Download Gene Section CDA (Cytidine Deaminase) Atlas of Genetics and Cytogenetics

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Gene Section
Mini Review
CDA (Cytidine Deaminase)
Yoshiro Saito
Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku,
Tokyo 158-8501, Japan (YS)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/CDAID998ch1p36.html
DOI: 10.4267/2042/44802
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: CDD
HGNC (Hugo): CDA
Location: 1p36.12
Note: CDA catalyzes hydrolytic deamination of
cytidine and deoxycytidine into uridine and
deoxyuridine, respectively.
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.
DNA/RNA
Description
Expression
The human CDA spans approximately 30 kB and
consists of 4 exons. No splice variant was reported.
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).
Transcription
The full length CDA mRNA is 985 bp with an open
reading frame of 441 bp.
Pseudogene
No pseudogene was reported.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7)
673
CDA (Cytidine Deaminase)
Saito Y
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 gemcitabineinduced 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).
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
2,2difluorodeoxycytidine (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 AfricanAmericans. 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).
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).
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).
Implicated in
References
Adverse reactions by anti-cancer drugs
Ho DH. Distribution of kinase and deaminase of 1-beta-Darabinofuranosylcytosine in tissues of man and mouse. Cancer
Res. 1973 Nov;33(11):2816-20
Note
CDA is involved in the metabolic inactivation of anticancer drug gemcitabine and cytosine arabinoside (araC). 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
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7)
Laliberté J, Momparler RL. Human cytidine deaminase:
purification of enzyme, cloning, and expression of its
complementary DNA. Cancer Res. 1994 Oct 15;54(20):5401-7
Yue L, Saikawa Y, Ota K, Tanaka M, Nishimura R, Uehara T,
Maeba H, Ito T, Sasaki T, Koizumi S. A functional singlenucleotide polymorphism in the human cytidine deaminase
gene contributing to ara-C sensitivity. Pharmacogenetics. 2003
Jan;13(1):29-38
674
CDA (Cytidine Deaminase)
Saito Y
Yonemori K, Ueno H, Okusaka T, Yamamoto N, Ikeda M, Saijo
N, Yoshida T, Ishii H, Furuse J, Sugiyama E, Kim SR, KikuraHanajiri R, Hasegawa R, Saito Y, Ozawa S, Kaniwa N,
Sawada J. Severe drug toxicity associated with a singlenucleotide polymorphism of the cytidine deaminase gene in a
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Tacca M, Peters GJ, Falcone A, Danesi R. Correlation of CDA,
ERCC1, and XPD polymorphisms with response and survival
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Sugiyama E, Kaniwa N, Kim SR, Kikura-Hanajiri R, Hasegawa
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S, Sugiyama E, Kim SR, Hasegawa R, Saito Y, Yoshida T,
Saijo N, Sawada J. Homozygous CDA*3 is a major cause of
life-threatening toxicities in gemcitabine-treated Japanese
cancer patients. Br J Cancer. 2009 Mar 24;100(6):870-3
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gemcitabine: can genetic studies lead to tailor-made therapy?
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childhood with acute leukemia and normal Chinese children].
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This article should be referenced as such:
Saito Y. CDA (Cytidine Deaminase). Atlas Genet Cytogenet
Oncol Haematol. 2010; 14(7):673-675.
Giovannetti E, Laan AC, Vasile E, Tibaldi C, Nannizzi S,
Ricciardi S, Falcone A, Danesi R, Peters GJ. Correlation
between cytidine deaminase genotype and gemcitabine
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7)
675