Genetic Variants in the Wingless Antagonist Genes (sFRP, DKK, and Axin2) Predict the Overall Survival and Prognosis of North Indian Lung Cancer Patients Treated with Platinum-Based Doublet Chemotherapy.

Abstract

Background: To investigate the prognostic implication of genetic variants within the wingless (Wnt) antagonist genes (DKK, sFRP, and Axin2) in North Indian lung cancer patients. Materials and Methods: A total of 212 subjects were genotyped using polymerase chain reaction-restriction fragment length polymorphism technique for 18 polymorphic sites in DKK4, DKK3, DKK2, sFRP3, sFRP4, and Axin2. Overall survival (OS) was estimated using the Kaplan-Meier survival analysis, and adjusted hazard ratio (HR) was obtained using the Cox regression method. Results: It was observed that the unfavorable genotypes of the three DKK2 variants collectively (rs447372, rs419558, and rs17037102) exhibited a highly decreased rate of death (adjusted HR = 0.37, p = 0.03). Adenocarcinoma (ADCC) patients carrying the heterozygous (CT) genotype for DKK4 rs2073664 showed a better OS compared with wild genotype (log rank p = 0.01). The two exonic variants (148 and 1386) of Axin2 gene showed contrasting results, where the ADCC subjects having TT genotype for Axin2 148 showed a better prognosis (adjusted HR = 0.48, p = 0.003) and those with TT genotype for Axin2 1386 showed a poor prognosis in small-cell lung carcinoma patients (adjusted HR = 2.33, p = 0.02). The intronic Axin2 1712 + 19 variant on the other hand indicated a highly increased death risk in ADCC patients with GG genotype. Survival tree analysis depicted DKK4 rs2073664 as the major contributor in predicting the survival of the lung cancer patients. Node 3 exhibited the lowest death rate (HR = 0.04, p = 0.008) and better median survival time (9 months vs. 3 months) when compared with reference node. Conclusions: A cumulative effect of three variants of DKK2 gene along with DKK4 rs2073664 can jointly predict the survival as shown by tree analysis.