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JNCI Journal of the National Cancer Institute 2002 94(12):936-942; doi:10.1093/jnci/94.12.936
© 2002 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 94, No. 12, 936-942, June 19, 2002
© 2002 Oxford University Press

ARTICLE

Association Between Glutathione S-Transferase P1, T1, and M1 Genetic Polymorphism and Survival of Patients With Metastatic Colorectal Cancer

Jan Stoehlmacher, David J. Park, Wu Zhang, Susan Groshen, Denice D. Tsao-Wei, Mimi C. Yu, Heinz-Josef Lenz

Affiliation of authors: J. Stoehlmacher, D. J. Park, W. Zhang, H.-J. Lenz (Department of Medical Oncology), S. Groshen, D. D. Tsao-Wei, M. C. Yu (Department of Preventive Medicine), University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA.

Corresponding author: Heinz-Josef Lenz, M.D., University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Ave., Suite 3456, Los Angeles, CA 90033 (e-mail: lenz{at}hsc.usc.edu).

Background: Members of the glutathione S-transferase (GST) superfamily are important in cellular defense mechanisms. These enzymes attach reduced glutathione to electrophilic groups in a wide variety of toxic compounds, including chemotherapeutic agents. Certain polymorphisms in GSTs are associated with changes in enzyme activity, sensitivity to chemotherapy, and overall patient survival. In a retrospective study, we investigated associations between common polymorphisms in genes for several GST subclasses (GSTP1, GSTT1, GSTM1) and survival of patients with metastatic colorectal cancer receiving 5-fluorouracil (5-FU)/oxaliplatin chemotherapy. Methods: During 1998–2000, 107 previously treated patients with advanced colorectal cancer received 5-FU/oxaliplatin combination chemotherapy. Associations between deletion polymorphisms in GSTM1 and GSTT1 genes and between a polymorphism in the GSTP1 gene that generates an Ile105Val in the GSTP1 protein and survival were evaluated using relative risks (RRs) of dying and the log-rank test. All statistical tests were two-sided. Results: Patients heterozygous for the GSTP1 polymorphism had an RR = 0.47 (95% confidence interval [CI] = 0.27 to 0.81) compared with patients homozygous for the GSTP1 105Ile allele. Patients homozygous for the mutant polymorphism had an RR = 0.16 (95% CI = 0.04 to 0.63). After adjustment for performance status and tumor site, the stratified RRs were 0.28 (95% CI = 0.07 to 1.10) for patients with two 105Val alleles and 0.64 (95% CI = 0.36 to 1.16) for those with one 105Val allele (P = .042). Patients with the 105Val/105Val genotype survived a median of 24.9 months, those with the 105Ile/105Ile genotype a median of 7.9 months, and those with the 105Ile/105Val genotype a median of 13.3 months (P<.001). The GSTM1 and GSTT1 genotypes were not associated with survival or clinical response. Conclusions: The GSTP1 Ile105Val polymorphism is associated in a dose-dependent fashion with increased survival of patients with advanced colorectal cancer receiving 5-FU/oxaliplatin chemotherapy.


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