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CDA (Cytidine Deaminase)

Written2009-09Yoshiro Saito
Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)CDD
Other alias
HGNC (Hugo) CDA
LocusID (NCBI) 978
Atlas_Id 998
Location 1p36.12  [Link to chromosome band 1p36]
Location_base_pair Starts at 20588951 and ends at 20618907 bp from pter ( according to hg19-Feb_2009)  [Mapping CDA.png]
,TABLM IDTH=80%> Fusion genes
(updated 2016)
CCHCR1 (6p21.33) / CDA (1p36.12)CDA (1p36.12) / GNPTAB (12q23.2)NEDD8-MDP1 (14q12) / CDA (1p36.12)
Note CDA catalyzes hydrolytic deamination of cytidine and deoxycytidine into uridine and deoxyuridine, respectively.

DNA/RNA

 
Description The human CDA spans approximately 30 kB and consists of 4 exons. No splice variant was reported.
Transcription The full length CDA mRNA is 985 bp with an open reading frame of 441 bp.
Pseudogene No pseudogene was reported.

Protein

Note X-ray crystal structures of CDA from Yeast (1R5T) and Bacillus Subtilis (1JTK, 1UX0, 1UX1 and 1UWZ) are publicized in the PDB.
Description The human CDA protein consists of 146 amino acids and has a molecular weight of 16,184. This is a soluble cytoplasmic protein and it is involved in pyrimidine salvaging.
Expression Although the protein expression profile in tissues has not been revealed, its mRNA expression determined by Nothern blotting was observed in high levels in liver and placenta, low in lung and kidney, but not in heart, brain and muscle (Laliberte and Momparler, 1994). High CDA activity was reported in liver and spleen, and moderate in lung, kidney, large intestine mucosa and colon mucosa (Ho, 1973).
Localisation This protein is localized in cytoplasm.
Function CDA catalyzes hydrolytic deamination of cytidine and deoxycytidine into uridine and deoxyuridine, respectively. This protein also inactivate chemotherapeutic nucleoside analogs 2,2-difluorodeoxycytidine (gemcitabine) and cytosine arabinoside (cytarabine, Ara-C).

Mutations

Germinal Two nonsynonymous genetic varitions, 79A>C (Lys27Gln) and 208G>A (Ala70Thr), have been found in the human CDA gene (Yue et al., 2003). Ethnic differences in the minor allele frequencies of these variations have been reported. The 79A>C (Lys27Gln) was found at 0.30-0.36 frequencies in Caucasians, at 0.20-0.21 in Japanese and at 0.04-0.10 in Africans (Ueno et al., 2007). In contrast, the 208G>A (Ala70Thr) was found at 0.13 in Africans and 0.04 in Japanese, but not in Caucasians. Interestingly, the 208G>A (Ala70Thr) has not been detected in African-Americans. The mutant protein with 70Thr was reported to have remarkably reduced activities in vitro (Yue et al., 2003) and in vivo (Sugiyama et al., 2007). On the other hand, controvertial results on the effects of activities have been obtained for 79A>C (Lys27Gln). The recombinant enzyme with Gln27 retained its catalytic activities for cytidine and ara-C as substrates (Yue et al., 2003), while showing reduced activity with increased Km value in the case of gemcitabine (Gilbert et al., 2006). However, the minor allele of this SNP was reported to be associated with higher enzymatic activities for gemcitbine based on tests using lysates of red blood cells taken from Caucasian cancer patients (Giovannetti et al., 2008; Tibaldi et al., 2008). In line with this, the minor allele was associated with decreased response, shorter time to progression and overall survival, and lower frequencies of grade 3 and 4 neutropenia in Caucasian non-small cell lung cancer patients treated with gemcitabine and cisplatin (Tibaldi et al., 2008).

