Novel Variants of and in the Interferon Gamma Signaling Pathway Are Associated with Non-Small Cell Lung Cancer Survival.

BACKGROUND

IFNγ is a pleiotropic cytokine that plays critical immunomodulatory roles in intercellular communication in innate and adaptive immune responses. Despite recognition of IFNγ signaling effects on host defense against viral infection and its utility in immunotherapy and tumor progression, the roles of genetic variants of the IFNγ signaling pathway genes in survival of patients with cancer remain unknown.

METHODS

We used a discovery genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial ( = 1,185) and a replication genotyping dataset from the Harvard Lung Cancer Susceptibility Study ( = 984) to evaluate associations between 14,553 genetic variants in 150 IFNγ pathway genes and survival of non-small cell lung cancer (NSCLC).

RESULTS

The combined analysis identified two independent potentially functional SNPs, rs7242481G>A and rs1049493T>C, to be significantly associated with NSCLC survival, with a combined HR of 0.85 (95% confidence interval, 0.78-0.92; < 0.0001) and 0.87 (0.81-0.93; < 0.0001), respectively. Expression quantitative trait loci analyses showed that the survival-associated rs7242481A allele was significantly associated with increased mRNA expression levels of elongator acetyltransferase complex subunit 2 () in 373 lymphoblastoid cell lines and 369 whole-blood samples. The rs1049493C allele was significantly associated with decreased mRNA expression levels of in 383 normal lung tissues and 369 whole-blood samples.

CONCLUSIONS

Genetic variants of IFNγ signaling genes are potential prognostic markers for NSCLC survival, likely through modulating the expression of key genes involved in host immune response.

IMPACT

Once validated, these variants could be useful predictors of NSCLC survival.