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Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20852-7234 [A. W. H.]; Shanghai Cancer Institute, Shanghai, China 200032 [Y-T. G., J. D.]; University of Rochester, Rochester, New York, 14642 [G. W., X. W., Y-L. C., C. C.]; Armed Forces Institute of Pathology, Washington, D.C. 20306 [I. A. S., F. K. M.]; and University of Rouen, 76031 Rouen, France [J. B.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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23 GGN repeats. Our study not only confirms
that Chinese men do have a longer CAG repeat length than western men
but also represents the first population-based study to show that even
in a very low-risk population, a shorter CAG repeat length confers a
higher risk of clinically significant prostate cancer. These results
imply that CAG repeat length can potentially serve as a useful marker
to identify a subset of individuals at higher risk of developing
clinically significant prostate cancer. Larger studies are needed to
evaluate the combined effect of CAG and GGN repeats. Because of the
significance of AR in prostate cancer, investigation of factors that
interact with the polyglutamine region of the AR gene to
alter AR function and modulate prostate cancer risk is an important
area for future research. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The growth, differentiation, and proliferation of prostatic cells are regulated by androgens (6) . The biological effects of androgens are mediated through binding to the intracellular AR,2 which in turn regulates the transcription of target genes with the assistance of transcriptional coactivators (7) . The AR protein, consisting of 918 amino acids and encoded singly by the AR gene located on the X chromosome (Xq11-12), has three major functional domains: a transactivating amino-terminal domain, a DNA binding domain, and a ligand (steroid) binding domain (8) . The open reading frame of the AR gene is separated over eight exons and has a length of 2730 bp. The sequence encoding the large amino-terminal transactivating domain is found in the first exon, the DNA binding domain is encoded by exons 2 and 3, and the information for the ligand binding domain is distributed over exons 4–8 (8) .
The first exon of the AR gene contains two polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts localized in the NH2-terminal transactivation domain of the AR protein. The polyglutamine tract is encoded by a CAG trinucleotide repeat, and the polyglycine stretch is encoded by a GGN repeat. The number of CAG repeats ranges from about 8 to 35 repeats in normal individuals. Longer CAG repeat lengths appear to result in reduced AR transcriptional activity both in vivo and in vitro (9 , 10) . Otherwise healthy men whose AR has a CAG repeat length at the long end of the normal range (>28) have an increased incidence of impaired spermatogenesis and infertility (11) , conditions that are extremely androgen-dependent (12) . Expansion of the CAG repeat length to >40 repeats is related to a rare neuromuscular disorder, spinal and bulbar muscular atrophy (Kennedy syndrome), which is also associated with androgen insensitivity, decreased virilization, testicular atrophy, reduced sperm production, and infertility (13, 14, 15) . Together, these clinical data suggest that a longer CAG repeat length decreases the functional competence of AR.
The length of the polyglycine (GGN) tract varies from about 10 to 30
repeats. The functional consequences of variation in the GGN tract are
less clear. Deletion of the polyglycine tract reduces AR
transcriptional activity by 
30% in transient transfection assays
(16)
, although there is no significant correlation between
polyglycine tract length and infertility (11)
.
Shorter AR polyglutamine tracts, and thus a more transcriptionally active AR, have been associated with increased prostate cancer risk (17, 18, 19, 20, 21, 22) , higher cancer grade at diagnosis (23) , earlier age of cancer onset in white men (24 , 25) , and aggressive early-stage prostate cancer (defined as clinically unsuspected metastatic disease in men undergoing radical prostatectomy) (22) . In addition, several epidemiological studies have shown that a shorter length of both CAG and GGN repeats confers a higher risk of prostate cancer (17 , 20 , 22) .