Implicated in

Note
  
Entity Adverse reactions by anti-cancer drugs
Note CDA is involved in the metabolic inactivation of anti-cancer drug gemcitabine and cytosine arabinoside (ara-C). CDA polymorphisms 208G>A (Ala70Thr) has been associated with adverse reactions including neutropenia by gemcitabine. Reduced clearance of gemcitabine and plasma CDA activities significantly depended on the number of minor allele 208A (70Thr) in 256 Japanese patients with cancer (Sugiyama et al., 2007). This polymorphism was also associated with increased incidences of grade 3/4 neutropenia in the patients coadministered with other anti-cancer drugs (Sugiyama et al., 2007). Notably, one patient with homozygous 208A (70Thr) showed severe hematologic and nonhematologic toxicities during chemotherapy with gemcitabine and cisplatin, and had 1/5 value of gemcitabine clearance and 12% of plasma CDA activity compared to those of the patients without CDA nonsynonymous polymorphisms (Yonemori et al., 2005, Sugiyama et al., 2007). Among the other panels of Japanese pancreatic cancer patients, three patients encountered life-threatening toxicities after chemotherapies including gemcitabine (Ueno et al., 2009). Two of them had homozygous CDA 208A (70Thr), and showed extremely low plasma CDA activity and gemcitabine clearance. Together with the previous one patient, homozygous 208A (70Thr) was suggested to be a key factor causing gemcitabine-induced severe adverse reactions in the Japanese (Ueno et al., 2009). With regard to another nonsynonymous polymorphism, the minor allele of CDA 79A>C (Lys27Gln) was associated with decreased response, shorter time to progression and overall survival, and lower frequencies of grade 3 and 4 neutropenia in Caucasian non-small cell lung cancer patients treated with gemcitabine and cisplatin (Tibaldi et al., 2008). Homozygous 79C (27Gln) was also associated with increased postinduction treatment-related motality with ara-C in patients with acute myeloid leukemia (Bhatla et al., 2008).
  
  
Entity Acute myeloid leukemia
Disease CDA genetic polymorphisms (79A>C, Lys27Gln; 208G>A, Ala70Thr; 435T>C, silent) were not associated with susceptibility to acute myeloid leukemia in Chinese children (Yue et al., 2007).
  
  
Entity Colorectal cancer
Note Combination of the five gene expression levels (CDA, MGC20553, BANK1, BCNP1 and MS4A1) in peripheral white blood cells could be used as a biomarker for diagnosis of colorectal cancer (Han et al., 2008).
  

Bibliography

Cytidine deaminase genotype and toxicity of cytosine arabinoside therapy in children with acute myeloid leukemia.
Bhatla D, Gerbing RB, Alonzo TA, Conner H, Ross JA, Meshinchi S, Zhai X, Zamzow T, Mehta PA, Geiger H, Perentesis J, Davies SM.
Br J Haematol. 2009 Feb;144(3):388-94. Epub 2008 Nov 22.
PMID 19036079
 
Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics.
Gilbert JA, Salavaggione OE, Ji Y, Pelleymounter LL, Eckloff BW, Wieben ED, Ames MM, Weinshilboum RM.
Clin Cancer Res. 2006 Mar 15;12(6):1794-803.
PMID 16551864
 
Correlation between cytidine deaminase genotype and gemcitabine deamination in blood samples.
Giovannetti E, Laan AC, Vasile E, Tibaldi C, Nannizzi S, Ricciardi S, Falcone A, Danesi R, Peters GJ.
Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):720-5.
PMID 18600531
 
Novel blood-based, five-gene biomarker set for the detection of colorectal cancer.
Han M, Liew CT, Zhang HW, Chao S, Zheng R, Yip KT, Song ZY, Li HM, Geng XP, Zhu LX, Lin JJ, Marshall KW, Liew CC.
Clin Cancer Res. 2008 Jan 15;14(2):455-60. Epub 2008 Jan 18.
PMID 18203981
 
Distribution of kinase and deaminase of 1-beta-D-arabinofuranosylcytosine in tissues of man and mouse.
Ho DH.
Cancer Res. 1973 Nov;33(11):2816-20.
PMID 4518302
 
Human cytidine deaminase: purification of enzyme, cloning, and expression of its complementary DNA.
Laliberte J, Momparler RL.
Cancer Res. 1994 Oct 15;54(20):5401-7.
PMID 7923172
 
Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism.
Sugiyama E, Kaniwa N, Kim SR, Kikura-Hanajiri R, Hasegawa R, Maekawa K, Saito Y, Ozawa S, Sawada J, Kamatani N, Furuse J, Ishii H, Yoshida T, Ueno H, Okusaka T, Saijo N.
J Clin Oncol. 2007 Jan 1;25(1):32-42.
PMID 17194903
 
Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients.
Tibaldi C, Giovannetti E, Vasile E, Mey V, Laan AC, Nannizzi S, Di Marsico R, Antonuzzo A, Orlandini C, Ricciardi S, Del Tacca M, Peters GJ, Falcone A, Danesi R.
Clin Cancer Res. 2008 Mar 15;14(6):1797-803.
PMID 18347182
 
Homozygous CDA*3 is a major cause of life-threatening toxicities in gemcitabine-treated Japanese cancer patients.
Ueno H, Kaniwa N, Okusaka T, Ikeda M, Morizane C, Kondo S, Sugiyama E, Kim SR, Hasegawa R, Saito Y, Yoshida T, Saijo N, Sawada J.
Br J Cancer. 2009 Mar 24;100(6):870-3.
PMID 19293806
 
Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy?
Ueno H, Kiyosawa K, Kaniwa N.
Br J Cancer. 2007 Jul 16;97(2):145-51. Epub 2007 Jun 26.
PMID 17595663
 
Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin.
Yonemori K, Ueno H, Okusaka T, Yamamoto N, Ikeda M, Saijo N, Yoshida T, Ishii H, Furuse J, Sugiyama E, Kim SR, Kikura-Hanajiri R, Hasegawa R, Saito Y, Ozawa S, Kaniwa N, Sawada J.
Clin Cancer Res. 2005 Apr 1;11(7):2620-4.
PMID 15814642
 
A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity.
Yue L, Saikawa Y, Ota K, Tanaka M, Nishimura R, Uehara T, Maeba H, Ito T, Sasaki T, Koizumi S.
Pharmacogenetics. 2003 Jan;13(1):29-38.
PMID 12544510
 
[Single-nucleotide polymorphisms of the cytidine deaminase gene in childhood with acute leukemia and normal Chinese children].
Yue LJ, Chen XW, Li CR, Li CG, Shi HS, Zhang M.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2007 Dec;24(6):699-702.
PMID 18067088
 

Citation

This paper should be referenced as such :
Saito, Y
CDA (Cytidine Deaminase)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(7):673-675.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CDAID998ch1p36.html


