Novel genetic variants of and involved in immunoregulatory interactions are associated with non-small cell lung cancer survival.

Immunoregulatory interactions play a pivotal role in immune surveillance, recognition, and killing, particularly its internal pathway, likely playing an important role in immune escape. By using two genotyping datasets, one from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer screening trial (n = 1,185) as the discovery, and the other from Harvard Lung Cancer Susceptibility (HLCS) study (n = 984) as the validation, we evaluated associations between 4,713 genetic variants (338 genotyped and 4,375 imputed) in 60 genes involved in immunoregulatory interactions and survival of non-small cell lung cancer (NSCLC). We found that 115 SNPs were significantly associated with NSCLC overall survival in the discovery, of which four remained significant after validation by the HLCS dataset after multiple test correction by Bayesian false discovery probability. Final combined analysis identified two independent SNPs ( rs4487030 A>G and rs35385129 C>A) that predicted NSCLC survival with a combined hazards ratio of 0.84 (95% confidence interval = 0.76-0.93, = 0.001) and 0.84 (95% confidence interval = 0.73-0.97, = 0.021), respectively. Besides, expression quantitative trait loci analyses showed that these two survival-associated SNPs of and were significantly associated with their mRNA expression levels in both normal lung tissues and whole blood cells. Additional analyses suggested an oncogenic role for and a suppressor role for on the survival. Once further validated, genetic variants of and may be potential prognostic markers for NSCLC survival.