Novel Variants of ELP2 and PIAS1 in the Interferon Gamma Signaling Pathway Are Associated with Non-Small Cell Lung Cancer Survival.

Abstract

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 (n = 1,185) and a replication genotyping dataset from the Harvard Lung Cancer Susceptibility Study (n = 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, ELP2 rs7242481G>A and PIAS1 rs1049493T>C, to be significantly associated with NSCLC survival, with a combined HR of 0.85 (95% confidence interval, 0.78-0.92; P < 0.0001) and 0.87 (0.81-0.93; P < 0.0001), respectively. Expression quantitative trait loci analyses showed that the survival-associated ELP2 rs7242481A allele was significantly associated with increased mRNA expression levels of elongator acetyltransferase complex subunit 2 (ELP2) in 373 lymphoblastoid cell lines and 369 whole-blood samples. The PIAS1 rs1049493C allele was significantly associated with decreased mRNA expression levels of PIAS1 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.

• Authors: Yu Chen Zhao, Dongfang Tang, Sen Yang, Hongliang Liu, Sheng Luo, Thomas E Stinchcombe, Carolyn Glass, Li Su, Sipeng Shen, David C Christiani, Qingyi Wei
• Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (Cancer Epidemiol Biomarkers Prev) Vol. 29 Issue 8 Pg. 1679-1688 (08 2020) ISSN: 1538-7755 [Electronic] United States
• PMID: 32493705 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• ELP2 protein, human
• Intracellular Signaling Peptides and Proteins
• PIAS1 protein, human
• Protein Inhibitors of Activated STAT
• Small Ubiquitin-Related Modifier Proteins
• Interferon-gamma

Topics

• Carcinoma, Non-Small-Cell Lung (genetics, mortality, pathology)
• Female
• Humans
• Interferon-gamma (metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Lung Neoplasms (genetics, mortality, pathology)
• Male
• Protein Inhibitors of Activated STAT (metabolism)
• Signal Transduction
• Small Ubiquitin-Related Modifier Proteins (metabolism)
• Survival Analysis