Glycosaminoglycan Profiling in Patients’ Plasma and Urine Predicts the Occurrence of Metastatic Clear Cell Renal Cell Carcinoma

• Coordinated regulation of glycosaminoglycan (GAG) biosynthesis is observed in ccRCC
• The plasma and urine GAG profile is strongly altered in metastatic ccRCC
• Three non-invasive GAG scores accurately predict the occurrence of metastatic ccRCC
• The GAG scores normalize in patients with no evidence of disease

SummaryMetabolic reprogramming is a hallmark of clear cell renal cell carcinoma (ccRCC) progression. Here, we used genome-scale metabolic modeling to elucidate metabolic reprogramming in 481 ccRCC samples and discovered strongly coordinated regulation of glycosaminoglycan (GAG) biosynthesis at the transcript and protein levels. Extracellular GAGs are implicated in metastasis, so we speculated that such regulation might translate into a non-invasive biomarker for metastatic ccRCC (mccRCC). We measured 18 GAG properties in 34 mccRCC samples versus 16 healthy plasma and/or urine samples. The GAG profiles were distinctively altered in mccRCC. We derived three GAG scores that distinguished mccRCC patients with 93.1%–100% accuracy. We validated the score accuracies in an independent cohort (up to 18 mccRCC versus nine healthy) and verified that the scores normalized in eight patients with no evidence of disease. In conclusion, coordinated regulation of GAG biosynthesis occurs in ccRCC, and non-invasive GAG profiling is suitable for mccRCC diagnosis.

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