Genetic variants in the glutathione S-transferase genes and survival in colorectal cancer patients after chemotherapy and differences according to treatment with oxaliplatin.
BACKGROUND
The glutathione S-transferase (GST) enzymes are involved in the detoxification of a range of carcinogenic compounds as well as chemotherapeutic agents. Therefore, genetic variants in the GST genes could influence survival in patients with colorectal cancer (CRC). Results from previous studies have been inconsistent and therefore we investigated the association between the GSTP1 ile105val polymorphism and the copy number variants of the GSTM1 and GSTT1 genes and survival in CRC patients treated with adjuvant/palliative chemotherapy.


METHODS
We included 755 CRC patients with stage II-IV disease from two population-based studies carried out in Germany. Genotyping of the GSTP1 polymorphism was carried out using fluorescence-based melting curve analysis and copy number variants were determined using a multiplex PCR. Survival analysis was carried out using the Cox regression model, adjusting for age, sex, UICC stage, cancer site, and radiation therapy.


RESULTS
Compared with noncarriers, CRC patients who were homozygote carriers of GSTM1 had significantly poorer survival after treatment with oxaliplatin [hazard ratio (HR) 2.25, 95% confidence interval (CI) 0.93-5.44] than those not treated with oxaliplatin (HR 0.64, 95% CI 0.30-1.34; P for heterogeneity=0.031). The association was significant in metastatic CRC patients treated with oxaliplatin (HR 3.59, 95% CI 1.29-10.03). Neither the GSTP1 105val allele nor the GSTT1 deletion was significantly associated with CRC survival.


CONCLUSIONS
Our data suggest that GSTM1 may be a predictive marker for oxaliplatin therapy; however, independent large studies are warranted to confirm these results.
aDivision of Cancer Epidemiology, German Cancer Research Center bDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center cDepartment of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University of Heidelberg dDivision of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany eCancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Elisabeth J
EJ
Kap
Swantje
S
Richter
Anja
A
Rudolph
Lina
L
Jansen
Alexis
A
Ulrich
Michael
M
Hoffmeister
Cornelia M
CM
Ulrich
Hermann
H
Brenner
Jenny
J
Chang-Claude
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D014644:Genetic Variation; D005838:Genotype; D005858:Germany; D005982:Glutathione Transferase / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D005982:Glutathione Transferase; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C413545:glutathione S-transferase T1