Isovalerylglycine and α-Ketobutyrate are novel biomarkers that discriminate clear cell renal cell carcinoma in biopsy specimens using two-dimensional magnetic resonance spectroscopy

Tumor heterogeneity and lack of pre-operative diagnostic biomarkers are key topics in the field of renal cell carcinoma (RCC) identification. Clear cell RCC (ccRCC) is an aggressive cancer subtype which accounts for most RCC related deaths. The capacity to monitor changes at a molecular or biochemical level using two-dimensional (2D) correlated magnetic resonance spectroscopy of human kidney cancer biopsies, offers an insight into how ccRCC differs from other kidney cancer subtypes (termed here, non-ccRCC). Using this technology, two new spectral assignments, isovalerylglycine and α-ketobutyrate, were elevated in the potentially aggressive ccRCC cancer subtype. The crosspeak at F2: 0.95 ppm, F1: 2.05 ppm was assigned to isovalerylglycine and the diagonal resonance at 2.77 ppm to α-ketobutyrate. Isovalerylglycine, an amino acid leucine catabolite, was 55% higher (p = 0.004) and α-ketobutyrate 108% higher (p < 0.001) in ccRCC compared with non-ccRCC tissue biopsies. They were also elevated compared with non-cancer kidney. The increase in α-ketobutyrate in ccRCC compared with non-ccRCC also provides further insight into the role of homocysteine metabolism in kidney cancer. These biomarkers provide metabolic insight that could have future diagnostic or clinical value. They may help develop a spectral signature that, preoperatively, improves distinction between life-threatening ccRCC, non-ccRCC and non-cancer kidney.