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Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression Lauren Edwards, Rohit Gupta, and Fabian Volker Filipp

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Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression Lauren Edwards, Rohit Gupta, and Fabian Volker Filipp Published OnlineFirst November 25, 2015; DOI: 10.1158/1541-7786.MCR-15-0403 Genomics Molecular Cancer Research Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression Lauren Edwards, Rohit Gupta, and Fabian Volker Filipp Abstract New strategies are needed to diagnose and target human the background mutation rate. Structural analysis of the DPYD melanoma. To this end, genomic analyses was performed to protein dimer reveals a potential hotspot of recurring somatic assess somatic mutations and gene expression signatures using mutations in the ligand-binding sites as well as the interfaces of a large cohort of human skin cutaneous melanoma (SKCM) protein domains that mediated electron transfer. Somatic muta- patients from The Cancer Genome Atlas (TCGA) project to tions of DPYD are associated with upregulation of pyrimidine identify critical differences between primary and metastatic degradation, nucleotide synthesis, and nucleic acid processing tumors. Interestingly, pyrimidine metabolism is one of the major while salvage and nucleotide conversion is downregulated in pathways to be significantly enriched and deregulated at the TCGA SKCM. transcriptional level in melanoma progression. In addition, dihy- dropyrimidine dehydrogenase (DPYD) and other important Implications: At a systems biology level, somatic mutations of pyrimidine-related genes: DPYS, AK9, CAD, CANT1, ENTPD1, DPYD cause a switch in pyrimidine metabolism and promote NME6, NT5C1A, POLE, POLQ, POLR3B, PRIM2, REV3L, and gene expression of pyrimidine enzymes toward malignant pro- UPP2 are significantly enriched in somatic mutations relative to gression. Mol Cancer Res; 14(2); 196–206. Ó2015 AACR. Introduction Pyrimidine synthesis is a key metabolic bottleneck important for DNA replication in tumor cells and, therefore, represents a Cancer cells take advantage of distinct metabolic pathways valuable diagnostic and therapeutic target. Early success in cancer promoting cellular proliferation or oncogenic progression. metabolism took advantage of this characteristic by making Emerging evidence highlights central metabolic pathways includ- cancer cells vulnerable to inhibition of this pathway. Heidelberger ing glucose- and glutamine-dependent biomass production to and colleagues designed fluorinated uracil-based pyrimidine support tumor growth (1). However, complex metabolic require- analogues, which disrupted tumor DNA biosynthesis and which ments of dividing, migrating, or nutrient and oxygen limited are to this day used to treat colorectal and breast cancer (4, 5). cancer cells suggest that tumor cells have much more complex To analyze TCGA SKCM dataset, we have employed a bottom- metabolic requirements than previously appreciated (2). The up strategy involving pathway enrichment analysis of RNASeq Cancer Genome Atlas (TCGA) puts an even-handed view on data and structural analysis of somatic mutations. The approach tissue-specific genomic determinants, revolutionizing our per- identifies DPYD (dihydropyrimidine dehydrogenase, Gene ID: spective on malignancies by next-generation sequencing (3). Here 1806) as a pivotal factor of pyrimidine metabolism and offers a we describe cross-talk between signatures of somatic mutations comprehensive view on how a hypermutated metabolic gene and gene expression of skin cutaneous melanoma (SKCM) based deregulates pyrimidine and nucleic acid synthesis and promotes on RNASeq data from 471 TCGA melanoma samples. By con- malignant progression of melanoma. necting pattern of somatic mutations with responses of gene expression at a pathway level, new features of melanoma metab- olism and progression are elucidated. Methods Patient cohort The TCGA SKCM cohort includes RNASeq data for 471 samples allowing us to extract statistical significant pattern of differential Systems Biology and Cancer Metabolism, Program for Quantitative expression between solid primary tumors (TP; 103 patients) and Systems Biology, University of California Merced, Merced, California. metastatic tumors (TM; 367 patients), while there is only one Note: Supplementary data for this article are available at Molecular Cancer dataset for blood-derived normal tissue (NB; 1 patient; Supple- Research Online (http://mcr.aacrjournals.org/). mentary Table S1). In addition, we utilized files from whole- Corresponding Author: Fabian Volker Filipp, Systems Biology and Cancer exome datasets of 339 patients (61 TP; 278 TM) (Supplementary Metabolism, Program for Quantitative Systems Biology, University of California Table S2; ref. 6). Clinical data including a history of drug treat- þ Merced, 5200 North Lake