CDA (Cytidine Deaminase)

2009-09-01 Yoshiro Saito Affiliation

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

Identity

HGNC

CDA

LOCATION

1p36.12

LOCUSID

978

ALIAS

CDD

FUSION GENES

Show Gene Fusions

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.

Proteins

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

Entity name

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 name

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 name

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

Pubmed ID	Last Year	Title	Authors
19036079	2009	Cytidine deaminase genotype and toxicity of cytosine arabinoside therapy in children with acute myeloid leukemia.	Bhatla D et al
16551864	2006	Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics.	Gilbert JA et al
18600531	2008	Correlation between cytidine deaminase genotype and gemcitabine deamination in blood samples.	Giovannetti E et al
18203981	2008	Novel blood-based, five-gene biomarker set for the detection of colorectal cancer.	Han M et al
4518302	1973	Distribution of kinase and deaminase of 1-beta-D-arabinofuranosylcytosine in tissues of man and mouse.	Ho DH et al
7923172	1994	Human cytidine deaminase: purification of enzyme, cloning, and expression of its complementary DNA.	Laliberté J et al
17194903	2007	Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism.	Sugiyama E et al
18347182	2008	Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients.	Tibaldi C et al
19293806	2009	Homozygous CDA*3 is a major cause of life-threatening toxicities in gemcitabine-treated Japanese cancer patients.	Ueno H et al
17595663	2007	Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy?	Ueno H et al
15814642	2005	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 et al
12544510	2003	A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity.	Yue L et al
18067088	2007	[Single-nucleotide polymorphisms of the cytidine deaminase gene in childhood with acute leukemia and normal Chinese children].	Yue LJ et al

Other Information

Locus ID:

NCBI: 978
MIM: 123920
HGNC: 1712
Ensembl: ENSG00000158825

Variants:

dbSNP: 978
ClinVar: 978
TCGA: ENSG00000158825
COSMIC: CDA

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000158825	ENST00000375071	P32320

Expression (GTEx)

100

150

200

250

300

350

400

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Pyrimidine metabolism	KEGG	ko00240
Drug metabolism - other enzymes	KEGG	ko00983
Pyrimidine metabolism	KEGG	hsa00240
Drug metabolism - other enzymes	KEGG	hsa00983
Metabolic pathways	KEGG	hsa01100
Immune System	REACTOME	R-HSA-168256
Innate Immune System	REACTOME	R-HSA-168249
Metabolism	REACTOME	R-HSA-1430728
Metabolism of nucleotides	REACTOME	R-HSA-15869
Pyrimidine metabolism	REACTOME	R-HSA-73848
Pyrimidine salvage reactions	REACTOME	R-HSA-73614
Neutrophil degranulation	REACTOME	R-HSA-6798695

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PK	PD	PMIDs
PA165966294	Palmar-plantar erythrodysaesthesia syndrome	Disease	ClinicalAnnotation	associated		PD	18473752, 21325291, 23736036
PA166131569	difluorodeoxyuridine	Chemical	ClinicalAnnotation	associated	PK		22838949
PA443622	Carcinoma, Non-Small-Cell Lung	Disease	ClinicalAnnotation	associated	PK	PD	16551864, 17194903, 17885621, 18347182, 18538445, 18600531, 20665488, 21325291, 21521023, 21590444, 21625252, 22134350, 22546611, 23651026
PA443937	Drug Toxicity	Disease	VariantAnnotation	associated		PD	25850965
PA444511	Hyperbilirubinemia	Disease	ClinicalAnnotation	associated		PD	28347776
PA444750	Leukemia	Disease	ClinicalAnnotation	associated	PK	PD	19458626, 21325291, 21521023, 22304580, 22379997, 23651026, 25003625
PA444760	Leukemia, Myeloid, Acute	Disease	ClinicalAnnotation	associated	PK	PD	21325291, 21521023, 22304580, 23651026
PA444761	Leukemia, Myeloid	Disease	ClinicalAnnotation	associated		PD	19458626, 21325291, 21521023, 23651026
PA444840	Lymphoma	Disease	ClinicalAnnotation	associated	PK	PD	19458626, 21325291, 21521023, 22304580, 22379997, 23651026, 25003625
PA444937	Mesothelioma	Disease	ClinicalAnnotation	associated	PK	PD	16551864, 17194903, 17885621, 18347182, 18538445, 18600531, 20665488, 21325291, 21521023, 21590444, 21625252, 22134350, 22546611, 23651026
PA445062	Neoplasms	Disease	ClinicalAnnotation	associated	PK	PD	15814642, 17194903, 17885621, 18473752, 21325291, 21521023, 22304580, 22838949, 23651026, 23736036, 24167597, 24300978, 24361227, 28347776
PA445113	Neutropenia	Disease	ClinicalAnnotation, VariantAnnotation	associated	PK	PD	15814642, 17194903, 24361227, 30889042
PA445218	Pancreatic Neoplasms	Disease	ClinicalAnnotation, VariantAnnotation	associated	PK	PD	16551864, 17194903, 17885621, 18347182, 18538445, 18600531, 20665488, 21325291, 21521023, 21590444, 21625252, 22134350, 22546611, 23651026, 30889042
PA448771	capecitabine	Chemical	ClinicalAnnotation	associated		PD	18473752, 21325291, 23736036, 24167597, 28347776
PA449177	cytarabine	Chemical	ClinicalAnnotation	associated	PK	PD	18473752, 19458626, 21325291, 21521023, 22304580, 22379997, 23230131, 23651026, 25003625
PA449748	gemcitabine	Chemical	ClinicalAnnotation, Literature, MultilinkAnnotation, Pathway, VariantAnnotation	ambiguous	PK	PD	15814642, 16551864, 17194903, 17885621, 18347182, 18538445, 18600531, 20665488, 21325291, 21521023, 21590444, 21625252, 22134350, 22546611, 22838949, 23651026, 24300978, 24361227, 25162786, 30889042
PA451996	azacitidine	Chemical	VariantAnnotation	associated		PD	25850965

References

Pubmed ID	Year	Title	Citations
12651944	2003	Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase.	261
18762567	2008	miR-181b negatively regulates activation-induced cytidine deaminase in B cells.	95
19898482	2009	Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy.	84
23995783	2014	Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase.	74
18347182	2008	Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients.	58
18347182	2008	Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients.	58
20173083	2010	Genetic variation in metabolizing enzyme and transporter genes: comprehensive assessment in 3 major East Asian subpopulations with comparison to Caucasians and Africans.	44
17194903	2007	Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism.	39
23736036	2013	Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity.	39
20028759	2010	Single nucleotide polymorphisms of gemcitabine metabolic genes and pancreatic cancer survival and drug toxicity.	34

Citation

Yoshiro Saito

CDA (Cytidine Deaminase)

Atlas Genet Cytogenet Oncol Haematol. 2009-09-01

Online version: http://atlasgeneticsoncology.org/gene/998/cda