Association of the ABCG2 C421A polymorphism with prostate cancer risk and survival.
OBJECTIVE
To determine if the C421A single nucleotide polymorphism (SNP) in the ATP-binding cassette transporter ABCG2 increases prostate cancer risk or affects survival.


METHODS
Numerous studies have suggested that dietary, hormonal and environmental factors all play a role in the initiation in prostate cancer; among these, the carcinogenic heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a known substrate of the ABCG2. A SNP of ABCG2, C421A, resulting in a glutamine to lysine change at amino acid 141, has been shown to result in decreased function of the protein. Due to the expression of ABCG2 in the prostate, together with the purported role of dietary carcinogens and steroids in the development and progression of prostate cancer, 311 individuals were genotyped for the ABCG2 C421A SNP, 170 patients with androgen-independent prostate cancer (AIPC) and 141 'healthy' controls. We also evaluated the effect of this SNP on the intracellular accumulation of PhIP and testosterone in vitro.


RESULTS
There were no significant differences in the prevalence of prostate cancer based on ABCG2 genetic variation in this population. However, survival was significantly longer for individuals with wild-type ABCG2, as compared with those hetero- or homozygous for the C421A SNP (7.4 years vs 5.3 years, P = 0.044). Intracellular accumulation of PhIP was 80% higher in HEK293 cells transfected with Q141K ABCG2 than in wild-type cells, confirming that this SNP decreases transport of PhIP. In contrast, testosterone was not transported by either wild-type or variant transfected cells, nor did it act as in inhibitor of ABCG2 in subsequent transport assays.


CONCLUSIONS
Increased exposure to PhIP may decrease survival, but the ABCG2 C421A polymorphism does not appear to increase the risk of prostate cancer.
Gardner
Erin R
ER
Clinical Pharmacology Program, SAIC-Frederick, National Cancer Institute-Frederick, Frederick, MD, USA.
Ahlers
Christoph M
CM
Shukla
Suneet
S
Sissung
Tristan M
TM
Ockers
Sandra B
SB
Price
Douglas K
DK
Hamada
Akinobu
A
Robey
Robert W
RW
Steinberg
Seth M
SM
Ambudkar
Suresh V
SV
Dahut
William L
WL
Figg
William D
WD
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004032:Diet; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality; D012307:Risk Factors
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000728:Androgens; D009363:Neoplasm Proteins