Previous studies have shown that the CAG repeat length is shortest in African Americans, intermediate in whites, and longest in Asians, which corresponds well with the high, intermediate, and low incidence of prostate cancer in these populations (26 , 27) . Because of the ethnic variation in CAG and GGN repeat lengths of the AR gene and the role of AR in androgenic activity, it has been suggested that these polymorphisms may help explain part of the large racial difference in prostate cancer risk. However, to date, data supporting the relationship between AR polymorphisms and prostate cancer came exclusively from white men, and presently there are no data on Asians or African Americans. To assess the importance of AR polymorphisms in prostate cancer, as part of our population-based case-control study conducted in China, we herein examine the polymorphic length of CAG and GGN repeats in relation to prostate cancer risk.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Based on the records at the Shanghai Resident Registry, which contains personal identification cards for all adult residents over age 18 in urban Shanghai, healthy subjects who were free of cancer were selected randomly from permanent residents of Shanghai (6.5 million) and frequency-matched to the expected age distribution (5-year category) of prostate cancer cases. Of the 495 eligible controls without a history of cancer, 472 (95%) were interviewed.
Information on potential risk factors was elicited through an in-person interview by trained interviewers using a structured questionnaire. The interview included information on demographic characteristics; dietary history; smoking history; consumption of alcohol and other beverages; medical history; family history of cancer; physical activity; body size; and sexual behavior.
Blood Collection and DNA Extraction.
Two hundred cases (84% of those interviewed) and 330 controls (70%)
provided 20 ml of fasting blood for the study. The blood samples were
processed within 3 h of collection at a central laboratory in
Shanghai and stored at -70°C. The frozen buffy coat samples
(separated from 5 ml of blood) were later shipped to the United States
on dry ice for DNA extraction at the American Type Culture Collection
(Manassas, Virginia) with standard protocols. DNA purity, yield, and
length were satisfactory, and there was no evidence of DNA degradation
or RNA contamination. After DNA extraction, 191 cases and 304 controls
had sufficient DNA for AR genotyping at the University of Rochester.
DNA samples for cases and controls were grouped into pairs to minimize
the effect of day-to-day laboratory variation. Laboratory personnel
were blinded to the case-control status.
Molecular Analysis and Assessment of the CAG and GGN Repeats.
As part of an ongoing molecular analysis of the AR gene,
genomic DNA from the 495 subjects was used to determine the usual sense
codon sequence and the exact number of CAG and GGN repeats in exon 1 of
the AR gene through PCR amplification and DNA sequencing.
For the CAG repeat analysis, we designed a set of oligonucleotide
primers that flank the CAG repeat, 5'-GCTCTGGGACGCAA-CCTCTCT-3' and
5'-GCAGCGACTACCGCATCATCA-3', for PCR amplification. We selected a pair
of nested primers, 5'-CGGG-GTAAGGGAAGTAGGTGGAAG-3' and
5'-CTCTACGATGGGCTTGGGGAGAAC-3', for DNA sequencing. For GGN
analysis, we used the oligonucleotide primers
5'-ACCCTCAGCCGCCGCTTCCTCATC-3' and 5'-CTGGGATAGGGCACTCTGCTCAAC-3' for
both PCR amplification and sequencing. The PCR products of the CAG and
GGN repeats were amplified, using the Advantage 2 Polymerase System
(Clontech) and the Advantage-GC Genomic Polymerase System (Clontech),
respectively. Subsequently, these PCR products were purified, using the
PCR Product Purification Kit (Qiagen), and sequenced directly, using
the Big Dye Terminator Cycle Sequencing Ready Reaction Kit (PE
Biosystems). All reactions were optimized to reach consistent
results, using genomic DNA samples extracted from cell lines. For the polyglutamine tract ((CAG)nCAA), the
number of CAG triplets was counted to yield the length of CAG repeats.
For the polyglycine tract
(GGT3GGG1GGT2GGCn),
the usual sense codon sequence of the GGN tract is: three GGT, one GGG,
two GGT, followed by a variable number of GGC repeats. For example, a
GGN repeat length of 23 in our study corresponded to a PCR fragment of
217 bp, encompassing 3 GGT, 1 GGG, 2 GGT, and 17 GGC triplets.
Because the PCR procedure is prone to contamination, a negative control (water blank) was always included in each batch of PCR reactions (usually 9–18 samples plus one negative control). The assay for one batch (9 samples) was repeated with new reagents because of an indication of minor contamination. Because exon 1 of the AR gene is GC-rich with CAG and GGN repeats, this region is difficult to amplify. Several samples had to be amplified and sequenced more than once. Overall, 5 (1%) of the 495 samples could not be typed for CAG repeats because of insufficient DNA or sequencing problems, whereas 14 (2.8%) could not be typed for GGN repeats for similar reasons. The percentages of samples that were unsuccessfully genotyped were similar in cases and controls.
Twenty-four split samples from the same individual were included as quality control samples to assess the reproducibility of genotyping. Of the 24 quality control samples, 23 and 20 were amplified and sequenced successfully for the CAG and GGN repeats, respectively. Of the 23 samples with CAG results, 21 (91%) had the same repeat length of 23, one had 24, and one had 22. Of the 20 samples with GGN results, 19 (95%) had the same repeat length of 23 and the other had a length of 24.
Statistical Analysis.
The mean numbers of CAG and GGN repeats were compared in cases and
controls using the t test. Unconditional logistic regression
models were used to estimate ORs and their corresponding 95% CIs for
prostate cancer in relation to CAG and GGN repeat lengths
(28)
. Repeat lengths were examined first as continuous
variables and later as categorical variables. The distributions of the
number of CAG or GGN repeats among controls were used to derive the
median or tertile cutoffs used to calculate ORs. In addition, the
combined effects of CAG and GGN were evaluated based on the median
lengths within the controls. The relationships between age, CAG and GGN
repeat length, and other variables were assessed by Spearman
correlation and ANOVA.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Compared with controls, cases had higher caloric intake, higher levels
of education, and a higher waist:hip ratio and were less likely
to use cigarettes or alcohol. Age at diagnosis ranged from 50 to 94
(median 73) for cancer cases. Sixty-nine cases (36%) were diagnosed as
having localized cancer, and most tumors (72%) were moderately or
poorly differentiated.
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. Although the median number of CAG repeats in controls was only
slightly larger than that in cases (23.0 versus 22.0), there
was a shift toward longer repeat length among controls (Fig. 1)
. For CAG repeat length shorter than 23, cases had higher percentages
than controls in 6 of the 10 categories. However, for CAG repeat length
longer than 22, controls had higher percentages than cases in 8 of the
12 categories. Age at diagnosis and stage of cancer were not related to
CAG repeat length, with similar distribution and average number of CAG
and GGN repeat lengths in various age categories and three clinical
stages.
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). About 72% of the study subjects had a GGN repeat length of 23.
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. When the number of CAG repeats was included in the model as a
continuous variable, there was a 7% increase in the risk of prostate
cancer for each decrement in length of one CAG repeat (OR, 1.07; 95%
CI, 1.00–1.15). The risks associated with decrements of three and six
repeats were 1.21 (95% CI, 1.14–1.32) and 1.42 (95% CI, 1.22–1.61),
respectively. When the median repeat length was used to dichotomize
study subjects, men with a CAG repeat length shorter than 23 had a 65%
increased risk (OR, 1.65; 95% CI, 1.14–2.39), compared with men with
a CAG repeat length of 23 or longer. Relative to the highest tertile of
CAG repeat length (24), men in the second and first tertiles (22–23
and <22, respectively) had ORs of 1.45 and 1.55, respectively
(Ptrend = 0.06).
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23 repeats. Because >72% of the subjects had 23 GGN
repeats, we could not estimate ORs by tertiles for GGN repeats.
Also shown in Table 4
are the ORs associated with combined categories
of CAG and GGN repeat lengths. Men with both CAG and GGN repeat lengths
shorter than 23 had a 75% elevated risk of prostate cancer. There was
little correlation between the number of CAG and GGN repeats
(r = -0.03; P > 0.05).
