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Cell. 2018 Sep 6;174(6):1559-1570.e22. doi: 10.1016/j.cell.2018.07.019. Epub 2018 Aug 9.

Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures.

Author information

1
Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA.
2
Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel.
3
Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA.
4
Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel; Department of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel.
5
Department of Plant and Environmental Science, Weizmann Institute of Science, 7610001 Rehovot, Israel.
6
Envision Genomics, Huntsville, AL 35806, USA.
7
Department of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
9
Life Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel.
10
Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel.
11
Faculty of Biology, Technion - Israel Institute of Technology, 3200003 Haifa, Israel.
12
Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
13
Department of Molecular Genetics, Weizmann Institute of Science, 7610001 Rehovot, Israel.
14
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
15
Department of Urology, Basurto University Hospital, 48013 Bilbao, Spain; CIBERONC, Madrid, Spain.
16
Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA.
17
Sackler Faculty of Medicine, Department of Pediatric Hemato Oncology, Sourasky Medical Center, Tel Aviv University, 6997801 Tel Aviv, Israel.
18
CIBERONC, Madrid, Spain; CIC bioGUNE, Bizkaia Technology Park, 801 Building, 48160 Derio, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain; Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Bilbao, Spain.
19
Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA; Schools of Medicine and Computer Science, Tel Aviv University, 6997801 Tel Aviv, Israel. Electronic address: ayelet.erez@weizmann.ac.il.
20
Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel. Electronic address: eyruppin@gmail.com.

Abstract

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.

KEYWORDS:

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

PMID:
30100185
PMCID:
PMC6225773
DOI:
10.1016/j.cell.2018.07.019
[Indexed for MEDLINE]
Free PMC Article

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