Transcript Multi-drug transporter ABCG2 gene polymorphisms and their

Multi-drug transporter ABCG2 gene
polymorphisms and their prognostic
value in patients with de novo acute
leukemia
Fang Wang Li-wu Fu*
中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
The ATP-binding cassette subfamily G member 2 (ABCG2)
gene, also known as breast cancer resistance protein (BCRP),
was first identified as a multidrug resistance protein.
ABCG2 is widely expressed in many normal tissues, including
intestine, placenta, mammary gland, brain, and liver, and has
been shown to play an important role against xenobiotics and
their metabolites.
The apical localization of ABCG2 in the intestinal epithelium
and the bile canalicular membrane indicates a possible role of
ABCG2 in intestinal absorption and hepatobiliary excretion of
its substrates.
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中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
3
中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
ABCG2 can influence its drug efflux function and
substrate specificity :
ABCG2 variants R482G and R482T lose methotrexatetransporting activity but confer increased mitoxantrone
resistance.
The C421A polymorphism was associated with decreased
protein expression and transport activity and altered
pharmacokinetic parameters of some BCRP substrates
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中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
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中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
In the present study :
we explored the positions and frequencies of SNPs in ABCG2 and
examined their possible prognostic impact in acute leukemia
patients
we analyzed the expression of ABCG2 using quantitative RTPCR to investigate its potential role in clinical outcome of acute
leukemia patients.
we determined the functional activity of ABCG2 in isolated patients
blast cells with flow cytometric assay
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中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
Summary of ABCG2 SNPs detected in the passage
Table 3. Summary of ABCG2 SNPs detected in the passage
Nucleotide change and
Position
Number of subjects
NT-016354.18 dbSNP(NCBI) Location flanking sequences Amino acid Wild- Hetero- Homo(5'to 3')
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change
Allele
type zygote zygote Frequency
13608835
rs2231137
Exon 2
TCCCAG/ATGTCA Val 12 Met
66
50
68
0.505
13600044
rs2231142
Exon 5
ACTTAC/AAGTTC Gln 141 Lys 128
56
0
0.152
13561218*
N.D.
182
2
0
0.005
13576005
rs2231149
Intron 10 TCAAGC/TTTATT No channge 145
39
0
0.106
13564503
rs2231162
Intron 13 TGACTC/TTTAGT No channge 111
73
0
0.198
13563578
rs2231164
Intron 14 TTCTTA/GAAATT No channge 131
53
0
0.144
Exon 16 GGCATC/TGATCT Ile 619 Ile
中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
8
中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
OS and DFS were significantly
longer in patients with the 34GG
genotype than those with the
34GA/34AA genotype patients
without BMT
OS and DFS were significantly
longer in patients with the
34GG genotype than those
with the 34GA/34AA genotype
in BMT patients
OS and DFS of patients with
the ABCG2 34GG genotype
were influenced by other
ABCG2 gene polymorphisms
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中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
Patient cells were exposed to
the indicated concentrations
of vincristine, daunorubicin,
doxorubicin and
mitoxantrone for 72 h.
Effects of BCRP
expression and G34A
polymorphism on the
accumulation of
doxorubicin and Rho 123.
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中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
P-gp expression of the
three patients was
comparable to those of
negative control.
BCRP expression was
low in patient 2 and 5
compared to the
negative control S1
cells, whereas patient 8
showed marked BCRP
overexpression.
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中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
Conclusions
six polymorphisms are identified in ABCG2, including
one novel synonymous polymorphism in exon 16 with a
low allele frequency (0.5%).
Our data also shows that ABCG2 G34A polymorphism
could be a potential independent prognostic factor in
acute leukemia patients.The patients carrying
34GA/AA genotype displayed worse overall survival
and shorter disease free survival than that with 34GG
genotype
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中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
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中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER