Association of MDR1 Gene (C3435T) Polymorphism and Gene Expression Profiling in Lung Cancer Patients Treated with Platinum-based Chemotherapy

Introduction: 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.

Methods And Results: 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.

Conclusion: 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.