SNP rs9387478 at ROS1-DCBLD1 Locus is Significantly Associated with Lung Cancer Risk and Poor Survival in Indian Population

OBJECTIVE: Receptor tyrosine kinases (RTK) are relevant therapeutic targets in the treatment of lung cancer. Germline susceptibility variants that influence these RTKs may provide new insights into their regulation. rs9387478 is located in the genomic interval between two RTK-genes ROS1/DCBLD1, of which ROS1 alterations are implicated in lung carcinogenesis and treatment response while the latter remains poorly understood. MATERIALS AND METHODS: Venous blood was drawn from 100 control and 231 case subjects. Genotype was scored by restriction fragment length polymorphism (RFLP), PCR amplification followed by HindIII digestion. Logistic regression was applied to compare the association between variables. Survival curve was plotted to draw a correlation between the genotype and overall survival. Also, eQTL and chromatin state changes were analyzed and correlated with the survival of patients using available datasets. RESULTS: In our population smoking correlated significantly with lung cancer [OR= 2.607] with the presence of the minor allele ‘A’ enhancing the nicotine dependence [CA (OR=3.23)]. Individuals with homozygous risk allele ‘A’ had a higher chance of developing lung cancer [OR=2.65] than individuals with CA/CC implying a recessive model of association. Patients with CC/CA genotype had better overall survival than patients with AA genotype [161 days/142 days vs 54 days, p=0.005]. The homozygous risk allele was significantly associated with increased DCBLD1 and ROS1 expression in lung cancer, with enriched active histone marks due to the polymorphism. Interestingly, increased DCBLD1 expression was associated with poor outcomes in lung cancer. CONCLUSION: Overall, our study provides strong evidence that rs9387478 is significantly associated with both nicotine dependence and lung cancer in our North Indian cohort. The association of the SNP with prognostic genes, DCBLD1 and ROS1 make rs9387478 a promising prognostic marker in the North Indian population. The results obtained are significant, however, the study needs to be performed in a larger sample size.