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Mol Cancer Res. 2016 Feb;14(2):196-206. doi: 10.1158/1541-7786.MCR-15-0403. Epub 2015 Nov 25.

Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression.

Author information

1
Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, Merced, California.
2
Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, Merced, California. filipp@ucmerced.edu.

Abstract

New strategies are needed to diagnose and target human melanoma. To this end, genomic analyses was performed to assess somatic mutations and gene expression signatures using a large cohort of human skin cutaneous melanoma (SKCM) patients from The Cancer Genome Atlas (TCGA) project to identify critical differences between primary and metastatic tumors. Interestingly, pyrimidine metabolism is one of the major pathways to be significantly enriched and deregulated at the transcriptional level in melanoma progression. In addition, dihydropyrimidine dehydrogenase (DPYD) and other important pyrimidine-related genes: DPYS, AK9, CAD, CANT1, ENTPD1, NME6, NT5C1A, POLE, POLQ, POLR3B, PRIM2, REV3L, and UPP2 are significantly enriched in somatic mutations relative to the background mutation rate. Structural analysis of the DPYD protein dimer reveals a potential hotspot of recurring somatic mutations in the ligand-binding sites as well as the interfaces of protein domains that mediated electron transfer. Somatic mutations of DPYD are associated with upregulation of pyrimidine degradation, nucleotide synthesis, and nucleic acid processing while salvage and nucleotide conversion is downregulated in TCGA SKCM.

IMPLICATIONS:

At a systems biology level, somatic mutations of DPYD cause a switch in pyrimidine metabolism and promote gene expression of pyrimidine enzymes toward malignant progression.

PMID:
26609109
PMCID:
PMC5024535
DOI:
10.1158/1541-7786.MCR-15-0403
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare that there is no competing financial interest as part of the submission process of this manuscript. Competing financial interest The authors declare that there is no competing financial interest as part of the submission process of this manuscript. We are thankful to all members of the TCGA Research Network for biospecimen collection, data acquisition, and benchmark analyses. F.V.F. is grateful for the support of grant CA154887 from the National Institutes of Health, National Cancer Institute.

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