Single nucleotide polymorphisms in and of the lymphocyte activation-related pathway affect survival of lung cancer patients.

BACKGROUND

Lymphocyte activation is part of a complex microenvironment that affects the development and progression of solid tumors. The present study analyzed the associations between genetic variants in lymphocyte activation-related genes and survival of patients with non-small cell lung cancer (NSCLC).

METHODS

Our study evaluated the associations of 14,400 (1,599 genotyped and 12,801 imputed) single-nucleotide polymorphisms (SNPs) in 176 lymphocyte activation pathway-related genes with survival of 1,185 NSCLC patients in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the results in another independent dataset of 984 NSCLC patients from the Harvard Lung Cancer Susceptibility (HLCS) trial.

RESULTS

Multivariable Cox proportional hazards regression analyses identified two distinct and possibly functional variants in forkhead box P1 (; rs2568847 G>C) and RAR-related orphan receptor A (; rs922782 T>G) that were significantly and independently associated with overall survival (OS) [adjusted hazards ratios (HRs) of 1.21 and 0.82, respectively; 95% confidence intervals (CI), 1.11 to 1.32 and 0.76 to 0.88, respectively; P=5.38×10 and 2.68×10, respectively]. Combined analysis of the unfavorable genotypes showed a significant correlation with both OS and disease-specific survival (DSS) in patients with NSCLC patients from PLCO trial (both P<0.0001). Further expression quantitative trait loci (eQTL) analysis using mRNA expression and genotype data in the 1000 Genomes Project demonstrated that the rs922782 G allele predicted mRNA expression levels.

CONCLUSIONS

Genetic variants in and of the lymphocyte activation pathway may be promising predictors of NSCLC survival. The rs922782 G allele may predict NSCLC survival, possibly by controlling mRNA expression.