The number of CAG or GGN repeats did not correlate with age, education, body mass index, waist:hip ratio, total calories, smoking, or drinking. These variables therefore were not included in the model for adjustment. The ORs were materially unchanged after further adjustment for BPH, although the cases had a higher prevalence of BPH (57% versus 23%) and there was a nonsignificant moderate association between CAG or GGN repeat lengths and BPH (data are reported separately). Associations of CAG or GGN repeat length were similar across all stages of disease at diagnosis (data not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our finding that a shorter CAG repeat length is associated with a higher risk of prostate cancer is consistent with four previous studies (17, 18, 19, 20, 21, 22) but differs from one study in a French-German population that reported no such association (29) . Despite the cross-sectional nature of our study, the observed inverse association may reflect some degree of genetic predisposition to clinically significant cancer (and thus to progression of prostate tumors) because most of the cases in our study had clinically advanced cancer and few, if any, were identified through screening (average serum levels of prostate-specific antigen among cases was 73). In addition, despite the large racial difference in clinical prostate cancer risk, the prevalence of latent prostate tumors has been reported to be similar across populations (5) , suggesting that racial variation in the polymorphisms of AR may be related to differences in genetic susceptibility to progression rather than to initiation of prostate cancer.
The observed inverse association with AR polymorphisms is biologically plausible because laboratory studies have shown that a long polyglutamine chain (>30 repeats) in the AR gene is associated with androgen insensitivity and reduced AR transactivation activity (13 , 14) . In vitro transfection studies also have demonstrated that elimination of the polyglutamine tracts results in elevated transcriptional activities (9 , 11 , 16) . Clinical studies have suggested that alteration in the AR function, through either polymorphisms of CAG repeat length or somatic mutations, may be associated with tumor progression. For example, the progression from latent to clinically invasive prostate cancer is initially androgen-dependent, although some tumors later become androgen-independent (thus becoming nonresponsive to hormonal treatment). Several non-germ-line-related changes of the AR gene, including amplification of the AR gene (usually a key step in the transition from a hormone-sensitive to a hormone-refractory state in prostate tumors; Refs. 30 and 31 ), AR somatic mutations (identified throughout transactivation, DNA binding, and ligand binding domains; Refs. 32 and 33 ), and contraction of CAG repeat length in cancer cells (31) , have been shown to be associated with tumor aggressiveness, cancer progression, and failure of hormonal therapy. AR expression studies in the majority of prostate tumors, including those that have become refractory to hormonal therapy, also suggest that AR plays a key role in androgen-independent tumors (34 , 35) .
The inverse relationship between CAG repeat length and AR transcriptional activity (thus androgen sensitivity) is the presently recognized underlying molecular mechanism by which AR polymorphisms modulate prostate cancer risk. Because transcriptional activation of the AR gene is influenced by not only polymorphisms in the AR gene but also a number of other factors, including tissue levels of dihydrotestosterone, estradiol, insulin-like growth factors, and AR coactivators (36, 37, 38, 39, 40, 41, 42) , it is likely that these factors may also affect prostate cancer risk by mediating transcriptional activities. Several AR coactivators, including AR-associated proteins (ARA70 and ARA55), amplified in breast cancer-1 (AIB1), cyclic AMP-responsive element-binding protein (CBP), Rb, and BRCA1, have been shown to enhance AR-mediated transcriptional activity from 2- to 10-fold, suggesting that in vivo coactivators are essential in attaining optimal AR transactivation in response to androgens (39, 40, 41, 42) . Future studies are needed to evaluate the effects of AR in conjunction with these coactivators to clarify further the underlying mechanism of androgenic pathways in prostate carcinogenesis.
It has been suggested that variations in CAG repeat length in the AR gene between populations may explain part of the large racial difference in prostate cancer risk and that a shorter CAG repeat length reported for African Americans may contribute to some of their higher risk of prostate cancer, although presently no data are available from this population. Our results confirm that, relative to western men, Chinese men do indeed have a longer CAG repeat length. For example, 22% of the 1722 white men in two United States studies (17 , 18) had a CAG repeat length shorter than 20 versus only 10% in our study and 55% reported for African Americans in a cross-sectional survey (26 , 27) . Our results, based on the population with the lowest reported incidence of prostate cancer in the world, cannot be generalized directly to African Americans. However, inverse associations have also been reported for Caucasians, suggesting that the underlying biological mechanism in various racial groups may be similar and that the polymorphisms of AR may be related, in part, to racial difference in prostate cancer risk.
