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Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures.

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.

SUBMITTER: Lee JS

PROVIDER: S-EPMC6225773 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures.

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

Cell 20180809 6

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 a ...[more]

PMID: 30100185

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Project description:BACKGROUND:Urea cycle disorders (UCDs) are inherited metabolic disorders that present with hyperammonemia, and cause significant mortality and morbidity in infants and children. These disorders are not well reported in the Indian population, due to lack of a thorough study of the clinical and molecular profile. RESULTS:We present data from two major metabolic centres in India, including 123 cases of various UCDs. The majority of them (72/123, 58%) presented in the neonatal period (before 30 days of age) with 88% on or before day 7 of life (classical presentation), and had a high mortality (64/72, 88%). Citrullinemia type 1 was the most common UCD, observed in 61/123 patients. Ornithine transcarbamylase (OTC) deficiency was the next most common, seen in 24 cases. Argininosuccinic aciduria was diagnosed in 20 cases. Deficiencies of arginase, N-acetylglutamate synthase, carbamoyl phosphate synthetase, citrin, and lysinuric protein intolerance were also observed. Molecular genetic analysis revealed two common ASS1 mutations: c.470G?>?A (p.Arg157His) and c.1168G?>?A (p.Gly390Arg) (36 of 55 tested patients). In addition, few recurrent point mutations in ASL gene, and a deletion of the whole OTC gene were also noted. A total of 24 novel mutations were observed in the various genes studied. We observed a poor clinical outcome with an overall all time mortality of 63% (70/110 cases with a known follow-up), and disability in 70% (28/40) among the survivors. Prenatal diagnosis was performed in 30 pregnancies in 25 families, including one pre-implantation genetic diagnosis. CONCLUSIONS:We report the occurrence of UCDs in India and the spectrum that may be different from the rest of the world. Citrullinemia type 1 was the most common UCD observed in the cohort. Increasing awareness amongst clinicians will improve outcomes through early diagnosis and timely treatment. Genetic diagnosis in the proband will enable prenatal/pre-implantation diagnosis in subsequent pregnancies.

Dataset Information

Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures.

Publications

Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures.

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