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 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 Ile(105)Val 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 (105)Ile 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 (105)Val alleles and 0.64 (95% CI = 0.36 to 1.16) for those with one (105)Val allele (P =.042). Patients with the (105)Val/(105)Val genotype survived a median of 24.9 months, those with the (105)Ile/(105)Ile genotype a median of 7.9 months, and those with the (105)Ile/(105)Val 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 Ile(105)Val polymorphism is associated in a dose-dependent fashion with increased survival of patients with advanced colorectal cancer receiving 5-FU/oxaliplatin chemotherapy.
Stoehlmacher
Jan
J
Department of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90033, USA.
Park
David J
DJ
Zhang
Wu
W
Groshen
Susan
S
Tsao-Wei
Denice D
DD
Yu
Mimi C
MC
Lenz
Heinz-Josef
HJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001483:Base Sequence; D002140:California; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D017931:DNA Primers; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D012150:Polymorphism, Restriction Fragment Length; D044469:Racial Groups / Q000235:genetics; D012189:Retrospective Studies; D016019:Survival Analysis; D013997:Time Factors
D000970:Antineoplastic Agents; D017931:DNA Primers; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human