The polymorphic CAG repeat length in the AR gene represents the first of a new class of common polymorphisms as genetic risk factors for prostate cancer. Rare genetic factors with high penetrance, such as HPC1 on chromosome 1, conferring a much higher relative risk to a few individuals who carry them (for example, HPC1 may explain about 10% of the prostate cancer cases in the United States), are unlikely to explain the large racial difference in prostate cancer risk. In contrast, the common CAG polymorphism of the AR gene confers variable risk upon all individuals, which in turn may result in a much larger proportion of prostate cancer cases attributable to having fewer CAG repeats. Assuming that the CAG polymorphism association is causal, we estimated that 25% (95% CI, 9–41%) of the cases in Shanghai can be attributed to a CAG repeat length shorter than 23. In an effort to provide insights into the reasons for the substantial racial difference in prostate cancer risk, using the CAG repeat length distribution in the two United States studies among white men (17 , 18) , we further estimated that 3–7% of cases among United States white men can be attributed to the CAG polymorphism (repeat length <23) and that this polymorphism alone potentially accounts for at least 5% of the difference in incidence between Chinese and United States men.
Similar to two previous studies (17 , 18) , we found that the number of GGN repeats clusters around 23 [in the study of Stanford et al. (17) , only the number of GGC repeats was counted and 15 was the peak of the repeat, which corresponds to 21 GGN repeats], and that a shorter GGN repeat length appears to be associated with a moderate increase in prostate cancer risk. Twenty-three GGN repeats may represent the coding sequence for optimal AR protein conformation and activity, since >70% of the study subjects in our study as well as in studies of western men had a GGN repeat length of 23.
Although it is well established that (GGC)n repeats in the polyglycine tract (GGT3GGG1GGT2GGCn) of the AR gene are polymorphic, to date there has been little information on variations in the GGG and GGT regions of the polyglycine tract because these regions are GC-rich and technically it has been difficult to amplify these regions. Our study represents the first successful effort to sequence the exact codon usage and number of the GGN trinucleotide repeats in a large number of population-based samples. We showed that GGT and GGG regions were quite stable and that there were no variations in these two regions in all of the 481 DNA samples analyzed.
Survival and selection biases in our study should be minimal because well over 90% of the eligible cases participated in the study and most cases were interviewed within 30 days after diagnosis. Seventy to 80% of the study subjects gave blood for the study, so it is unlikely that response status among cases and controls was related to the number of CAG or GGN repeats.
In summary, results from our population-based multidisciplinary case-control study in China confirm the hypothesis that a shorter CAG repeat length is associated with clinically significant prostate cancer and that relative to western men, Chinese men do have longer CAG and GGN repeat lengths. Larger studies are needed to evaluate the combined effect of CAG and GGN repeats, especially among African Americans. Because of the importance of AR in prostate cancer etiology, investigation of factors that might interact with the polyglutamine region of the AR gene to alter AR function and modulate prostate cancer risk is an important area for future research.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Division of Cancer Epidemiology and Genetics, National
Cancer Institute, EPS-MSC 7234, 6120 Executive Boulevard, Bethesda, MD
20852-7234. Fax: (301) 402-0916; E-mail: hsinga{at}exchange.nih.gov 
2 The abbreviations used are: AR, androgen
receptor; CI, confidence interval; OR, odds ratio; BPH, benign
prostatic hyperplasia.
3 A. W. Hsing, J. Deng, T. Xie, I. A.
Sesterhenn, F. K. Mostofi, and Y-T. Gao. Body size and prostate
cancer: a population-based case-control study in Shanghai, China,
submitted for publication.
Received 2/ 7/00. Accepted 7/19/00.
