Evidence map›Paper›PMID 30100185›Full record

ArticleCell2018

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 and 24 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 181 papers.

0numbers the graph read from it
0cells of the map it votes in
181citing papers in PubMed
8.7field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

181 citing papers in PubMed, 285 citations in OpenAlex.

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121 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

34 authors at 10 institutions in 3 countries.

Joo Sang LeeCancer 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.
Lital AdlerDepartment of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Hiren KarathiaCenter 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.
Narin CarmelDepartment of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Shiran RabinovichDepartment of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Noam AuslanderCancer 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.
Rom KeshetDepartment of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Noa StettnerDepartment of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel; Department of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Alon SilbermanDepartment of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Lilach AgemyDepartment of Plant and Environmental Science, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Daniel HelblingEnvision Genomics, Huntsville, AL 35806, USA.
Raya EilamDepartment of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Qin SunDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Alexander BrandisLife Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Sergey MalitskyLife Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Maxim ItkinLife Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Hila WeissDepartment of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Sivan PintoDepartment of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Shelly KalaoraDepartment of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Ronen LevyDepartment of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Eilon BarneaFaculty of Biology, Technion - Israel Institute of Technology, 3200003 Haifa, Israel.
Arie AdmonFaculty of Biology, Technion - Israel Institute of Technology, 3200003 Haifa, Israel.
David DimmockRady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
Noam Stern-GinossarDepartment of Molecular Genetics, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Avigdor ScherzDepartment of Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Sandesh C S NagamaniDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Miguel UndaDepartment of Urology, Basurto University Hospital, 48013 Bilbao, Spain; CIBERONC, Madrid, Spain.
David M WilsonLaboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA.
Ronit ElhasidSackler Faculty of Medicine, Department of Pediatric Hemato Oncology, Sourasky Medical Center, Tel Aviv University, 6997801 Tel Aviv, Israel.
Arkaitz CarracedoCIBERONC, 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.
Yardena SamuelsDepartment of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Sridhar HannenhalliCenter 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.
Eytan RuppinCancer 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.
Ayelet ErezDepartment of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel. Electronic address: eyruppin@gmail.com.
Weizmann Institute of Science · ILNational Institutes of Health · USBaylor College of Medicine · USTechnion – Israel Institute of Technology · ILUniversity of Maryland, College Park · USChildren’s Institute · USHospital de Basurto · ESIkerbasque · ESNational Institute on Aging · USTel Aviv University · IL

Funding

Discovery of genetic interactions in cancerZIABC011802 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI RUPPIN, EYTAN · 2018 to 2025
$19.6M
Base Excision DNA Repair in Disease Susceptibility and TreatmentZIAAG000750 · NIA · NATIONAL INSTITUTE ON AGING · PI BOHR, VILHELM A · 2009 to 2019
$5.4M
Area C: Genome-wide identification and targeting of resistance to cancer therapyR33CA225291 · NCI · UNIV OF MARYLAND, COLLEGE PARK · PI GUTKIND, JORGE SILVIO, RUPPIN, EYTAN · 2017 to 2017
$1.5M
European Research Council 336343Intramural NIH HHS Z99 AG999999Intramural NIH HHS ZIA AG000750NCI NIH HHS R33 CA225291
6 · The paper itself

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.

Indexed as

GenomicsMetabolomicsAmino Acid Transport Systems, BasicAnimalsAspartate CarbamoyltransferaseCarbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)Cell Line, TumorDihydroorotaseFemaleHumansMiceMice, Inbred C57BLMice, SCIDMitochondrial Membrane Transport ProteinsNeoplasmsOrnithine CarbamoyltransferaseAmino Acid Transport Systems, BasicAspartate CarbamoyltransferaseCAD trifunctional enzymeCarbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)DihydroorotaseMitochondrial Membrane Transport ProteinsMTOR protein, humanOrnithine CarbamoyltransferasepyrimidinePyrimidinesRNA, Small InterferingSirolimusSLC25A15 protein, humanTOR Serine-Threonine KinasesUreaCADcancer metabolismimmunotherapymutagenesispyrimidinesurea cycle

Identifiers

PMID30100185
PMCPMC6225773
OpenAlexW2887301398

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.