Association of MDR1 gene (C3435T) polymorphism and gene expression profiling in lung cancer patients treated with platinum-based chemotherapy.

Abstract

Chemotherapy is the standard and recommended treatment for lung cancer apart from surgery and radiotherapy. Chemotherapy is administered as mono-agents or as combination therapy. In this study, we examined the role of MDR1 C3435T polymorphisms in lung cancer patients undergoing chemotherapy. We genotyped 126 cases with lung cancer and 111 healthy controls, using the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Frequencies of MDR1 C3435C, C3435T and T3435T genotypes were 61, 16 and 23% in lung cancer patients and 86, 9 and 5% in the controls, respectively. The T3435T genotypes had a 5.23-fold increased risk for lung cancer. (OR 5.23; 95% CI 2.082-13.146; p=0.0004). Patients with TT genotypes were more frequent in stage IV and were significantly associated with the disease (p=0.05). Habitual smoker lung cancer patients were 50% CC genotypes whereas TT genotypes were 34%. The non-smokers had 46% CC genotypes and 23% TT genotypes. Furthermore, we collected tissue biopsy samples for expression analysis from 20 patients (for controls we used the non-cancerous region of the same tissue). The present study showed mRNA expression of MDR1 was up-regulated in 80% of the cancer group in comparison with the control group (p=0.0002). We also correlated the association between MDR1 genotypes with different combinations of chemotherapy. The combinations and genotype distributions in the group receiving paclitaxel+cisplatin were as follows: CC (67%), CT (24%) and TT (9%) genotypes, respectively, and the group receiving carboplatin+gemcitabine CC (46%), CT (19%) and TT (35%) genotypes, respectively. We found that MDR1 (rs1045642) C3435T polymorphism and gene expression was significantly associated with the clinical outcome in lung carcinoma patients. In conclusion, it is suggested that MDR1 TT genotypes had higher risk for the development of lung cancer. Also, this polymorphism could be used as a genetic marker for predicting the clinical outcome of lung cancer patients.