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 A. J. Li, R. L. Baldwin, and B. Y. Karlan Short Androgen Receptor Allele Length Is a Poor Prognostic Factor in Epithelial Ovarian Carcinoma Clin. Cancer Res., September 1, 2003; 9(10): 3667 - 3673. [Abstract] [Full Text] [PDF]
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 W. G. Nelson, A. M. De Marzo, and W. B. Isaacs Prostate Cancer N. Engl. J. Med., July 24, 2003; 349(4): 366 - 381. [Full Text] [PDF]
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N. M. Suter, K. E. Malone, J. R. Daling, D. R. Doody, and E. A. Ostrander Androgen Receptor (CAG)n and (GGC)n Polymorphisms and Breast Cancer Risk in a Population-Based Case-Control Study of Young Women Cancer Epidemiol. Biomarkers Prev., February 1, 2003; 12(2): 127 - 135. [Abstract] [Full Text] [PDF]
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 A. W. Hsing, Y.-T. Gao, S. Chua Jr., J. Deng, and F. Z. Stanczyk Insulin Resistance and Prostate Cancer Risk J Natl Cancer Inst, January 1, 2003; 95(1): 67 - 71. [Abstract] [Full Text] [PDF]
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A. W. Hsing, A. P. Chokkalingam, Y.-T. Gao, M. P. Madigan, J. Deng, G. Gridley, and J. F. Fraumeni Jr. Allium Vegetables and Risk of Prostate Cancer: A Population-Based Study J Natl Cancer Inst, November 6, 2002; 94(21): 1648 - 1651. [Abstract] [Full Text] [PDF]
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T. R. Rebbeck Inherited Genotype and Prostate Cancer Outcomes Cancer Epidemiol. Biomarkers Prev., October 1, 2002; 11(10): 945 - 952. [Abstract] [Full Text] [PDF]
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E. Giovannucci Is the Androgen Receptor CAG Repeat Length Significant for Prostate Cancer? : Commentary re: C. Chen et al., Androgen Receptor Polymorphisms and the Incidence of Prostate Cancer. Cancer Epidemiol. Biomark. Prev., 11: 1033-1040, 2002 Cancer Epidemiol. Biomarkers Prev., October 1, 2002; 11(10): 985 - 986. [Full Text] [PDF]
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C. Chen, N. Lamharzi, N. S. Weiss, R. Etzioni, D. A. Dightman, M. Barnett, D. DiTommaso, and G. Goodman Androgen Receptor Polymorphisms and the Incidence of Prostate Cancer Cancer Epidemiol. Biomarkers Prev., October 1, 2002; 11(10): 1033 - 1040. [Abstract] [Full Text] [PDF]
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C. L. Bennett, D. K. Price, S. Kim, D. Liu, B. D. Jovanovic, D. Nathan, M. E. Johnson, J. S. Montgomery, K. Cude, J. C. Brockbank, et al. Racial Variation in CAG Repeat Lengths Within the Androgen Receptor Gene Among Prostate Cancer Patients of Lower Socioeconomic Status J. Clin. Oncol., September 1, 2002; 20(17): 3599 - 3604. [Abstract] [Full Text] [PDF]
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E. P. Gelmann Molecular Biology of the Androgen Receptor J. Clin. Oncol., July 1, 2002; 20(13): 3001 - 3015. [Abstract] [Full Text] [PDF]
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E. P. Gelmann, D. J. Steadman, J. Ma, N. Ahronovitz, H. J. Voeller, S. Swope, M. Abbaszadegan, K. M. Brown, K. Strand, R. B. Hayes, et al. Occurrence of NKX3.1 C154T Polymorphism in Men with and without Prostate Cancer and Studies of Its Effect on Protein Function Cancer Res., May 1, 2002; 62(9): 2654 - 2659. [Abstract] [Full Text] [PDF]
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A. W. Hsing, A. P. Chokkalingam, Y.-T. Gao, G. Wu, X. Wang, J. Deng, J. Cheng, I. A. Sesterhenn, F. K. Mostofi, T. Chiang, et al. Polymorphic CAG/CAA Repeat Length in the AIB1/SRC-3 Gene and Prostate Cancer Risk: A Population-based Case-Control Study Cancer Epidemiol. Biomarkers Prev., April 1, 2002; 11(4): 337 - 341. [Abstract] [Full Text] [PDF]
