Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures

Joo Sang Lee, Lital Adler, Hiren Karathia, Narin Carmel, Shiran Rabinovich, Noam Auslander, Rom Keshet, Noa Stettner, Alon Silberman, Lilach Agemy, Daniel Helbling, Raya Eilam, Qin Sun, Alexander Brandis, Sergey Malitsky, Maxim Itkin, Hila Weiss, Sivan Pinto, Shelly Kalaora, Ronen LevyEilon Barnea, Arie Admon, David Dimmock, Noam Stern-Ginossar, Avigdor Scherz, Sandesh C.S. Nagamani, Miguel Unda, David M. Wilson, Ronit Elhasid, Arkaitz Carracedo, Yardena Samuels, Sridhar Hannenhalli, Eytan Ruppin, Ayelet Erez

Research output: Contribution to journalArticlepeer-review


The urea cycle (UC) is the main pathway by which mammals dispose of waste nitrogen. We find that specific alterations in the expression of most UC enzymes occur in many tumors, leading to a general metabolic hallmark termed “UC dysregulation” (UCD). UCD elicits nitrogen diversion toward carbamoyl-phosphate synthetase2, aspartate transcarbamylase, and dihydrooratase (CAD) activation and enhances pyrimidine synthesis, resulting in detectable changes in nitrogen metabolites in both patient tumors and their bio-fluids. The accompanying excess of pyrimidine versus purine nucleotides results in a genomic signature consisting of transversion mutations at the DNA, RNA, and protein levels. This mutational bias is associated with increased numbers of hydrophobic tumor antigens and a better response to immune checkpoint inhibitors independent of mutational load. Taken together, our findings demonstrate that UCD is a common feature of tumors that profoundly affects carcinogenesis, mutagenesis, and immunotherapy response. Urea cycle dysregulation (UCD) in cancer is a prevalent phenomenon in multiple cancers. UCD increases nitrogen utilization for pyrimidine synthesis, generating nucleotide imbalance that leads to detectable mutation patterns and biochemical signatures in cancer patients’ samples. UCD is associated with a worse prognosis but a better response to immunotherapy.

Original languageEnglish
Pages (from-to)1559-1570.e22
Issue number6
StatePublished - 6 Sep 2018


  • CAD
  • cancer metabolism
  • immunotherapy
  • mutagenesis
  • pyrimidines
  • urea cycle

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology


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