Role of TGF-β and Wnt antagonist gene sFRP4 in predicting overall survival and clinic-pathological outcomes in lung cancer patients treated with platinum based doublet chemotherapy

Abstract

Title: Role of TGF beta and Wnt antagonists gene sFRP4 in predicting overall survival and clinic-pathological outcomes in lung cancer patients treated with platinum based doublet chemotherapy. TGF-β1 gene is located at chromosome no. 19q13.1-13.39. TGF-β1 maintains balance between cell renewal and cell differentiation by inhibiting cell cycle progression through G1 arrest. Depending upon the tumor type and stage, TGF-β has been reported for tumor suppression as well as for tumor activation properties. sFRP4 is 346 amino acid long sequence, 10.99 Kb long and located on 7p14.1. They are extracellular glycoproteins which act as Wnt antagonists as they bind with Wnt proteins and block Wnt signaling pathways. Objectives: To investigate the role of TGF-β1 polymorphism in modulating the survival and clinical outcomes of lung cancer patients and to examine the role of sFRP4 polymorphisms in affecting the overall survival and prognosis of lung cancer patients. Materials and methods: A total of 186 and 340 cases were genotyped in case of TGF beta and sFRP4 respectively using PCR-RFLP. The overall survival was done using Kaplan-Meier and Cox regression analysis. Results: Subjects with CA and CA+AA genotype for sFRP4 rs1802073 and ECOG (0-1) showed significant association with overall survival when analyzed by using univariate analysis (HR=1.97; 95%CI=1.06-3.66; P=0.004 and HR=1.93; 95%CI=1.04-3.56; P=0.005), whereas analysis by Cox regression showed significant association in genotypes AA (HR=0.42; 95%CI=0.24-0.72; P=0.001), CA (HR=0.43; 95%CI=0.20-0.92; P=0.03) and CA+AA (HR=0.46; 95%CI=0.27-0.79; P=0.005). Subjects with ECOG (2-4) sFRP4 rs1802073 with Cox regression model showed significant for mutant AA genotype (HR=2.54; 95%CI=1.33-4.86; P=0.004). Conclusion: Our study demonstrated that TGF-β1 rs1800469 C/T polymorphism is not an important factor contributing to survival and clinical outcomes of lung cancer patients in north Indian population. On the other hand sFRP4 rs1802073 (Pro320Thr) is significantly contributing in increasing survival and clinical outcomes of lung cancer.