| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Null Results in Brief |
The Lank Center for Genitourinary Oncology, Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [T. F. S., P. W. K., P. G. F.]; Departments of Nutrition [E. A. P., M. J. S., E. G.] and Epidemiology [M. J. S., E. G.], Harvard School of Public Health, Channing Laboratory [M. J. S., E. G.], Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts 02115; and The Brady Urological Institute and Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287 [W. G. N., W. B. I., D. F.]
Introduction
GSTs3 conjugate glutathione to harmful substances facilitating their removal. Allelic variants of the GSTP1 gene have been identified, one isoleucine (GSTP1-1/I-105) and one valine (GSTP1-1/V-105) at codon 105. The allele frequency varies between ethnic groups. The isozymes have activities that differ by substrate. GSTs noncovalently bind and sequester steroid hormones. Smaller epidemiologic studies have reported an association between the GSTP1-1/Val-105 allele and higher risk of CaP.
We sought to test the hypothesis that men homozygous for GSTP1-1/Val-105 would be at higher risk for developing CaP than men who are GSTP1-1/Ile-105 homozygotes or heterozygotes and to determine whether smoking alters any such association. We also hypothesized that circulating levels of androgens would be higher in men homozygous for GSTP1-1/Val-105.
Materials and Methods
Study Population.
Blood was obtained in 1982 from 14,916 men enrolled in The Physicians’
Health Study and men were followed until 1995. Study characteristics
including blood collection and processing, stage classification,
clinical follow-up and documentation of prostate cancer were described
previously.
Genotyping.
Genomic DNA was isolated from whole blood using a Qiamp DNA extraction
kit (Qiagen, Chatsworth, CA) with investigators blinded to status.
Samples were diluted to 20 ng/µl and stored at -20°C. Twenty ng of
DNA were added to the PCR reaction mixture: 0.3 mM primers
P105F and P105R, 1.5 mM MgCl2, and 1.5 units of
Qiagen Taq in a final volume of 22 µl. Cycling conditions were 94°C
for 2 min, 35 cycles of 94°C for 30 s, 60°C for 1 min, 72°C
for 30 s, and 72°C for 8 s in a Perkin-Elmer GeneAmp PCR
System 9600 or an MJ Research PTC-200 (MJ Research, Waltham, MA).
Digestion was with 2.5 units of BsmA1 (New England Biolabs,
Beverly, MA), separated on a 2% agarose gel stained with ethidium
bromide. The genotypes were successfully determined for 590 cases and
803 controls.
Hormone Levels.
Plasma hormone concentrations were measured as described by Gann
et al. (5)
.
Statistical Analysis.
We used the 
2 test to evaluate whether the distribution
of GSTP1 alleles or genotypes varied among cases and
controls. We calculated ORs as an estimate of relative risk and 95%
CIs from logistic regression models. To increase power in the analysis
of genotype by stage and grade, we included all controls while
controlling for the matching factors of baseline age (5-year intervals)
and smoking status. We used stratified analysis to evaluate whether CaP
risk associated with genotype varied by smoking status and assessed
interaction by use of a cross-product term. From a previous analysis,
plasma steroid hormone concentrations were available for 389 controls.
We calculated mean levels of testosterone, dihydrotestosterone, and
androstanediol glucuronide by genotype and assessed whether hormone
levels varied by genotype using the Kruskal-Wallis test.
Results
The valine frequencies did not differ between CaP cases and
controls (Table 1)
. Neither val/val nor ile/val genotype was
associated with CaP overall or with high or low stage/grade disease
(Table 1)
. No difference (P-interaction = 0.4) was
found in the OR for developing CaP by GSTP1 genotype between
761 ever-smokers (ile/ile referent, ile/val OR,
0.84; 95% CI, 0.62–1.13; val/val OR, 0.80; 95% CI,
0.47–1.36) and 632 never-smokers (ile/ile referent;
ile/val OR, 0.91; 95% CI, 0.65–1.28; val/val
OR, 0.87; 95% CI, 0.52–1.48). We saw no important differences by
stage/grade of CaP when considering smoking status either. Levels of
testosterone, dihydrotestosterone and androstanediol glucuronide did
not differ by GSTP1 genotype (all P 
0.08).
|
We had 80% power to detect as statistically significant an OR of 1.4 when comparing the val/val and ile/val genotypes to the ile/ile genotype.
Limitations
The population examined in this study was predominantly United States Caucasian. Allele and genotype frequencies vary at this locus between ethnic groups; the impact it may have on CaP occurrence in other groups requires further study. Smoking status was assigned at baseline in 1982. Heavy, recent smoking may be a risk factor for developing highly aggressive CaP.
Conclusion
In this large, nested case-control study, we found no evidence of a differential risk for CaP among primarily Caucasian, United States men possessing the isoleucine or valine variants of codon 105 of GSTP1 in any genotypic combination. Our large sample size resulted in narrow CIs and allowed us to examine high and low stage/grade CaP while maintaining adequate statistical power. The upper CI limit of 1.22 excludes a large risk associated with the val/val genotype. Selection or survival bias was not an issue because of the prospective design and the high follow-up response rate.
Acknowledgments
We thank Stephanie Parker, Rachel Meyer, and Kathryn Starzyk for administrative support and management of the plasma samples and Xiaoyang Liu for assistance with computer programming.
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Supported by NIH grant numbers HL-26490,
HL-34595, CA-34944, CA-42182, CA-58684 and the Dana Farber Cancer
Institute prostate cancer research fund. This report is dedicated to
the memory of Tom Shepard, one of the 41,800 victims of CaP in 1997. 
2 To whom requests for reprints should be
addressed, at Department of Nutrition, Harvard School of Public Health,
665 Huntington Avenue, Boston, MA 02115. Phone: (617) 432-4648; Fax:
(617) 432-2435; E-mail: edward.giovannucci{at}channing.harvard.edu
3 The abbreviations used are: GST, glutathione
S-transferase; CaP, prostate cancer; OR, odds ratio; CI,
confidence interval.
Received 11/18/99; revised 8/11/00; accepted 9/11/00.
References
This article has been cited by other articles:
|
|
 |
|
  Q. K.Y. Chan, U.-S. Khoo, H. Y.S. Ngan, C.-Q. Yang, W.-C. Xue, K. Y.K. Chan, P.-M. Chiu, P. P.C. Ip, and A. N.Y. Cheung Single Nucleotide Polymorphism of Pi-Class Glutathione S-Transferase and Susceptibility to Endometrial Carcinoma Clin. Cancer Res., April 15, 2005; 11(8): 2981 - 2985. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ntais, A. Polycarpou, and J. P.A. Ioannidis Association of GSTM1, GSTT1, and GSTP1 Gene Polymorphisms with the Risk of Prostate Cancer: A Meta-analysis Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 176 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhu, M. R. Spitz, C. I. Amos, J. Lin, M. B. Schabath, and X. Wu An Evolutionary Perspective on Single-Nucleotide Polymorphism Screening in Molecular Cancer Epidemiology Cancer Res., March 15, 2004; 64(6): 2251 - 2257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Jeronimo, G. Varzim, R. Henrique, J. Oliveira, M. J. Bento, C. Silva, C. Lopes, and D. Sidransky I105V Polymorphism and Promoter Methylation of the GSTP1 Gene in Prostate Adenocarcinoma Cancer Epidemiol. Biomarkers Prev., May 1, 2002; 11(5): 445 - 450. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
