changes in relative risk with increasing body mass index (BMI), based on Australian mean BMI data. 27…”