Dysregulated Urea Cycle–Associated Signatures Are Tumor Biomarkers

It has been anecdotally shown that ablation of the critical urea cycle–associated enzymes results in increased pyrimidine synthesis and cancer cell dependency on urea cycle–derived nitrogen. To further elucidate the role of urea cycle dysregulation (UCD) in cancer, Lee, Adler, and colleagues analyzed The Cancer Genome Atlas (TCGA) for the expression of urea cycle enzymes and transporters. Urea cycle components in cancer exhibited a pattern of dysregulation in many tumor types compared to normal controls, and in vitro induction of UCD caused increased pyrimidine synthesis and proliferation. Further, UCD scores, which are based on the level of expression changes in urea cycle components driving pyrimidine synthesis, were elevated in tumors that were highly proliferative and associated with poor patient prognosis. Pyrimidines were increased in urine from patients with prostate cancer and mice with colon cancer compared to healthy controls, and purine (R)-to-pyrimidine (Y) metabolite ratios were increased in patient tumors with high UCD scores. In vitro, UCD-mediated increased R-to-Y nucleotide imbalance resulted in a significant tendency toward R -> Y mutations on the DNA sense strand termed “pyrimidine-rich transversion mutational bias” (PTMB). Analysis of TCGA data showed that PTMB is significantly associated with UCD and worse patient prognosis, and is distinct from other described mutational signatures. Beyond gene level mutations, PTMB was detected in their corresponding mRNA and protein sequences, suggesting that PTMB can have important functional implications. Patients with melanoma that harbored high UCD scores exhibited a strong response to immune checkpoint blockade (ICB) therapy, and induction of UCD in a syngeneic mouse model of colon cancer significantly enhanced response to ICB; additionally, PTMB scores were shown to be a stronger predictor of ICB response than tumor mutational burden. These results identify and characterize UCD-associated genomic and biochemical signatures in tumors and suggest that UCD alterations may be a future potential biomarker for cancer detection and ICB treatment stratification.

Lee JS, Adler L, Karathia H, Carmel N, Rabinovich S, Auslander N, et al. Urea cycle dysregulation generates clinically relevant genomic and biochemical signatures. Cell 2018 Aug 9 [Epub ahead of print].

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