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

Cancer Biother Radiopharm. 2018 Dec;33(10):466-477. doi: 10.1089/cbr.2018.2491. Epub 2018 Oct 20.

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.

Keywords: Wnt antagonists; interaction; lung cancer; polymorphisms; prognosis; survival.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / epidemiology
  • Adenocarcinoma / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Axin Protein / genetics
  • Carboplatin / administration & dosage
  • Carcinoma, Small Cell / drug therapy
  • Carcinoma, Small Cell / epidemiology
  • Carcinoma, Small Cell / genetics
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / epidemiology
  • Carcinoma, Squamous Cell / genetics
  • Cisplatin / administration & dosage
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Docetaxel / administration & dosage
  • Epistasis, Genetic
  • Female
  • Gemcitabine
  • Genetic Variation*
  • Genotype
  • Humans
  • India / epidemiology
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Irinotecan / administration & dosage
  • Kaplan-Meier Estimate
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / epidemiology
  • Lung Neoplasms / genetics*
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Pemetrexed / administration & dosage
  • Polymerase Chain Reaction
  • Polymorphism, Restriction Fragment Length
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Proportional Hazards Models
  • Smoking / genetics
  • Wnt Proteins / antagonists & inhibitors

Substances

  • AXIN2 protein, human
  • Axin Protein
  • DKK2 protein, human
  • DKK4 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Wnt Proteins
  • Pemetrexed
  • Deoxycytidine
  • Docetaxel
  • Irinotecan
  • Carboplatin
  • Cisplatin
  • Gemcitabine