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fact
sheet
Androgen
Receptor Gene and Prostate Cancer
Rovshan
Ismailov, MD, MPH
University
of Pittsburgh
Published
May, 2002
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AR
Gene |
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The
androgen receptor (AR) gene is located in the Xq11.2–q12 chromosome
and consists of eight exons. This gene is a member of the steroid/nuclear
receptor gene superfamily. There are two domains that are directly responsible
for the transactivation activity of the AR protein. Of these domains, the ligand-independent
AF-1 is encoded within exon 1. |
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Prevalence of
Gene Variants |
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There
are three known AR gene polymorphisms: the (CAG)n trinucleotide repeat,
the (GGC)n trinucleotide repeat, and the R726L single nucleotide polymorphism
(1). Studies have suggested that twenty-seven alleles ranging from
5 to 31 repeats were observed in various populations. Short CAG repeats (less than or equal to 22 repeats) were
found to be more prevalent in African-American males who are at high risk for
prostate cancer and less prevalent in Asians who are at lower risk for this
disease (2). This observation reveals that variation in androgen receptor CAG
repeat length differs considerably among human populations. African Americans
have the lowest frequency (20%) of the GGC allele with 16 repeats; the
comparable values for intermediate-risk whites were 57% and low-risk Asians were
70% (2). |
Disease
Burden |
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In
recent years, prostate cancer has become the most common cancer and the second
leading cause of cancer death in men in the United States. There is a 65-fold
difference in incidence of prostate cancer between the populations with the
highest (African-American) and lowest (Asian) risk (3). Compared with rates of prostate cancer in the United States, rates are
slightly lower in some countries of Western Europe such as Denmark, United
Kingdom, Italy, and Spain. In Asia,
prostate cancer rates in Singapore, Hong Kong, and Bombay are less than half of
those in Israel (4).
Consistent
with the interracial variation in CAG and GGC distributions, there was an excess
among white patients with fewer than 22 CAG and not-16 GGC repeats relative to
white controls (relative risk, 2.1; one-sided P = 0.08) (2). No linkage disequilibrium was observed between the two numbers of CAG and
GGC repeats among unaffected subjects. However,
there was a statistically significant negative association between the numbers
of CAG and GGC repeats among the prostate cancer patients studied (two-sided P =
0.008). The (CAG)n repeat was found to play a role in predisposition to prostate
cancer. In one of the case-control
studies conducted in Australia, the odds ratio of prostate carcinoma for a
change of 5 CAG repeats was 0.98 (95% confidence interval, 0.84-1.15);
therefore, investigators concluded that the AR CAG repeat polymorphism
was not a risk factor for prostate carcinoma. However, in this study, a shorter
repeat sequence was found to be associated with earlier age at diagnosis (5).
In
another study conducted in China, Chinese men have been found to have longer CAG (equal or longer than 23) repeats compared with western men.
Another finding of this study suggests that even in a very low-risk population,
a shorter CAG repeat length confers a higher risk of clinically significant
prostate cancer. Chinese men with a
CAG repeat length shorter than 23 (median length) had a 65% increased risk of
prostate cancer (odds ratio, 1.65; 95% confidence interval, 1.14-2.39) (6).
Finally, according to the study by Miller et al., the (CAG)n
and (GGN)n repeats do not play a major role in familial prostate cancer (7).
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Interactions |
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Studies
show a two-fold increase in relative risk for combination of CAG and GGN short
repeats (less or equal to 22). The AR, by transactivating some genes, might
influence prostate cancer risk through several pathways. Other genes can
directly or indirectly activate the AR, augmenting prostate cancer risk.
For instance, HSD17B3, the gene that encodes 17
b
-hydroxysteroid dehydrogenase type III, the testicular 17-ketoreductase, favors
the reduction of androstenedione to testosterone in the testis and can
indirectly (through dihydrotestosterone) activate AR.
In the
study by Xue et al. (8), men who carry a short AR
CAG (less or equal to 22) allele and who also carry two copies of the
PSA G allele, had a nearly 3-fold increase in risk of advanced prostate
cancer; however, the limitation of this study was a small sample size, and
results need to be replicated before they can be considered conclusive.
