Renal cell carcinoma (RCC) contributes significantly to the global cancer burden, annually accounting for over 140,000 deaths worldwide. Several lifestyle risk factors have been strongly implicated in RCC aetiology, most notably obesity and hypertension, as well as other factors associated with the metabolic syndrome (MetS). While these factors appear to be implicated in RCC aetiology from an epidemiological point of view, the underlying causal pathways remain to be elucidated. Our aim was to identify metabolites associated with RCC risk in pre-diagnostic blood samples.

A targeted metabolomic platform based on liquid chromatography tandem mass spectrometry (LC-MS; AbsoluteIDQ™ p180 kit from BIOCRATES), was used to quantify 145 metabolites in pre-diagnostic blood samples from 634 RCC case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC), and 140 case-control pairs from the Melbourne Collaborative Cohort study (MCCS). After excluding metabolites with more than 20% samples below the limit of detection or quantification, 127 metabolites were analysed in relation to RCC risk using conditional logistic regression. Metabolites associated with the risk of RCC in EPIC, after correction for multiple testing, were evaluated in MCCS. Further adjustment for body mass index (BMI), waist-to-hip ratio, alcohol and smoking was performed.

After multiple testing correction (P-value<9.62×10⁻⁴), five metabolites were inversely associated with RCC risk in EPIC: 2 lysophosphatidylcholines (lysoPC), 2 phosphatidylcholines (PC), and the ratio of total lysoPC over total PC (an indicator of phospholipase activity). One amino-acid was positively associated with the risk of RCC. In MCCS, one of the PC replicated. Upon adjustment for BMI, waist-to-hip ratio, alcohol and smoking, the association of metabolites with risk of RCC in EPIC were attenuated for three of the six metabolites.

Our study is the first to evaluate the association between metabolites measured in pre-diagnostic blood samples and risk of RCC. The results highlight glycerophospholipids as a group of metabolites that may be important in RCC aetiology, but their causal relevance remains to be confirmed.