External links

Nomenclature
HGNC (Hugo)CDA   1712
Cards
AtlasCDAID998ch1p36
Entrez_Gene (NCBI)CDA  978  cytidine deaminase
AliasesCDD
GeneCards (Weizmann)CDA
Ensembl hg19 (Hinxton)ENSG00000158825 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000158825 [Gene_View]  chr1:20588951-20618907 [Contig_View]  CDA [Vega]
ICGC DataPortalENSG00000158825
TCGA cBioPortalCDA
AceView (NCBI)CDA
Genatlas (Paris)CDA
WikiGenes978
SOURCE (Princeton)CDA
Genetics Home Reference (NIH)CDA
Genomic and cartography
GoldenPath hg38 (UCSC)CDA  -     chr1:20588951-20618907 +  1p36.12   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CDA  -     1p36.12   [Description]    (hg19-Feb_2009)
EnsemblCDA - 1p36.12 [CytoView hg19]  CDA - 1p36.12 [CytoView hg38]
Mapping of homologs : NCBICDA [Mapview hg19]  CDA [Mapview hg38]
OMIM123920   
Gene and transcription
Genbank (Entrez)AJ000474 AY634312 BC048284 BC054036 CD675458
RefSeq transcript (Entrez)NM_001785
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CDA
Cluster EST : UnigeneHs.466910 [ NCBI ]
CGAP (NCI)Hs.466910
Alternative Splicing GalleryENSG00000158825
Gene ExpressionCDA [ NCBI-GEO ]   CDA [ EBI - ARRAY_EXPRESS ]   CDA [ SEEK ]   CDA [ MEM ]
Gene Expression Viewer (FireBrowse)CDA [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)978
GTEX Portal (Tissue expression)CDA
Protein : pattern, domain, 3D structure
UniProt/SwissProtP32320   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP32320  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP32320
Splice isoforms : SwissVarP32320
Catalytic activity : Enzyme3.5.4.5 [ Enzyme-Expasy ]   3.5.4.53.5.4.5 [ IntEnz-EBI ]   3.5.4.5 [ BRENDA ]   3.5.4.5 [ KEGG ]   
PhosPhoSitePlusP32320
Domaine pattern : Prosite (Expaxy)CYT_DCMP_DEAMINASES_1 (PS00903)    CYT_DCMP_DEAMINASES_2 (PS51747)   
Domains : Interpro (EBI)APOBEC/CMP_deaminase_Zn-bd    CMP_dCMP_Zn-bd    Cyt_deam_tetra    Cytidine_deaminase-like   
Domain families : Pfam (Sanger)dCMP_cyt_deam_1 (PF00383)   
Domain families : Pfam (NCBI)pfam00383   
Conserved Domain (NCBI)CDA
DMDM Disease mutations978
Blocks (Seattle)CDA
PDB (SRS)1MQ0   
PDB (PDBSum)1MQ0   
PDB (IMB)1MQ0   
PDB (RSDB)1MQ0   
Structural Biology KnowledgeBase1MQ0   
SCOP (Structural Classification of Proteins)1MQ0   
CATH (Classification of proteins structures)1MQ0   
SuperfamilyP32320
Human Protein AtlasENSG00000158825
Peptide AtlasP32320
HPRD11744
IPIIPI00027983   IPI01018243   
Protein Interaction databases
DIP (DOE-UCLA)P32320
IntAct (EBI)P32320
FunCoupENSG00000158825
BioGRIDCDA
STRING (EMBL)CDA
ZODIACCDA
Ontologies - Pathways
QuickGOP32320
Ontology : AmiGOnucleoside binding  cytidine deaminase activity  cytidine deaminase activity  protein binding  extracellular region  cytosol  cytosol  cell surface receptor signaling pathway  zinc ion binding  zinc ion binding  pyrimidine-containing compound salvage  cytidine deamination  cytosine metabolic process  negative regulation of cell growth  secretory granule lumen  protein homodimerization activity  pyrimidine nucleoside salvage  neutrophil degranulation  negative regulation of nucleotide metabolic process  protein homotetramerization  tertiary granule lumen  ficolin-1-rich granule lumen  
Ontology : EGO-EBInucleoside binding  cytidine deaminase activity  cytidine deaminase activity  protein binding  extracellular region  cytosol  cytosol  cell surface receptor signaling pathway  zinc ion binding  zinc ion binding  pyrimidine-containing compound salvage  cytidine deamination  cytosine metabolic process  negative regulation of cell growth  secretory granule lumen  protein homodimerization activity  pyrimidine nucleoside salvage  neutrophil degranulation  negative regulation of nucleotide metabolic process  protein homotetramerization  tertiary granule lumen  ficolin-1-rich granule lumen  
Pathways : KEGGPyrimidine metabolism    Drug metabolism - other enzymes   
REACTOMEP32320 [protein]
REACTOME PathwaysR-HSA-73614 [pathway]   
NDEx NetworkCDA
Atlas of Cancer Signalling NetworkCDA
Wikipedia pathwaysCDA
Orthology - Evolution
OrthoDB978
GeneTree (enSembl)ENSG00000158825
Phylogenetic Trees/Animal Genes : TreeFamCDA
HOVERGENP32320
HOGENOMP32320
Homologs : HomoloGeneCDA
Homology/Alignments : Family Browser (UCSC)CDA
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCDA [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CDA
dbVarCDA
ClinVarCDA
1000_GenomesCDA 
Exome Variant ServerCDA
ExAC (Exome Aggregation Consortium)CDA (select the gene name)
Genetic variants : HAPMAP978
Genomic Variants (DGV)CDA [DGVbeta]
DECIPHERCDA [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCDA 
Mutations
ICGC Data PortalCDA 
TCGA Data PortalCDA 
Broad Tumor PortalCDA
OASIS PortalCDA [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCDA  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCDA
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CDA
DgiDB (Drug Gene Interaction Database)CDA
DoCM (Curated mutations)CDA (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CDA (select a term)
intoGenCDA
NCG5 (London)CDA
Cancer3DCDA(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM123920   
Orphanet
MedgenCDA
Genetic Testing Registry CDA
NextProtP32320 [Medical]
TSGene978
GENETestsCDA
Target ValidationCDA
Huge Navigator CDA [HugePedia]
snp3D : Map Gene to Disease978
BioCentury BCIQCDA
ClinGenCDA
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD978
Chemical/Pharm GKB GenePA98
Clinical trialCDA
Miscellaneous
canSAR (ICR)CDA (select the gene name)
Other databasePharmGKB
Other databasePharmacogenomics/Pharmacogenetics Database for Japanese
Probes
Litterature
PubMed89 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCDA
EVEXCDA
GoPubMedCDA
iHOPCDA
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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