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C. A. Heinlein and C. Chang Androgen Receptor (AR) Coregulators: An Overview Endocr. Rev., April 1, 2002; 23(2): 175 - 200. [Abstract] [Full Text] [PDF]
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A. Mifsud, A. T. Choon, D. Fang, and E.L. Yong Prostate-specific antigen, testosterone, sex-hormone binding globulin and androgen receptor CAG repeat polymorphisms in subfertile and normal men Mol. Hum. Reprod., November 1, 2001; 7(11): 1007 - 1013. [Abstract] [Full Text] [PDF]
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A. W. Hsing, C. Chen, A. P. Chokkalingam, Y.-T. Gao, D. A. Dightman, H. T. Nguyen, J. Deng, J. Cheng, I. A. Sesterhenn, F. K. Mostofi, et al. Polymorphic Markers in the SRD5A2 Gene and Prostate Cancer Risk: A Population-based Case-control Study Cancer Epidemiol. Biomarkers Prev., October 1, 2001; 10(10): 1077 - 1082. [Abstract] [Full Text] [PDF]
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 M. Stanbrough, I. Leav, P. W. L. Kwan, G. J. Bubley, and S. P. Balk Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium PNAS, September 4, 2001; (2001) 191235898. [Abstract] [Full Text] [PDF]
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A. P. Chokkalingam, K. A. McGlynn, Y.-T. Gao, M. Pollak, J. Deng, I. A. Sesterhenn, F. K. Mostofi, J. F. Fraumeni Jr., and A. W. Hsing Vitamin D Receptor Gene Polymorphisms, Insulin-like Growth Factors, and Prostate Cancer Risk: A Population-based Case-Control Study in China Cancer Res., June 1, 2001; 61(11): 4333 - 4336. [Abstract] [Full Text] [PDF]
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A. W. Hsing, S. Chua Jr, Y.-T. Gao, E. Gentzschein, L. Chang, J. Deng, and F. Z. Stanczyk Prostate Cancer Risk and Serum Levels of Insulin and Leptin: a Population-Based Study J Natl Cancer Inst, May 16, 2001; 93(10): 783 - 789. [Abstract] [Full Text] [PDF]
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A. P. Chokkalingam, M. Pollak, C.-M. Fillmore, Y.-T. Gao, F. Z. Stanczyk, J. Deng, I. A. Sesterhenn, F. K. Mostofi, T. R. Fears, M. P. Madigan, et al. Insulin-like Growth Factors and Prostate Cancer: A Population-based Case-Control Study in China Cancer Epidemiol. Biomarkers Prev., May 1, 2001; 10(5): 421 - 427. [Abstract] [Full Text]
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G. Buchanan, N. M. Greenberg, H. I. Scher, J. M. Harris, V. R. Marshall, and W. D. Tilley Collocation of Androgen Receptor Gene Mutations in Prostate Cancer Clin. Cancer Res., May 1, 2001; 7(5): 1273 - 1281. [Abstract] [Full Text]
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A. W. Hsing, J. Deng, I. A. Sesterhenn, F. K. Mostofi, F. Z. Stanczyk, J. Benichou, T. Xie, and Y.-T. Gao Body Size and Prostate Cancer: A Population-based Case-Control Study in China Cancer Epidemiol. Biomarkers Prev., December 1, 2000; 9(12): 1335 - 1341. [Abstract] [Full Text]
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 X. Wang, S. Yeh, G. Wu, C.-L. Hsu, L. Wang, T. Chiang, Y. Yang, Y. Guo, and C. Chang Identification and Characterization of a Novel Androgen Receptor Coregulator ARA267-alpha in Prostate Cancer Cells J. Biol. Chem., October 26, 2001; 276(44): 40417 - 40423. [Abstract] [Full Text] [PDF]
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M. Stanbrough, I. Leav, P. W. L. Kwan, G. J. Bubley, and S. P. Balk Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium PNAS, September 11, 2001; 98(19): 10823 - 10828. [Abstract] [Full Text] [PDF]
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