Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures.
Cell
; 174(6): 1559-1570.e22, 2018 09 06.
Article
en En
| MEDLINE
| ID: mdl-30100185
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Urea
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Genómica
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Metabolómica
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Neoplasias
Límite:
Animals
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Female
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Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article