title: Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, Merced, California.
authors.forename: Lauren
authors.initials: L
authors.lastname: Edwards
authors.affiliation: Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, Merced, California.
authors.forename: Rohit
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, Merced, California. filipp@ucmerced.edu.
authors.forename: Fabian Volker
authors.initials: FV
authors.lastname: Filipp
mesh_terms: D001665:Binding Sites; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000737:chemistry / Q000235:genetics*; D018450:Disease Progression; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D011743:Pyrimidines / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics*; D049490:Systems Biology
chemical_list: D011743:Pyrimidines; D042943:Dihydrouracil Dehydrogenase (NADP); C030986:pyrimidine