The
study by Yeh et al. (9) suggests that the BRCA1
may function as an AR coregulator and play positive roles in androgen-induced
cell death in prostate cancer cells and other androgen/AR target organs. BRCA1 has been identified by
linkage studies with a familial history of prostate cancer in addition to breast
and ovarian cancer. Struewing et
al. reported a risk of prostate cancer of up to 25%
by the age of 70 years for carriers of any of the two BRCA1
mutations, whereas the risk was only 5% for carriers of the BRCA2
mutation and 3.8% for those who were not carriers (10).
There
is strong evidence that environmental factors can influence the risk of prostate
cancer: The wide variation in disease incidence observed worldwide, the
observation that prostate cancer rates among immigrants tend to approach those
of the host country, and results from studies such as the Physicians' Health
Study that showed that men who consumed at least two and a half servings of
dairy foods daily were about 30% more likely to develop prostate cancer than men
who consume only half a serving per day. No
studies have examined the interaction between specific environmental risk
factors for prostate cancer and the AR gene.
Larger
studies are needed to evaluate the combined effect of CAG and GGN repeats.
Because gene-gene and gene-environment interactions may potentially contribute
to prostate cancer risk, it would be desirable to conduct studies in which both
biomarkers (or other measures) of exposure and polymorphism of multiple genes
are examined.
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Laboratory
Tests
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CAG and GGC genotypes were assayed by separating
radioactively labeled polymerase chain reaction (PCR) products on polyacrylamide
gels. In addition, automated sequencing systems have been used to assay these
polymorphisms.
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Population
Testing |
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No
laboratory tests are available to the general public for AR gene diagnostic
purposes.
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References |
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Mononen N, Syrjakoski K, Matikainen M, Tammela TL, Schleutker J,
Kallioniemi OP, Trapman J, Koivisto PA. Two percent of Finnish prostate cancer
patients have a germ-line mutation in the hormone-binding domain of the androgen
receptor gene. Cancer Res 2000;60(22):6479-81.
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Irvine RA, Yu MC,
Ross RK: The CAG and GGC microsatellites of the androgen receptor gene are in
linkage disequilibrium in men with prostate cancer. Cancer Res 1995;
55(9):1937-40.
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Stanford JL, Stephenson RA, Coyle LM, Cerhan J, Correa R, Eley JW, Gilliland F,
Hankey B, Kolonel LN, Kosary C, Ross R, Severson R, West D. Prostate Cancer
Trends 1973-1995, SEER Program, National Cancer Institute. NIH Pub. No.
99-4543. Bethesda, MD, 1999.
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Hsing AW, Tsao L, Devesa SS. International trends in prostate cancer
incidence and mortality. Int J Cancer 2000; 85:60-7.
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Beilin J, Harewood L,
Frydenberg M, et al. A case-control study of the androgen receptor gene CAG
repeat polymorphism in Australian prostate carcinoma subjects. Cancer 2001;
92(4):941-949.
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Hsing AW, Gao YT, Wu G, Wang X, Deng J, Chen YL, Sesterhenn IA, Mostofi FK, Benichou J, Chang C. Polymorphic CAG and GGN repeat lengths
in the androgen receptor gene and
prostate cancer risk: a population-based case-control study in China. Cancer Res
2000;60(18):5111-6.
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Miller EA, Stanford
JL, Hsu L, Noonan E, Ostrander EA. Polymorphic repeats in the androgen receptor
gene in high-risk sibships. Prostate 2001; 48(3): 200-5.
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Xue
W, Irvine AR, Yu CM., Ross R., Coetzee GA, Ingles SA. Susceptibility to prostate cancer:
interaction between genotypes at the androgen receptor and prostate-specific
antigen loci. Cancer Res 2000;60, 839-41.
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Yeh S, Hu YC, Rahman M, Lin HK, Hsu CL, Ting HJ, Kang HY, Chang C. Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells. Proceedings of the National Academy
of Sciences of the United States of America. 97(21):11256-61, 2000 Oct 10.
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Struewing J, Hartge P, Wacholder S, et
al. The risk of cancer associated with specific mutations of BRCA1 and
BRCA2 among Ashkenazi Jews. N Engl J
Med 1997; 336:
1401-8.
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Web sites |
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Fred Hutchinson
Cancer Research Center
National
Cancer Institute- Prostate Cancer Home Page
National
Cancer Institute-
Planning for Prostate Cancer Research
National Cancer
Institute - The Surveillance,
Epidemiology, and End Results (SEER) Program
British
Columbia Cancer Research Center
The National
Cancer Institute of Canada
American Cancer
Society
HuGENet™ Review
Androgen
Receptor (AR) CAG Repeats and Prostate Cancer
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