Road, Merced, CA 95343. Phone: 1-858-349-0349; ment was available for 447 patients (Supplementary Table S3). E-mail: fi[email protected] The study was carried out as part of Institutional review board doi: 10.1158/1541-7786.MCR-15-0403 approved study dbGap ID 5094 "Somatic mutations in melano- Ó2015 American Association for Cancer Research. ma" and conducted in accordance with the Helsinki Declaration 196 Mol Cancer Res; 14(2) February 2016 Downloaded from mcr.aacrjournals.org on September 23, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst November 25, 2015; DOI: 10.1158/1541-7786.MCR-15-0403 DPYD Is a Driver and Switch of Pyrimidine Metabolism in Human Cancer of 1975. The results shown are based upon next-generation olism of cytochrome P450 (ID:00980), tyrosine metabolism sequencing data generated by the TCGA Research Network (ID:00350), as well as glutathione metabolism (ID:00480) to be http://cancergenome.nih.gov. Restricted access clinical, RNASeq, significantly enriched pathways with deregulated gene expression and whole-exome sequences were obtained from the TCGA with P values lower than 0.001. Interestingly, metabolic pathways genome data access center and the data portal. show comparably high enrichment as pathways known to be closely associated with an invasive, metastatic phenotype. Next to Identification of somatic mutations pyrimidine metabolism, focal adhesion, actin cytoskeleton reg- Identification of somatic mutations took advantage of compo- ulation, and tight junctions are highly enriched in the metastatic nents of the modular multistep filter as described (6). TCGA data melanoma cohort with P values below 1.0EÀ04. Pyrimidine portal was used for cohort selection and CGHub for access of raw metabolism stands out as highly enriched pathway (enrichment data. Whole-exome sequencing data for 339 patients with primary ratio down 3.60, ratio up 2.19, adjusted P value down 3.49EÀ10 tumor or metastatic tumor were matched with blood-derived and adjusted P value up 4.00EÀ04). There are 34 and 23, in total normal reference. For the MuTect 1.1.4 analysis (7) GrCh37 57 genes in pyrimidine metabolism, which are significantly (Broad Institute variant of HG19), dbSNP build 132.vcf, and down- and upregulated, respectively (Supplementary Table S4). COSMIC_54.vcf library were referenced. Somatic incidences file Pyrimidine enzymes undergoing differential expression between was queried in bash prompt to retain all the statically significant skin cutaneous primary and metastatic tumors include all steps in KEEP mutations. The coverage.wig files served as input to model nucleoside triphosphate synthesis, DNA and RNA polymerases, and account for Intron versus Exon functional mutation burden in as well as pyrimidine degradation. The top downregulated InVEx 1.0.1 (8). In addition, MutSig 2.0 assessed the clustering of enzyme of pyrimidine metabolism is CDA (cytidine deaminase, mutations in hotspots as well as conservation of the sites (9). It is Gene ID: 978, log2 change between primary and metastatic noted that the SKCM cohort contains an interesting case, patient tumor: 1.66, P 5.06EÀ15), the highest upregulated enzyme is TCGA-FW-A3R5, who has more than 20,000 mutations and an DPYD (log2 difference between primary and metastatic tumor: APOBEC signature (10). This patient shows multiple missense þ1.43, P 2.85EÀ13). Genes differentially expressed in pathways mutations in DPYD with nucleotide transitions according to in cancer include important signaling molecules in MAPK signal- canonical UVB signature, C>T and G>A. Including or excluding ing like BRAF, NRAS, KRAS, MAPK8, MAP2K1, in WNT signaling, this patient had no implications on the outcome of this study. CTNNB1, FZD1/3/4/8, in STAT signaling, PIAS1, STAT1, STAT5B, in AKT signaling AKT3, MTOR, and others like RB1, NFKB1. Structural model and molecular dynamics simulation Another remarkable theme of enriched genes during metastatic The structural model of human DPYD was based on Sus scrofa progression is dedifferentiation of melanogenesis, keratinocytes, X-ray structure (PDB entry 1gth) using swiss-model. Mutations and Wingless (WNT) signaling (Table 1). Such gene sets are were plotted on the modeled human structure and ligand important for cell differentiation of normal melanocytes, epider- proximity was evaluated by a 5Å cut-off. The solvent accessible mal development, and pigmentation. surface of each residue of DPYD was determined on the basis of a molecular dynamics simulation over a 5 ns trajectory using Hypermutation of dihydropyrimidine dehydrogenase in GROMACS 5.0.2 (11). pyrimidine metabolism To identify potential melanoma driver genes in pyrimidine metabolism, we assessed recurrence and statistical enrichment of Gene expression analysis and statistical analysis somatic mutations for all pyrimidine genes in melanoma. DPYD Level 3 RNASeq Log2-transformed expression levels for
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