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

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...

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Bibliographic Details
Published in:JNCI : Journal of the National Cancer Institute 2002-06, Vol.94 (12), p.936-942
Main Authors: Stoehlmacher, Jan, Park, David J., Zhang, Wu, Groshen, Susan, Tsao-Wei, Denice D., Yu, Mimi C., Lenz, Heinz-Josef
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Amino Acid Substitution
Antineoplastic agents
Antineoplastic Agents - therapeutic use
Base Sequence
Biological and medical sciences
California
Chemotherapy
Colorectal Neoplasms - enzymology
Colorectal Neoplasms - genetics
Colorectal Neoplasms - mortality
Colorectal Neoplasms - pathology
Continental Population Groups - genetics
DNA Primers
Ethnic Groups - genetics
Female
Follow-Up Studies
Glutathione S-Transferase pi
Glutathione Transferase - genetics
Humans
Isoenzymes - genetics
Male
Medical sciences
Middle Aged
Neoplasm Metastasis
Organoplatinum Compounds - therapeutic use
Oxaliplatin
Pharmacology. Drug treatments
Polymorphism, Restriction Fragment Length
Retrospective Studies
Survival Analysis
Time Factors
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Summary: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
ISSN:0027-8874
1460-2105
1460-2105
DOI:10.1093/jnci/94.12.936