Genetic polymorphisms in GST genes and survival of colorectal cancer patients treated with chemotherapy.
Glutathione S-transferases (GSTs) participate in the detoxification of chemotherapeutic agents. Genetic polymorphisms in GST genes (GSTP1 Ile105Val, copy-number variants of GSTM1 and GSTT1) that lead to diminished enzyme activity have been associated with increased chemotherapeutic treatment benefit in colorectal cancer patients.


OBJECTIVE
We assessed the effect of genetic polymorphisms in GST genes on survival in colorectal cancer patients treated with adjuvant/palliative chemotherapy. As GSTs participate in the metabolism of platinum metabolites, we also assessed the association between genetic variants in GST genes and survival of colorectal cancer patients who received treatment with oxaliplatin.


METHODS
We followed 338 colorectal cancer patients treated with chemotherapy for a median of 36.4 months since treatment start. A total of 65 of the patients received treatment with oxaliplatin. Polymorphisms were genotyped by fluorescence-based melting curve analysis (GSTP1 Ile105Val), a relative quantification method (copy-number variants of GSTM1 and GSTT1), and PCR followed by gel electrophoresis (null/non-null genotypes for GSTM1 and GSTT1). Associations between genotypes and overall survival were assessed using Kaplan-Meier curves and Cox proportional hazards regression.


RESULTS
As hypothesized, GSTM1 copy number variant was inversely associated with survival in colorectal cancer patients treated with chemotherapy. Mortality was significantly reduced in patients with one GSTM1 copy (hazard ratio: 0.45, 95% CI: 0.23-0.90, p = 0.02) and nonsignificantly reduced in those with the null genotype (HR: 0.67, 95% CI: 0.35-1.27, p = 0.22) compared with carriers of two copies. Both GSTP1 genotype and GSTT1 genotype were not associated with survival.


CONCLUSIONS
This is the first study to provide suggestive evidence for an effect of copy-number variation of GSTM1 on survival in colorectal cancer patients who received chemotherapy. Large studies are warranted to establish the impact of GST genotypes on treatment outcome in colorectal cancer patients.
Funke
Silvia
S
German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Timofeeva
Maria
M
Risch
Angela
A
Hoffmeister
Michael
M
Stegmaier
Christa
C
Seiler
Christoph M
CM
Brenner
Hermann
H
Chang-Claude
Jenny
J
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016016:Proportional Hazards Models; D016019:Survival Analysis
D000970:Antineoplastic Agents; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C413545:glutathione S-transferase T1