Genetic Polymorphisms in GST Genes and Survival of Colorectal Cancer Patients Treated with Chemotherapy

Abstract

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. Aims: 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. Materials & 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. Conclusion: 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.

KEYWORDS::

• chemotherapy
• colorectal cancer
• GSTM1 CNV
• GSTP1 Ile105Val
• GSTT1 CNV
• oxaliplatin
• pharmacogenetics

Financial & competing interests disclosure

Funding was provided by German Research Foundation (grant numbers: BR 1704/6–1, BR 1704/6–3, CH 117/1–1) and Baden-Württemberg State Ministry of Science, Research and Arts. Silvia Funke has a scholarship from the Deutsche Forschungsgemeinschaft, Graduiertenkolleg 793. Helmholtz-DAAD fellowship for Maria Timofeeva. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

Funding was provided by German Research Foundation (grant numbers: BR 1704/6–1, BR 1704/6–3, CH 117/1–1) and Baden-Württemberg State Ministry of Science, Research and Arts. Silvia Funke has a scholarship from the Deutsche Forschungsgemeinschaft, Graduiertenkolleg 793. Helmholtz-DAAD fellowship for Maria Timofeeva. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.